Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2887—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
  • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

• the present invention relates to the treatment of subjects having relapsed and/or refractory (R/R) follicular lymphoma (FL). More specifically, the invention pertains to combination treatment of subjects having R/R FL, who may have received prior therapy with an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment, by administration of mosunetuzumab and lenalidomide.
• an anti-CD20 antibody e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab
• other treatment by administration of mosunetuzumab and lenalidomide.
• Cancers are characterized by the uncontrolled growth of cell subpopulations. Cancers are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over eight million cancer deaths occurring each year. Indolent cancers can also severely effect quality of life. Cancer care thus represents a significant and ever-increasing societal burden.
• B cell proliferative disorders are a leading cause of cancer-related deaths.
• NHL non-Hodgkin’s lymphoma
• NHL non-Hodgkin’s lymphoma
• Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL accounting for approximately 30%-40% of all NHL diagnosis, followed by follicular lymphoma (FL; 20%-25% of all NHL diagnosis) and mantle cell lymphoma (MCL; 6%-10% of all NHL diagnosis).
• B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, with approximately 15,000 new cases per year in the United States (American Cancer Society 2015).
• Lymphomas of B-cell origin constitute a diverse set of neoplasms within the larger context of non-Hodgkin lymphoma (NHL).
• Follicular lymphoma FL is the most common subtype of indolent NHL (Al-Hamandi et al. 2015).
• NHL non-Hodgkin lymphoma
• Follicular lymphoma FL is the most common subtype of indolent NHL (Al-Hamandi et al. 2015).
• mAbs monoclonal antibodies
• mAbs monoclonal antibodies
• FL remains an incurable disease with currently available therapies.
• rituximab to commonly used induction chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); fludarabine; or bendamustine (Zelenetz et al. 2014, Forstpointer et al. 2006), followed by rituximab maintenance therapy led to prolonged remission and improved patient outcomes.
• treatment with said therapies only result in partial, but not complete, responses in the majority of patients with relapsed or refractory (R/R) FL. As such, multiply relapsed FL remains a disease with a high, unmet medical need for which improved therapies are needed.
• the present invention relates to methods of treating a subject having a relapsed and/or refractory (R/R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy, in particular, the present invention relates to methods of treating a subject having a R/R FL that is R/R to at least one prior systemic therapy which included an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment.
• an anti-CD20 antibody e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen (e.g., R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or BR (bendamustine and rituximab)) (e.g., at least one chemoimmunotherapy that included an anti-CD20 monoclo
• the subject has received only one prior line of systemic therapy and either: (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al.. Blood. 2004; 104 (5): 1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) has been refractory to prior anti-CD20 monoclonal antibody treatment, or (c) has disease progression within 24 months after initiation of prior therapy.
• FLIPI Follicular Lymphoma International Prognostic Index
• the subject has not been treated with the anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more) prior to being administered the effective amount of mosunetuzumab and lenalidomide.
• mosunetuzumab and lenalidomide have a synergistic effect on the R/R FL.
• the synergistic effect is a partial response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the synergistic effect is a complete response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to
• the C1 D1 is between 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1 .0 mg to 4.0 mg, 1 .25 mg to 4.0 mg, 1 .5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1 .0 mg, 0.75 mg to 1 .25 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .
• the C1 D1 is between 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1 .0 mg to 3.0 mg, 1 .25 mg to 3.0 mg, 1 .5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1 .5 mg, 0.8 mg to 1 .0 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .75 mg, about 2.0 mg, about 2.25 mg, about
• the C1 D2 is between 1 .0 mg to 6.0 mg (e.g., 1 .5 mg to 6.0 mg, 2.0 mg to 6.0 mg, 2.5 mg to 6.0 mg, 3.0 mg to 6.0 mg, 3.5 mg to 6.0 mg, 4.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 1 .0 mg to 5.0 mg, 1 .0 mg to 4.5 mg, 1 .0 mg to 4.0 mg, 1 .0 mg to
• the C1 D3 is between 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg
• 3.0 mg to 45.0 mg e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg,
• the C2D1 is between 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 0.0
• the C1 D1 and C1 D2 are each less than the C1 D3. In some embodiments, the C1 D1 and C1 D2 are about equal. In some embodiments, the C1 D2 is greater than the C1 D1 by about 50% to about 250% (e.g., the C1 D2 is greater than the C1 D1 by about 50% to about 225%, the C1 D2 is greater than the C1 D1 by about 50% to about 200%, the C1 D2 is greater than the C1 D1 by about 50% to about 175%, the C1 D2 is greater than the C1 D1 by about 50% to about 150%, the C1 D2 is greater than the C1 D1 by about 50% to about 125%, the C1 D2 is greater than the C1 D1 by about 50% to about 100%, or the C1 D2 is greater than the C1 D1 by about 50% to about 75%; e.g., the C1 D2 is greater than the C1 D1 by about 50%, the C1 D2 is greater than the C1 D1 by about
• the C1 D1 is 0.8 mg, the C1 D2 is 2.0 mg, the C1 D3 is 4.2 mg, and the C2D1 is 4.2 mg;
• the C1 D1 is 1 .0 mg, the C1 D2 is 1 .0 mg, the C1 D3 is 3.0 mg, and the C2D1 is 30.0 mg; or
• the C1 D1 is 1 .0 mg, the C1 D2 is 2.0 mg, the C1 D3 is 30.0 mg, and the C2D1 is 30.0 mg.
• the length of the first dosing cycle is 21 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject the C1 D1 , the C1 D2, and the C1 D3 on or about Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle. In some embodiments, the length of the second dosing cycle is 28 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject the C2D1 on Day 1 of the second dosing cycle.
• the dosing regimen comprises one or more additional dosing cycles (e.g., one dosing cycle, two dosing cycles, three dosing cycles, four dosing cycles, five dosing cycles, six dosing cycles, seven dosing cycles, eight dosing cycles, nine dosing cycles, ten dosing cycles, or more).
• the dosing regimen comprises one to ten additional dosing cycles (e.g., one dosing cycle, two dosing cycles, three dosing cycles, four dosing cycles, five dosing cycles, six dosing cycles, seven dosing cycles, eight dosing cycles, nine dosing cycles, or ten dosing cycles).
• the dosing regimen comprises ten additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is 28 days ( ⁇ 1 day). In some embodiments, each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab. In some embodiments, the method comprises administering to the subject each additional dose of mosunetuzumab on Day 1 of each of the one or more additional dosing cycles.
• each additional dose of mosunetuzumab is between 0.2 mg to 50.0 mg(e.g., 0.3 mg to 50.0 mg, 0.4 mg to 50.0 mg, 0.5 mg to 50.0 mg, 1 .0 mg to 50.0 mg, 2.0 mg to 50.0 mg, 3.0 mg to 50.0 mg, 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1 .0 mg to 45.0 mg, 1 .0 mg to 40.0 mg, 1 .0 mg to 35.0 mg, 1 .0 mg to 30.0 mg, 1 .0 mg to 25.0 mg, 1 .0 mg to 20.0 mg, 1 .0 mg to 15.0 mg, 1 .0 mg to 10.0 mg, 1 .0 mg to 5.0 mg, 10.0 mg to 5.0 mg,
• administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising twelve dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1 .0 mg to 4.0 mg, 1 .25 mg to 4.0 mg, 1 .5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg,
• the C1 D2 is between 0.05 mg to 20.0 mg (e.g., 0.1 mg to 20.0 mg, 0.2 mg to 20.0 mg, 0.3 mg to 20.0 mg, 0.4 mg to 20.0 mg, 0.5 mg to 20.0 mg, 1 .0 mg to 20.0 mg, 1 .5 mg to 20.0 mg, 2.0 mg to 20.0 mg, 3.0 mg to 20.0 mg,
• the C1 D1 is between 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1 .0 mg to 4.0 mg, 1 .25 mg to 4.0 mg, 1 .5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1 .0 mg, 0.75 mg to 1 .25 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .
• the C1 D1 is between 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1 .0 mg to 3.0 mg, 1 .25 mg to 3.0 mg, 1 .5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1 .5 mg, 0.8 mg to 1 .0 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, or about 3.0 mg), the C1 D2 is between 1 .0 mg to 3.0 mg (e.g.
• the C1 D3 is between 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg
• 3.0 mg to 45.0 mg e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg,
• the C1 D1 and C1 D2 are each less than the C1 D3.
• the C1 D2 is greater than the C1 D1 by about 50% to about 250% (e.g., the C1 D2 is greater than the C1 D1 by about 50% to about 225%, the C1 D2 is greater than the C1 D1 by about 50% to about 200%, the C1 D2 is greater than the C1 D1 by about 50% to about 175%, the C1 D2 is greater than the C1 D1 by about 50% to about 150%, the C1 D2 is greater than the C1 D1 by about 50% to about 125%, the C1 D2 is greater than the C1 D1 by about 50% to about 100%, or the C1 D2 is greater than the C1 D1 by about 50% to about 75%; e.g., the C1 D2 is greater than the C1 D1 by about 50%, the C1 D2 is greater than the C1 D1 by about 100%, the C1 D2 is greater than the C1 D1 D1
• the C1 D1 is 0.8 mg, the C1 D2 is 2.0 mg, the C1 D3 is 4.2 mg, and each single dose C2D1 -C12D1 is 4.2 mg;
• the C1 D1 is 1 .0 mg, the C1 D2 is 1 .0 mg, the C1 D3 is 3.0 mg, and each single dose C2D1 -C12D1 is 30.0 mg; or
• the C1 D1 is 1 .0 mg, the C1 D2 is 2.0 mg, the C1 D3 is 30.0 mg, and each single dose C2D1 -C12D1 is 30.0 mg.
• the length of the first dosing cycle is 21 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject the C1 D1 , the C1 D2, and the C1 D3 on or about Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle. In some embodiments, the length of each of the second to twelfth dosing cycles is 28 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject each of the C2D1 -C12D1 on Day 1 of each respective dosing cycle. In some embodiments, the length of each of the second to twelfth dosing cycles is 28 days ( ⁇ 1 day).
• mosunetuzumab is administered intravenously.
• lenalidomide is administered during the second and subsequent cycles. In some embodiments, lenalidomide is not administered during the first cycle. In some embodiments, lenalidomide is administered daily. In some embodiments, lenalidomide is administered daily on the first 21 days of each dosing cycle comprising administration of lenalidomide. In some embodiments, lenalidomide is not administered on the last 7 days of each dosing cycle comprising administration of lenalidomide. In some embodiments, lenalidomide is administered at a dose of 20 mg. In some embodiments, lenalidomide is administered orally.
• the subject was previously treated with at least one anti-CD20 monoclonal antibody. In some embodiments, the subject is relapsed or refractory to the treatment comprising the anti-CD20 monoclonal antibody. In some embodiments, the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included obinutuzumab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzuma
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included obinutuzumab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intraven
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included rituximab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzuma
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included rituximab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intraven
• the subject has received only one prior line of systemic therapy and either: (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004; 104 (5): 1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) has been refractory to prior obinutuzumab treatment, (c) has been refractory to prior rituximab treatment, or (d) has disease progression within 24 months after initiation of prior therapy.
• FLIPI Follicular Lymphoma International Prognostic Index
• the subject has not been treated with obinutuzumab or rituximab for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more) prior to being administered the effective amount of mosunetuzumab and lenalidomide.
• 4 weeks e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more
• mosunetuzumab and lenalidomide have a synergistic effect on the R/R FL.
• the synergistic effect is a partial response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the synergistic effect is a complete response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the FL is histologically documented as Grade 1 , 2, or 3a, but not 3b according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016; 127:2375-90).
• the invention features a method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered
• the invention features a method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1
• each subject has received only one prior line of systemic therapy and either: (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004; 104 (5): 1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) has been refractory to prior anti-CD20 monoclonal antibody treatment, or (c) has disease progression within 24 months after initiation of prior therapy.
• FLIPI Follicular Lymphoma International Prognostic Index
• the FL of each subject is histologically documented as Grade 1 , 2, or 3a, but not 3b according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016; 127:2375-90).
• each subject has not been treated with the anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more) prior to being administered the effective amount of mosunetuzumab and lenalidomide.
• 4 weeks e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more
• mosunetuzumab and lenalidomide have a synergistic effect on the R/R FL.
• the synergistic effect is a partial response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the synergistic effect is a complete response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the incidence of an adverse event is not significantly higher than if mosunetuzumab was administered alone to the population of subjects.
• the incidence of an adverse event is not significantly higher than if lenalidomide is not administered to the population of subjects.
• the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome is less than 45% (e.g., less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., between about 0% to about 50%, between about 5% to about 40%, between about 5% to about 20%, between about 5% to about 10%, between about 20% to about 45%, between about 30% to about 40%, between about 20% to about 40%, between about 15% to about 35%, between about 15% to about 25%, between about 35% to about 45%, or between about 25% to about 45%; e.g., about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%
• the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading") is less than 35%. In some embodiments, the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading”) is less than 25%.
• the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading") is less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1 %; e.g., between 0% and 10%, between 0% and 9%, between 0% and 8%, between 0% and 7%, between 0% and 6%, between 0% and 5%, between 0% and 4%, between 0% and 3%, between 0% and 2%, between 0% and 1 %, between 1 % and 3%, between 1 % and 5%, between 1 % and 10%, between 3% and 5%, between 5% and 8%, between 5% and 10%, between 8% and 10%, .
• ASTCT CRS grading
• the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading”) is less than 5%. In some embodiments, the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading”) is less than 3%.
• the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading") is less than 1 %.
• the incidence rate of neutropenia is less than 40% (e.g., less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1 %; e.g., between about 0% to about 40%, between about 5% to about 40%, between about 5% to about 20%, between about 5% to about 10%, between about 20% to about 40%, between about 30% to about 40%, between about 15% to about 35%, between about 15% to about 25%, between about 35% to about 40%, or between about 25% to about 40%; e.g., about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 3%, about 1 %, or about 0%). In some embodiments, the incidence rate of neutropenia is less than 30%. In some embodiments, the incidence rate of neutropenia is less than 20%.
• the overall response rate is at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 80%-100%, between 85-100%, between 87- 100%, between 90-100%, between 95-100%, between 80%-90%, between 80-85%, between 85-97%, between 85-95%, between 85-90%, between 85-87%, between 90-95%, or between 93-97%; e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about
• the complete response rate is at least 65% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 65-100%, between 75-100%, between 85-100%, between 95-100%, between 65-90%, between 65-80%, between 65-70%, between 65-75%, or between 75-85%; e.g., about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 80%, about 85%, about 90%, or more). In some embodiments, the complete response rate is at least 75%. In some embodiments, the complete response rate is at least 85%.
• each subject was previously treated with at least one anti-CD20 monoclonal antibody.
• the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.
• the subject is human. In some embodiments, each subject in the population is human.
• the subject exhibits a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.
• the reduction in tumor burden is determined by computed tomography (CT).
• CT computed tomography
• the reduction in tumor burden is a decrease in the sum of the product of the diameters (SPD) of target lesions.
• the decrease in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 40-100%, between 40-80%, between 40-60%, between 50-70%, between 70-90%, between 75-85%, between 60-100%, between 55-65%, between 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%).
• the decrease in SPD is at least 60%. In some embodiments, the decrease in SPD is at least 80%.
• At least 45% e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 45-100%, between 45-80%, between 45-60%, between 50-70%, between 55-65%, between 70-90%, between 70-80%, between 60-100%, between 80-100%; e.g., about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.
• At least 60% of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 75% of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.
• the reduction in tumor burden is determined by computed tomography (CT). In some embodiments, the reduction in tumor burden is a decrease in the sum of the product of the diameters (SPD) of target lesions.
• the decrease in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 40-100%, between 40-80%, between 40-60%, between 50-70%, between 70-90%, between 75-85%, between 60-100%, between 55-65%, between 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%).
• the decrease in SPD is at least 60%. In some embodiments, the decrease in SPD is at least 80%.
• the dosing regimen further comprises administration of a corticosteroid.
• the corticosteroid is administered to the subject during the first dosing cycle.
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the corticosteroid.
• the C1 D1 , the C1 D2, and the C1 D3 of the corticosteroid are administered to the subject on Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subject before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• the corticosteroid is administered to the subject on the first dosing cycle and not on the second dosing cycle.
• the corticosteroid is administered to the subject on the second dosing cycle.
• the second dosing cycle comprises a single dose (C2D1 ) of the corticosteroid.
• the C2D1 of the corticosteroid is administered to the subject on Day 1 of the second dosing cycle.
• the C2D1 of the corticosteroid is administered to the subject before administration of the C2D1 of mosunetuzumab.
• the C2D1 of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C2D1 of mosunetuzumab.
• the dosing regimen further comprises administration of a corticosteroid.
• the corticosteroid is administered to the subjects during the first dosing cycle.
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the corticosteroid.
• the C1 D1 , the C1 D2, and the C1 D3 of the corticosteroid are administered to the subjects on Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subjects before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 - C1 D3 of the corticosteroid is administered to the subjects 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• the corticosteroid is administered to the subjects on the first dosing cycle and not on the second dosing cycle.
• the corticosteroid is administered to the subjects on the second dosing cycle.
• the second dosing cycle comprises a single dose (C2D1 ) of the corticosteroid.
• the C2D1 of the corticosteroid is administered to the subjects on Day 1 of the second dosing cycle.
• the C2D1 of the corticosteroid is administered to the subjects before administration of the C2D1 of mosunetuzumab.
• the C2D1 of the corticosteroid is administered to the subjects 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C2D1 of mosunetuzumab.
• each additional dosing cycle comprises administering to the subject an additional dose of the corticosteroid. In some embodiments, each additional dose of the corticosteroid is administered on Day 1 of each additional dosing cycle. In some embodiments, each additional dose of the corticosteroid is administered to the subject before administration of each additional dose of mosunetuzumab.
• each additional dose of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of each additional dose of mosunetuzumab.
• the corticosteroid is administered intravenously.
• the corticosteroid is dexamethasone.
• each dose of dexamethasone is about 10 mg (e.g., about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg).
• FIG. 1 A is a schematic of the study design described in Example 1 for the dosing regimen of the combination therapy of mosunetuzumab and lenalidomide.
• FIG. 1B is a schematic of the dosing regimen described in Example 1 .
• Lenalidomide begins at cycle 2 to minimize risk with mosunetuzumab initiation during Cycle 1 , when CRS risk is highest.
• FIG. 2 is a butterfly plot showing adverse events that occurred in > 10% of safety-evaluable patients described in Example 1 classified by MedDRA System Organ Class and MedDRA Preferred Term. Based on MedDRA version 23.1 . Grade of adverse events is shown in legend. Left side shows all adverse events. Right side shows adverse events attributable to treatment with mosunetuzumab (Mosun) or lenalidomide. Clinical cut-off date (CCOD) of April 5, 2021 .
• FIG. 3 is a butterfly plot showing adverse events that occurred in > 10% of safety-evaluable patients described in Example 1 classified by MedDRA System Organ Class and MedDRA Preferred Term. Based on MedDRA version 23.1 . Grade of adverse events is shown in legend. Left side shows all adverse events. Right side shows adverse events attributable to treatment with mosunetuzumab (Mosun). CCOD of April 5, 2021 .
• FIG. 4 is a butterfly plot showing adverse events that occurred in > 10% of safety-evaluable patients described in Example 1 classified by MedDRA System Organ Class and MedDRA Preferred Term. Based on MedDRA version 23.1 . Grade of adverse events is shown in legend. Left side shows all adverse events. Right side shows adverse events attributable to treatment with lenalidomide. CCOD of April 5, 2021 .
• FIG. 5 is a swimlane plot showing onset of cytokine release syndrome (CRS) events in 5 patients treated with the 1/2/30 mg dosing regimen of mosunetuzumab described in Example 1 . Onset of Grade 1 or Grade 2 CRS is indicated by the light or dark diamond, respectively. CCOD of April 5, 2021.
• CRS cytokine release syndrome
• FIG. 6 is a plot showing observed concentration-time data of mosunetuzumab (in combination with lenalidomide) from Study CO41942 overlaid with popPK model simulations based on mosunetuzumab monotherapy data from Study GO29781 ; Simulations were performed at 1/2/30 mg Q4W. Filled red circles and lines represent the individual and mean observed mosunetuzumab concentration measurements from Study CO41942 at 1 /2/30 mg IV dose in combination with lenalidomide. Shaded area represents simulated concentration-time profile for mosunetuzumab monotherapy based on the preliminary population PK model simulations (5 ,h -95 ,h prediction interval) which was developed based on clinical data from Study GO29781 .
• FIG. 7 is a butterfly plot showing adverse events that occurred in > 10% of safety-evaluable patients described in Example 3 classified by MedDRA System Organ Class and MedDRA Preferred Term. Based on MedDRA version 23.1 . Grade of adverse events is shown in legend. Left side shows all adverse events. Right side shows adverse events attributable to treatment with mosunetuzumab (Mosun) or lenalidomide. CCOD of September 13, 2021 .
• FIG. 8 is a bar graph showing cytokine release syndrome (CRS) events by dosing cycle (C) and day (D) and by CRS Grade (Gr). Values below the graph show the dose of mosunetuzumab associated with each dosing cycle (C) and day (D).
• the C1 D1 dose is administered on Cycle 1 Day 1
• the C1 D2 dose is administered on Cycle 1 Day 8
• the C1 D3 dose is administered on Cycle 1 Day 15.
• Subsequent doses are administered on Day 1 of each respective dosing cycle (C2, C3+).
• FIG. 9 is a bar graph showing neutropenia and febrile neutropenia events by dosing cycle (C) and by neutropenia Grade (Gr). The number of patients who received granulocyte colonystimulating factor (G-CSF) per dosing cycle (C) is shown below the graph.
• G-CSF granulocyte colonystimulating factor
• FIG. 10 is a bar graph showing anti-tumor activity in patients with > 1 diagnostic computed tomography (CT) scan at response assessment. The number above each bar shows % change from baseline. Changes in tumor burden are quantified by comparing the sum of the product of the diameters (SPD) of target lesions to baseline measurements.
• CT computed tomography
• FIG. 11 is a bar graph showing the overall response rate (ORR), complete response rate (CR), and partial response rate (PR) in the 29 patients treated with the 1/2/30 mg dosing regimen of mosunetuzumab and 20 mg oral lenalidomide described in Example 3. Response rates are shown for 29 patients as of data cut-off date of September 13, 2021 . 95% confidence interval (Cl) for each response rate value is shown in parentheses below. Response rates are determined by positron emission tomography-computed tomography (PET-CT).
• PET-CT positron emission tomography-computed tomography
• FIG. 12 is a swimlane plot showing duration of response in all 29 patients treated with the 1/2/30 mg dosing regimen of mosunetuzumab and 20 mg oral lenalidomide described in Example 3. Duration of response are shown for 29 patients as of data cut-off date of September 13, 2021 .
• the present invention relates to methods of treating a subject having a relapsed and/or refractory (R/R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy.
• the present invention relates to methods of treating a subject having a R/R FL that is R/R to at least one prior systemic therapy (e.g., one prior treatment with a chemo-immunotherapy regimen) which included an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment.
• the method comprises administering the effective amount of mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg, the C1 D2 is between 0.05 mg to 20.0 mg and the C1 D3 is between 0.2 mg to 50.0 mg; and (b) the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab, wherein the C2D1 is equal to or greater than the C1 D3 and is between 0.2 mg to 50 mg.
• a dosing cycle comprises a first dose (C1 D1 ), a second dose
• the invention is based, in part, on the discovery that combination therapy involving intravenous administration of mosunetuzumab and oral administration of lenalidomide over multiple dosing cycles (e.g., wherein the first dosing cycle is a step-up, fractionated dosing cycle) exhibits synergistic effects between mosunetuzumab and lenalidomide and can effectively treat subjects having relapsed/refractory (R/R) follicular lymphoma (FL), in particular those who are R/R to prior systemic therapy including an anti- CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab; e.g., R-CHOP) while maintaining an acceptable safety profile (e.g., with respect to frequency and severity of adverse events).
• R/R refractory follicular lymphoma
• FL relapsed/refractory follicular lymphoma
• cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
• examples of cancer include, but are not limited to, hematologic cancers, such as mature B cell cancers, excluding Hodgkin’s lymphoma, but including non-Hodgkin’s lymphoma (NHL), such as diffuse large B cell lymphoma (DLBCL), which may be relapsed or refractory DLBCL or a Richter’s transformation.
• hematologic cancers such as mature B cell cancers, excluding Hodgkin’s lymphoma, but including non-Hodgkin’s lymphoma (NHL), such as diffuse large B cell lymphoma (DLBCL), which may be relapsed or refractory DLBCL or a Richter’s transformation.
• NHL non-Hodgkin’s lymphoma
• DLBCL diffuse large B cell lymphoma
• cancer also include germinal-center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, mantle cell lymphoma (MCL), acute myeloid leukemia
• GCB germinal-center B cell-like
• DLBCL diffuse large B cell lymphoma
• ABSC activated B cell-like
• FL follicular lymphoma
• FL follicular lymphoma
• MCL mantle cell lymphoma
• acute myeloid leukemia acute myeloid leukemia
• AML acute lymphoid leukemia
• CLL chronic lymphoid leukemia
• MZL marginal zone lymphoma
• high grade B-cell lymphoma high grade B-cell lymphoma
• PMLBCL primary mediastinal (thymic) large B cell lymphoma
• SLL small lymphocytic leukemia
• LL lymphoplasmacytic lymphoma
• WM central nervous system lymphoma
• BL Burkitt’s lymphoma
• B cell prolymphocytic leukemia splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, heavy chain diseases, a heavy chain disease, y heavy chain disease, p heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell/histiocyte rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL, leg
• cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies, including B cell lymphomas. More particular examples of such cancers include, but are not limited to, multiple myeloma (MM); low- grade/follicular NHL; small lymphocytic (SL) NHL; intermediate-grade/follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small noncleaved cell NHL; bulky disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD).
• MM multiple myeloma
• SL small lymphocytic
• NHL intermediate-grade/follicular NHL
• intermediate-grade diffuse NHL high-grade immunoblastic NHL
• high-grade lymphoblastic NHL high-grade small noncleaved
• Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
• cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
• cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells
• a “disorder” is any condition that would benefit from treatment including, but not limited to, chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question.
• cell proliferative disorder and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation.
• the cell proliferative disorder is cancer.
• the cell proliferative disorder is a tumor.
• B cell proliferative disorder or “B cell malignancy” refer to disorders that are associated with some degree of abnormal B cell proliferation and include, for example, lymphomas, leukemias, myelomas, and myelodysplastic syndromes.
• the B cell proliferative disorder is a lymphoma, such as non-Hodgkin’s lymphoma (NHL), including, for example, follicular lymphoma (FL) (e.g., a relapsed and/or refractory FL or transformed FL), diffuse large B cell lymphoma (DLBCL) (e.g., a relapsed or refractory DLBCL or a Richter’s transformation), MCL, high grade B-cell lymphoma, or PMLBCL).
• NHL non-Hodgkin’s lymphoma
• FL follicular lymphoma
• DLBCL diffuse large B cell lymphoma
• MCL high grade B-cell lymphoma
• PMLBCL high grade B-cell lymphoma
• the B cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL).
• CLL chronic lymphocytic leukemia
• FLIPI Fibricular Lymphoma International Prognostic Index
• a scoring system or index for determining prognostic risk of patients e.g., with cancer; e.g., an NHL; e.g., a follicular lymphoma (FL)
• FLIPI score ranges from 0-5, depending on how many of the five conditions or risk factors a patient may have among the following: (i) age > 60 years; (ii) Ann Arbor stage lll-IV; hemoglobin level ⁇ 120 g/L; serum lactate dehydrogenase (LDH) level > upper limit of normal (ULN) (e.g., > 280 units/L); and (v) number of nodal sites > 4. See e.g., Solal-Celigny et al. Blood. 2004; 104 (5): 1258-1265. at Table 4.
• annular staging refers to a system for classification of stages of lymphoma (e.g., non-Hodgkin’s lymphoma (NHL); e.g., a DLBCL, an FL, an MCL, a high-grade B cell lymphoma, a PMLBCL, or a CLL).
• Lymphomas e.g., NHLs
• Stage I refers to lymphomas exhibiting involvement of a single lymph node region or of a single extralymphatic organ or site.
• Stage II refers to lymphomas exhibiting involvement of 2 or more lymph node regions on the same side of the diaphragm.
• Stage III refers to lymphomas exhibiting involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organ or site or by involvement of the spleen, or both.
• Stage IV refers to lymphomas exhibiting diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues with or without associated lymph node enlargement. Liver involvement is always considered to be diffuse, and, thus, always considered Ann Arbor stage IV. Lymphatic structures include the lymph nodes, thymus, spleen, appendix, Waldeyer’s ring, and Peyer’s patches. See Carbone, P.P. et al., Cancer Res. 1971 , 31 (11 ):1860-1861 .
• Refractory disease is defined as no complete remission to at least a first-line therapy. In one embodiment, refractory disease defined as no response to or relapse within 6 months of prior therapy. In one embodiment, refractory disease is characterized by one or more of the following: progressive disease (PD) as best response to first-line therapy, stable disease (SD) as best response after at least one first line therapy (e.g., at least one containing an anti CD20-directed therapy, e.g., including an anti-CD20 antibody, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab), or partial response (PR) as best response, and biopsy-proven residual disease or disease progression after the partial response.
• progressive disease as best response to first-line therapy
• SD stable disease
• PR partial response
• Relapsed disease is defined as complete remission to first-line therapy.
• disease relapse is proven by biopsy.
• patients have relapsed after or failed to respond to at least one prior systemic treatment regimen (e.g., at least one containing an anti CD20- directed therapy, e.g., including an anti-CD20 antibody, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab).
• at least one prior systemic treatment regimen e.g., at least one containing an anti CD20- directed therapy, e.g., including an anti-CD20 antibody, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab.
• treatment refers to clinical intervention in an attempt to alter the natural course of the subject being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
• antibodies of the invention are used to delay development of a disease or to slow the progression of a disease.
• “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., a relapsed and/or refractory FL).
• This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
• a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
• a latestage cancer such as development of metastasis, may be delayed.
• reduce or “inhibit” is meant the ability to cause an overall decrease, for example, of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater.
• reduce or “inhibit” is meant the ability to cause an overall decrease, for example, of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater.
• the term includes also reduction to zero (or below the detection limit of the analytical method), i.e., complete abolishment or elimination.
• reduce or inhibit can refer to the reduction or inhibition of undesirable events, such as cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion- related reactions (IRRs), macrophage activation syndrome (MAS), neurologic toxicities, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and/or central nervous system (CNS) toxicities, following treatment with mosunetuzumab using the step-up dosing regimen of the invention relative to unchanging, preset dosing with the target dose of mosunetuzumab.
• undesirable events such as cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion- related reactions (IRRs), macrophage activation syndrome (MAS), neurologic toxicities, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and/or central nervous system (CNS) toxicities
• CRS central nervous system
• reduce or inhibit can refer to effector function of an antibody that is mediated by the antibody Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).
• CDC complement-dependent cytotoxicity
• ADCC antibody-dependent cellular cytotoxicity
• ADCP antibody-dependent cellular phagocytosis
• reduce or inhibit can refer to the symptoms of the R/R FL being treated, the presence or size of metastases, or the size of the primary tumor.
• reducing or inhibiting cancer relapse means to reduce or inhibit tumor or cancer relapse, or tumor or cancer progression.
• administering is meant a method of giving a dosage of a compound (e.g., a bispecific antibody, e.g., an anti-CD20/anti-CD3 bispecific antibody, e.g., mosunetuzumab) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including a bispecific antibody (e.g., mosunetuzumab)) to a subject.
• a compound e.g., a bispecific antibody, e.g., an anti-CD20/anti-CD3 bispecific antibody, e.g., mosunetuzumab
• a composition e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including a bispecific antibody (e.g., mosunetuzumab)
• the compounds and/or compositions utilized in the methods described herein can be administered intravenously (e.g., by intravenous infusion).
• a “fixed” or “flat” dose of a therapeutic agent herein refers to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
• the fixed or flat dose is therefore not provided as a mg/kg dose or a mg/m 2 dose, but rather as an absolute amount of the therapeutic agent (e.g., mg).
• a “subject” or an “individual” is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), domesticated animals (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human.
• primates e.g., humans and non-human primates such as monkeys
• domesticated animals e.g., cows, sheep, cats, dogs, and horses
• rabbits e.g., mice and rats
• rodents e.g., mice and rats
• “Individual response” or “response” can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1 ) inhibition, to some extent, of disease progression (e.g., progression of a R/R FL, including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e., reduction, slowing down or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the R/R FL; (6) increase or extend in the length of survival, including overall survival and progression-free survival; and/or (9) decreased mortality at a given point of time following treatment.
• (1 ) inhibition, to some extent, of disease progression e.g., progression of a R/R FL, including slowing down and complete arrest
• inhibition i.e., reduction, slowing down or complete
• partial response refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, or at least a 50% decrease in the sum of the product of the diameters (SPD) of target lesions, taking as reference the baseline SPD.
• ORR objective response rate
• tumor burden refers to the total amount of tumor (e.g., tumor cells or tumor mass) in a subject (e.g., a human subject) having a cancer, e.g., an NHL, e.g., an FL.
• tumor burden is defined as the sum of diameters of target lesions or the sum of the product of target lesions.
• tumor burden is defined as the sum of the product of the diameters of (SPD) target lesions.
• the diameters of target lesions is quantified by computed tomography (CT).
• sustained response refers to the sustained effect on reducing tumor growth after cessation of a treatment.
• the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase.
• the sustained response has a duration at least the same as the treatment duration, at least 1 .5x, 2. Ox, 2.5x, or 3. Ox length of the treatment duration.
• an “effective response” of a subject or a subject’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a subject as risk for, or suffering from, a disease or disorder, such as cancer.
• a disease or disorder such as cancer.
• such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
• a subject who “does not have an effective response” to treatment refers to a subject who does not have any one of extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
• survival refers to the patient remaining alive, and includes overall survival as well as progression-free survival.
• overall survival refers to the percentage of subjects in a group who are alive after a particular duration of time, e.g., 1 year or 5 years from the time of diagnosis or treatment.
• progression-free survival refers to the length of time during and after treatment during which the disease being treated (e.g., a R/R FL) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
• stable disease or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.
• PD progressive disease
• “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., a relapsed and/or refractory (R/R) follicular lymphoma (FL)).
• This delay can be of varying lengths of time, depending on the history of the disease and/or subject being treated.
• a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease. For example, in a late-stage cancer, development of central nervous system (CNS) metastasis, may be delayed.
• CNS central nervous system
• extending survival is meant increasing overall or progression free survival in a treated patient relative to an untreated patient (e.g., relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent.
• An objective response refers to a measurable response, including complete response (CR) or partial response (PR).
• antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
• antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
• antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.
• full-length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
• binding domain is meant a part of a compound or a molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include but are not limited to antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab’2, scFv antibodies, SMIP, domain antibodies, diabodies, minibodies, scFv- Fc, affibodies, nanobodies, and VH and/or VL domains of antibodies), receptors, ligands, aptamers, and other molecules having an identified binding partner.
• antibodies e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies
• antibody fragments or portions thereof e.g., Fab fragments, Fab’2, scFv antibodies, SMIP, domain antibodies, diabodies, mini
• Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
• the term includes native sequence Fc regions and variant Fc regions.
• a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
• the C-terminal lysine (Lys447) of the Fc region may or may not be present.
• numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
• the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain.
• the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 6, £, y, and p, respectively.
• IgG “isotype” or “subclass” as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.
• “Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues.
• the FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1 - H1 (L1 )-FR2-H2(L2)-FR3-H3(L3)-FR4.
• a “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.
• the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
• the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91 -3242, Bethesda MD (1991 ), vols. 1 -3.
• the subgroup is subgroup kappa I as in Kabat et al., supra.
• the subgroup is subgroup III as in Kabat et al., supra.
• acceptor human framework for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below.
• An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.
• the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
• a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from nonhuman HVRs and amino acid residues from human FRs.
• a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
• a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
• a “humanized form” of an antibody, e.g., a non-human antibody refers to an antibody that has undergone humanization.
• a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
• Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991 ); Marks et al., J. Mol. Biol., 222:581 (1991 ).
• Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos.
• variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody (i.e., mosunetuzumab) to antigen.
• the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs).
• FRs conserved framework regions
• HVRs hypervariable regions
• antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991 ).
• hypervariable region refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”) and/or form structurally defined loops (“hypervariable loops”) and/or contain the antigencontacting residues (“antigen contacts”).
• CDRs complementarity determining regions
• hypervariable loops form structurally defined loops
• antigen contacts antigen contacts
• antibodies comprise six HVRs: three in the VH (H1 , H2, H3), and three in the VL (L1 , L2, L3).
• Exemplary HVRs herein include:
• HVR residues and other residues in the variable domain are numbered herein according to Kabat et al., supra.
• an “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
• an “isolated antibody” when used to describe the various antibodies disclosed herein, means an antibody that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
• an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS- PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC).
• the antibody i.e., mosunetuzumab
• the antibody will be purified (1 ) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
• Isolated antibody includes antibodies in situ within recombinant cells, because at least one component of the polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.
• the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e ., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
• polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
• each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
• the modifier “monoclonal” indicates the character of the antibody (i.e., mosunetuzumab) as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
• the monoclonal antibodies (i.e., mosunetuzumab) to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
• Binding affinity refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
• binding affinity refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen).
• the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.
• an “affinity matured” antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.
• HVRs hypervariable regions
• anti-CD3 antibody and “an antibody that binds to CD3” refer to an antibody that is capable of binding CD3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD3.
• the extent of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3 as measured, e.g., by a radioimmunoassay (RIA).
• RIA radioimmunoassay
• an antibody that binds to CD3 has a dissociation constant (KD) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
• KD dissociation constant
• an anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.
• cluster of differentiation 3 refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3e, CD3y, CD3a, and CD3p chains.
• the term encompasses “full-length,” unprocessed CD3 (e.g., unprocessed or unmodified CD3e or CD3y), as well as any form of CD3 that results from processing in the cell.
• the term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants.
• CD3 includes, for example, human CD3e protein (NCBI RefSeq No. NP_000724), which is 207 amino acids in length, and human CD3y protein (NCBI RefSeq No. NP_000064), which is 182 amino acids in length.
• NCBI RefSeq No. NP_000724 human CD3e protein
• NCBI RefSeq No. NP_000064 human CD3y protein
• anti-CD20 antibody and “an antibody that binds to CD20” refer to an antibody that is capable of binding CD20 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD20.
• the extent of binding of an anti-CD20 antibody to an unrelated, non-CD20 protein is less than about 10% of the binding of the antibody to CD20 as measured, e.g., by a radioimmunoassay (RIA).
• RIA radioimmunoassay
• an antibody that binds to CD20 has a dissociation constant (KD) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
• KD dissociation constant
• an anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.
• the anti-CD20 antibody is a monoclonal antibody.
• the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab.
• the anti-CD20 antibody or anti-CD20 monoclonal antibody is obinutuzumab.
• rituximab or “RITUXAN®” refers to an anti-CD20 antibody (e.g., anti- CD20 monoclonal antibody) having the Proposed International Nonproprietary Names for Pharmaceutical Substances (Proposed INN) List 77 (WHO Drug Information, Vol. 11 , No. 2, 1997, p. 99), or the CAS Registry Number 174722-31 -7.
• the term “obinutuzumab” or “GAZYVA®” refers to an anti-CD20 antibody (e.g., anti-CD20 monoclonal antibody) having the Proposed International Nonproprietary Names for Pharmaceutical Substances (Proposed INN) List 99 (WHO Drug Information, Vol. 22, No. 2, 2008, p. 396), Proposed International Nonproprietary Names for Pharmaceutical Substances (Proposed INN) List 108 (WHO Drug Information, Vol. 26, No. 4, 2012, p. 453), or the CAS Registry Number 949142-50-1 .
• cluster of differentiation 20 refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
• the term encompasses “full-length,” unprocessed CD20, as well as any form of CD20 that results from processing in the cell.
• the term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allelic variants.
• CD20 includes, for example, human CD20 protein (see, e.g., NCBI RefSeq Nos.
• NP_068769.2 and NP_690605.1 which is 297 amino acids in length and may be generated, for example, from variant mRNA transcripts that lack a portion of the 5’ UTR (see, e.g., NCBI RefSeq No. NM_021950.3) or longer variant mRNA transcripts (see, e.g., NCBI RefSeq No. NM_152866.2).
• anti-CD20/anti-CD3 bispecific antibody refers to a multispecific antibody (e.g., a bispecific antibody) that is capable of binding to CD20 and CD3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD20 and/or CD3.
• a bispecific antibody that binds to CD20 and CD3 to an unrelated, non-CD3 protein and/or non-CD20 protein is less than about 10% of the binding of the antibody to CD3 and/or CD20 as measured, e.g., by a radioimmunoassay (RIA).
• RIA radioimmunoassay
• a bispecific antibody that binds to CD20 and CD3 has a dissociation constant (KD) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
• KD dissociation constant
• a bispecific antibody that binds to CD20 and CD3 binds to an epitope of CD3 that is conserved among CD3 from different species and/or an epitope of CD20 that is conserved among CD20 from different species. In one embodiment, the bispecific antibody binds monovalently to CD20 and binds monovalently to CD3. In some embodiments, a bispecific antibody that binds to CD20 and CD3 is mosunetuzumab.
• mosunetuzumab refers to an anti-CD20/anti-CD3 bispecific antibody having the International Nonproprietary Names for Pharmaceutical Substances (INN) List 1 17 (WHO Drug Information, Vol. 31 , No. 2, 2017, p. 303), or the CAS Registry Number 1905409-39-3.
• the term “lenalidomide” refers to a compound having the CAS Registry Number 191732-72-6 and ILJPAC name (3RS)-3-(4-Amino-1 -oxo-1 ,3-dihydro-2H-isoindol-2-yl)piperidine-2, 6-dione.
• Lenalidomide is also known by tradenames including REVLIMID®, linamid, and lenalid.
• Lenalidomide has the DrugBank Accession Number DB00480, PubChem CID 216326, and chemical formula C13H13N3O3.
• the term “binds,” “specifically binds to,” or is “specific for” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.
• an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets.
• the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, for example, by a radioimmunoassay (RIA).
• an antibody that specifically binds to a target has a dissociation constant (KD) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, or ⁇ 0.1 nM.
• KD dissociation constant
• an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species.
• specific binding can include, but does not require exclusive binding.
• the term as used herein can be exhibited, for example, by a molecule having a KD for the target of 10 -4 M or lower, alternatively 10 -5 M or lower, alternatively 10 -6 M or lower, alternatively 10 -7 M or lower, alternatively 10 -8 M or lower, alternatively 10 -9 M or lower, alternatively 10 -10 M or lower, alternatively 10 -11 M or lower, alternatively 10 -12 M or lower or a KD in the range of 10 -4 M to 10 -6 M or 10 -6 M to 10 -10 M or 10 -7 M to 10 -9 M.
• affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value.
• the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
• Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN® (DNASTAR®) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
• % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
• the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
• the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code.
• the ALIGN- 2 program should be compiled for use on a UNIX® operating system, including digital UNIX® V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
• % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
• pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
• a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
• a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
• chemotherapeutic agent refers to a compound useful in the treatment of a cancer, such as a R/R FL.
• chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech/OSI Pharm.); PD 183805 (Cl 1033, 2- propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amin
• Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (
• chemo-immunotherapy refers to combination therapy that includes both chemotherapy drugs and immunotherapeutic agents.
• chemo-immunotherapy is used to treat a cancer, e.g., a CD20-positive cancer, e.g., a NHL, e.g., a FL.
• immunotherapeutic agents include an antibody, e.g., an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody).
• the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab or obinutuzumab.
• chemo-immunotherapy includes R-CHOP.
• R-CHOP refers to a treatment comprising rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
• R-CHOP is a chemotherapy treatment or regimen used in the treatment of a cancer, optionally a B cell proliferative disorder (e.g., a non-Hodgkin’s lymphoma; e.g., a DLBCL or a high grade B-cell lymphoma).
• a B cell proliferative disorder e.g., a non-Hodgkin’s lymphoma; e.g., a DLBCL or a high grade B-cell lymphoma.
• R-CHOP is the standard of care (SOC) or standard therapy to be administered to a subject to treat the cancer, optionally the B cell proliferative disorder (e.g., the non-Hodgkin’s lymphoma; e.g., the DLBCL or the high grade B-cell lymphoma).
• R-CHOP is the standard front-line or first-line therapy to be administered to a previously untreated subject.
• R-CHOP is administered every 3 weeks (in 21 -day dosing cycles) for 3 to 6 dosing cycles.
• the dosing regimen for R- CHOP therapy comprises 21 -day dosing cycles, wherein during each dosing cycle, the subject is administered 375 mg/m 2 rituximab IV, and also administered cyclophosphamide, doxorubicin, vincristine, and prednisone.
• the dosing regimen for R-CHOP therapy further comprises 750 mg/m 2 cyclophosphamide IV, 50 mg/m 2 doxorubicin IV, 1 .4 mg/m 2 vincristine IV, and 5 days of 100 mg or 40 mg/m 2 per day prednisone oral.
• a maximum single dose of vincristine is 2 mg.
• Cytotoxic agent refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits proliferation, or otherwise hinders a cellular function).
• Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., 211 At, 131 l, 125 l, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212 Pb, and radioactive isotopes of Lu); chemotherapeutic agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
• radioactive isotopes e.g., 211 At, 131 l, 125 l, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212 Pb, and radioactive isotopes of Lu
• Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.
• the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin).
• the cytotoxic agent is an antagonist of EGFR, e.g., N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib).
• the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor.
• the RAF inhibitor is vemurafenib.
• the cytotoxic agent is a PI3K inhibitor.
• package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
• synergistic effect is used to refer to an effect resulting from the combination use of two or more therapeutic products (e.g., mosunetuzumab and lenalidomide), which is greater than the sum of the effects observed when the two or more therapeutic products are used individually.
• synergistic effect is observed in the response rate (e.g., complete response rate or overall response rate) of a population of subjects having relapsed and/or refractory (R/R) non-Hodgkin’s Lymphoma (NHL; e.g., R/R follicular lymphoma (FL)) treated with a combination therapy comprising mosunetuzumab and lenalidomide.
• a population of subjects having R/R FL exhibits a higher complete response rate when treated with combination therapy comprising mosunetuzumab and lenalidomide compared to a population of subjects treated with monotherapy mosunetuzumab or lenalidomide. In some embodiments, a population of subjects having R/R FL exhibits a higher overall response rate when treated with combination therapy comprising mosunetuzumab and lenalidomide compared to a population of subjects treated with monotherapy mosunetuzumab or lenalidomide.
• the present invention relates to methods of treating a subject having a relapsed and/or refractory (R/R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy.
• the present invention relates to methods of treating a subject having a R/R FL that is R/R to at least one prior systemic therapy (e.g., one prior treatment with a chemo-immunotherapy regimen) which included an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody; e.g., rituximab or obinutuzumab) or other treatment.
• an anti-CD20 antibody e.g., an anti-CD20 monoclonal antibody; e.g., rituximab or obinutuzumab
• the FL is a Graded FL (e.g., Grade 1 , 2, or 3a, but not Grade 3b FL).
• the FL of each subject is histologically documented as Grade 1 , 2, or 3a, but not 3b according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016; 127:2375-90).
• the subject has received only one prior line of systemic therapy and either: (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al.. Blood.
• FLIPI Follicular Lymphoma International Prognostic Index
• each subject has not been treated with the anti- CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more) prior to being administered the effective amount of mosunetuzumab and lenalidomide.
• mosunetuzumab and lenalidomide have a synergistic effect on the R/R FL.
• the synergistic effect is a partial response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9). In some embodiments the synergistic effect is a complete response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the present invention relates to methods ot treating a subject having a relapsed and/or refractory (R/R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy.
• R/R refractory follicular lymphoma
• the present invention reiates to methods of treating a subject having a R/R FL.
• mosunetuzumab and lenalidomide have a synergistic effect on the R/R FL.
• the synergistic effect is a partial response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the synergistic effect is a complete response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to
• the C1 D1 is between 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1 .0 mg to 4.0 mg, 1 .25 mg to 4.0 mg, 1 .5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1 .0 mg, 0.75 mg to 1 .25 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .
• the C1 D1 is between 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1 .0 mg to 3.0 mg, 1 .25 mg to 3.0 mg, 1 .5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1 .5 mg, 0.8 mg to 1 .0 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .75 mg, about 2.0 mg, about 2.25 mg, about
• the C1 D2 is between 1 .0 mg to 6.0 mg (e.g., 1 .5 mg to 6.0 mg, 2.0 mg to 6.0 mg, 2.5 mg to 6.0 mg, 3.0 mg to 6.0 mg, 3.5 mg to 6.0 mg, 4.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 1 .0 mg to 5.0 mg, 1 .0 mg to 4.5 mg, 1 .0 mg to 4.0 mg, 1 .0 mg to
• the C1 D3 is between 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg
• 3.0 mg to 45.0 mg e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg,
• the C2D1 is between 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 0.0
• the C1 D1 and C1 D2 are each less than the C1 D3. In some embodiments, the C1 D1 and C1 D2 are about equal. In some embodiments, the C1 D2 is greater than the C1 D1 by about 50% to about 250% (e.g., the C1 D2 is greater than the C1 D1 by about 50% to about 225%, the C1 D2 is greater than the C1 D1 by about 50% to about 200%, the C1 D2 is greater than the C1 D1 by about 50% to about 175%, the C1 D2 is greater than the C1 D1 by about 50% to about 150%, the C1 D2 is greater than the C1 D1 by about 50% to about 125%, the C1 D2 is greater than the C1 D1 by about 50% to about 100%, or the C1 D2 is greater than the C1 D1 by about 50% to about 75%; e.g., the C1 D2 is greater than the C1 D1 by about 50%, the C1 D2 is greater than the C1 D1 by about
• the C1 D1 is 0.8 mg, the C1 D2 is 2.0 mg, and the C1 D3 is 4.2 mg, and the C2D1 is 4.2 mg;
• the C1 D1 is 1 .0 mg, the C1 D2 is 1 .0 mg, and the C1 D3 is 3.0 mg, and the C2D1 is 30.0 mg; or
• the C1 D1 is 1 .0 mg, the C1 D2 is 2.0 mg, and the C1 D3 is 30.0 mg, and the C2D1 is 30.0 mg.
• the length of the first dosing cycle is 21 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject the C1 D1 , the C1 D2, and the C1 D3 on or about Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle. In some embodiments, the length of the second dosing cycle is 28 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject the C2D1 on Day 1 of the second dosing cycle.
• the dosing regimen comprises one or more additional dosing cycles (e.g., one dosing cycle, two dosing cycles, three dosing cycles, four dosing cycles, five dosing cycles, six dosing cycles, seven dosing cycles, eight dosing cycles, nine dosing cycles, ten dosing cycles, or more).
• the dosing regimen comprises one to ten additional dosing cycles (e.g., one dosing cycle, two dosing cycles, three dosing cycles, four dosing cycles, five dosing cycles, six dosing cycles, seven dosing cycles, eight dosing cycles, nine dosing cycles, or ten dosing cycles).
• the dosing regimen comprises ten additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is 28 days ( ⁇ 1 day). In some embodiments, each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab. In some embodiments, the method comprises administering to the subject each additional dose of mosunetuzumab on Day 1 of each of the one or more additional dosing cycles.
• each additional dose of mosunetuzumab is between 0.2 mg to 50.0 mg(e.g., 0.3 mg to 50.0 mg, 0.4 mg to 50.0 mg, 0.5 mg to 50.0 mg, 1 .0 mg to 50.0 mg, 2.0 mg to 50.0 mg, 3.0 mg to 50.0 mg, 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1 .0 mg to 45.0 mg, 1 .0 mg to 40.0 mg, 1 .0 mg to 35.0 mg, 1 .0 mg to 30.0 mg, 1 .0 mg to 25.0 mg, 1 .0 mg to 20.0 mg, 1 .0 mg to 15.0 mg, 1 .0 mg to 10.0 mg, 1 .0 mg to 5.0 mg, 10.0 mg to 5.0 mg,
• administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising twelve dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1 .0 mg to 4.0 mg, 1 .25 mg to 4.0 mg, 1 .5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg,
• the C1 D2 is between 0.05 mg to 20.0 mg (e.g., 0.1 mg to 20.0 mg, 0.2 mg to 20.0 mg, 0.3 mg to 20.0 mg, 0.4 mg to 20.0 mg, 0.5 mg to 20.0 mg, 1 .0 mg to 20.0 mg, 1 .5 mg to 20.0 mg, 2.0 mg to 20.0 mg, 3.0 mg to 20.0 mg,
• the C1 D1 is between 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1 .0 mg to 4.0 mg, 1 .25 mg to 4.0 mg, 1 .5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1 .0 mg, 0.75 mg to 1 .25 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .
• the C1 D1 is between 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1 .0 mg to 3.0 mg, 1 .25 mg to 3.0 mg, 1 .5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1 .5 mg, 0.8 mg to 1 .0 mg, 1 .0 mg to 3.0 mg, 1 .5 mg to 2.0 mg, or 0.9 mg to 1 .1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1 .0 mg, about 1 .1 mg, about 1 .2 mg, about 1 .3 mg, about 1 .4 mg, about 1 .5 mg, about 1 .75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, or about 3.0 mg), the C1 D2 is between 1 .0 mg to 3.0 mg (e.g.
• the C1 D3 is between 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg
• 3.0 mg to 45.0 mg e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg,
• the C1 D1 and C1 D2 are each less than the C1 D3.
• the C1 D2 is greater than the C1 D1 by about 50% to about 250% (e.g., the C1 D2 is greater than the C1 D1 by about 50% to about 225%, the C1 D2 is greater than the C1 D1 by about 50% to about 200%, the C1 D2 is greater than the C1 D1 by about 50% to about 175%, the C1 D2 is greater than the C1 D1 by about 50% to about 150%, the C1 D2 is greater than the C1 D1 by about 50% to about 125%, the C1 D2 is greater than the C1 D1 by about 50% to about 100%, or the C1 D2 is greater than the C1 D1 by about 50% to about 75%; e.g., the C1 D2 is greater than the C1 D1 by about 50%, the C1 D2 is greater than the C1 D1 by about 100%, the C1 D2 is greater than the C1 D1 D1
• the C1 D1 is 0.8 mg, the C1 D2 is 2.0 mg, the C1 D3 is 4.2 mg, and each single dose C2D1 -C12D1 is 4.2 mg;
• the C1 D1 is 1 .0 mg, the C1 D2 is 1 .0 mg, the C1 D3 is 3.0 mg, and each single dose C2D1 -C12D1 is 30.0 mg; or
• the C1 D1 is 1 .0 mg, the C1 D2 is 2.0 mg, the C1 D3 is 30.0 mg, and each single dose C2D1 -C12D1 is 30.0 mg.
• the length of the first dosing cycle is 21 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject the C1 D1 , the C1 D2, and the C1 D3 on or about Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle. In some embodiments, the length of each of the second to twelfth dosing cycles is 28 days ( ⁇ 1 day). In some embodiments, the method comprises administering to the subject each of the C2D1 -C12D1 on Day 1 of each respective dosing cycle. In some embodiments, the length of each of the second to twelfth dosing cycles is 28 days ( ⁇ 1 day).
• mosunetuzumab is administered intravenously.
• lenalidomide is administered during the second and subsequent cycles. In some embodiments, lenalidomide is not administered during the first cycle. In some embodiments, lenalidomide is administered daily. In some embodiments, lenalidomide is administered daily on the first 21 days of each dosing cycle comprising administration of lenalidomide. In some embodiments, lenalidomide is not administered on the last 7 days of each dosing cycle comprising administration of lenalidomide. In some embodiments, lenalidomide is administered at a dose of 20 mg. In some embodiments, lenalidomide is administered orally.
• the subject was previously treated with at least one anti-CD20 monoclonal antibody. In some embodiments, the subject is relapsed or refractory to the treatment comprising the anti-CD20 monoclonal antibody. In some embodiments, the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included obinutuzumab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzuma
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included obinutuzumab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intraven
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included rituximab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzuma
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab administered on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg
• the second dosing cycle further comprises administering 20 mg lenalidomide daily orally on Days 1 -21 of the second dosing cycle.
• the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject: (i) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (ii) has been previously treated with at least one chemo-immunotherapy regimen that included rituximab; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intraven
• the second to twelfth dosing cycles each comprises a single dose (C2D1 -C12D1 ) of mosunetuzumab intravenously administered on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg
• the second to twelfth dosing cycles each further comprises orally administering 20 mg lenalidomide daily on Days 1 -21 of each dosing cycle.
• the invention features a method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered
• At least one chemo-immunotherapy regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).
• the invention features a method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first do
• the dosing regimen further comprises administration of a corticosteroid.
• the corticosteroid is administered to the subject during the first dosing cycle.
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the corticosteroid.
• the C1 D1 , the C1 D2, and the C1 D3 of the corticosteroid are administered to the subject on Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subject before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• the corticosteroid is administered to the subject on the first dosing cycle and not on the second dosing cycle.
• the corticosteroid is administered to the subject on the second dosing cycle.
• the second dosing cycle comprises a single dose (C2D1 ) of the corticosteroid.
• the C2D1 of the corticosteroid is administered to the subject on Day 1 of the second dosing cycle.
• the C2D1 of the corticosteroid is administered to the subject before administration of the C2D1 of mosunetuzumab.
• the C2D1 of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C2D1 of mosunetuzumab.
• the dosing regimen further comprises administration of a corticosteroid.
• the corticosteroid is administered to the subjects during the first dosing cycle.
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the corticosteroid.
• the C1 D1 , the C1 D2, and the C1 D3 of the corticosteroid are administered to the subjects on Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subjects before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 - C1 D3 of the corticosteroid is administered to the subjects 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• the corticosteroid is administered to the subjects on the first dosing cycle and not on the second dosing cycle.
• the corticosteroid is administered to the subjects on the second dosing cycle.
• the second dosing cycle comprises a single dose (C2D1 ) of the corticosteroid.
• the C2D1 of the corticosteroid is administered to the subjects on Day 1 of the second dosing cycle.
• the C2D1 of the corticosteroid is administered to the subjects before administration of the C2D1 of mosunetuzumab.
• the C2D1 of the corticosteroid is administered to the subjects 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C2D1 of mosunetuzumab.
• each additional dosing cycle comprises administering to the subject an additional dose of the corticosteroid. In some embodiments, each additional dose of the corticosteroid is administered on Day 1 of each additional dosing cycle. In some embodiments, each additional dose of the corticosteroid is administered to the subject before administration of each additional dose of mosunetuzumab.
• each additional dose of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of each additional dose of mosunetuzumab.
• the corticosteroid is administered intravenously.
• the corticosteroid is dexamethasone.
• each dose of dexamethasone is about 10 mg (e.g., about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg).
• the overall response rate in a population of subjects having R/R FL is at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 80%- 100%, between 85-100%, between 87-100%, between 90-100%, between 95-100%, between 80%-90%, between 80-85%, between 85-97%, between 85-95%, between 85-90%, between 85-87%, between 90- 95%, or between 93-97%; e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about
• the overall response rate in a population of subjects having R/R FL is at least 90%. In some embodiments, the overall response rate in a population of subjects having R/R FL is at least 95%. In some embodiments, the overall response rate in a population of subjects having R/R FL is at least 99%.
• the complete response rate in a population of subjects having R/R FL is at least 65% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 65-100%, between 75-100%, between 85-100%, between 95-100%, between 65-90%, between 65-80%, between 65-70%, between 65-75%, or between 75-85%; e.g., about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 80%, about 85%, about 90%, or more).
• the complete response rate in a population of subjects having R/R FL is at least 75%. In some embodiments, the complete response rate in a population of subjects having R/R FL is at least 85%.
• combination therapy with mosunetuzumab and lenalidomide exhibits synergistic effects in the efficacy of the therapy compared to therapy with mosunetuzumab or lenalidomide alone for treating subjects with R/R FL.
• a population of subjects with R/R FL treated with a combination therapy with mosunetuzumab and lenalidomide exhibits a higher overall response rate compared to a population of subjects treated with monotherapy of mosunetuzumab or lenalidomide alone.
• a population of subjects with R/R FL treated with a combination therapy with mosunetuzumab and lenalidomide exhibits a higher complete response rate compared to a population of subjects treated with monotherapy of mosunetuzumab or lenalidomide alone.
• the subject exhibits a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.
• the reduction in tumor burden is determined by computed tomography (CT).
• CT computed tomography
• the reduction in tumor burden is a decrease in the sum of the product of the diameters (SPD) of target lesions.
• the decrease in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 40-100%, between 40-80%, between 40-60%, between 50-70%, between 70-90%, between 75-85%, between 60-100%, between 55-65%, between 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%).
• the decrease in SPD is at least 60%. In some embodiments, the decrease in SPD is at least 80%.
• At least 45% e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 45-100%, between 45-80%, between 45-60%, between 50-70%, between 55-65%, between 70-90%, between 70-80%, between 60-100%, between 80-100%; e.g., about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.
• At least 60% of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 75% of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, the reduction in tumor burden is determined by computed tomography (CT).
• CT computed tomography
• the reduction in tumor burden is a decrease in the sum of the product of the diameters (SPD) of target lesions.
• the decrease in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., between 40-100%, between 40-80%, between 40-60%, between 50-70%, between 70-90%, between 75-85%, between 60-100%, between 55-65%, between 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%).
• the decrease in SPD is at least 60%. In some embodiments, the decrease in SPD is at least 80%.
• the subject is human. In some embodiments, each subject in the population is human.
• the present invention relates to methods of treating a subject having a relapsed and/or refractory (R/R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy.
• the present invention relates to methods of treating a subject having a R/R FL that is R/R to at least one prior systemic therapy (e.g., one prior treatment with a chemo-immunotherapy regimen) which included an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody; e.g., rituximab or obinutuzumab) or other treatment.
• the therapies and dosing regimens described herein provide acceptable safety profiles in subjects with R/R FL treated with the described dosing regimens.
• Any of the methods described herein may involve monitoring a subject for cytokine release syndrome (CRS), e.g., a CRS event following commencement of any of the methods described above.
• CRS cytokine release syndrome
• Current clinical management focuses on treating the individual signs and symptoms, providing supportive care, and attempting to dampen the inflammatory response using a high dose of corticosteroids. However, this approach is not always successful, especially in the case of late intervention.
• the CRS grading criteria used by the methods described herein are published by the American Society for Transplantation and Cellular Therapy (ASTCT) to define mild, moderate, severe, or life-threatening CRS and harmonize reporting across clinical trials to allow rapid recognition and treatment of CRS (Lee et al. Biol Blood Marrow Transplantation. 25(4): 625-638, 2019).
• the ASTCT criteria is intended to be objective, easy to apply, and more accurately categorize the severity of CRS. This CRS grading system is shown below in Table 1 .
• ASTCT American Society for Transplantation and Cellular Therapy
• BiPAP bilevel positive airway pressure
• CPAP continuous positive airway pressure
• CRS cytokine release syndrome
• CTCAE Common Terminology Criteria for Adverse Events.
• Fever is defined as a temperature > 38 °C not attributable to any other cause.
• subjects who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity.
• CRS grading is determined by hypotension and/or hypoxia.
• CRS grade is determined by the more severe event, hypotension or hypoxia not attributable to any other cause. For example, a subject with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS.
• Low-flow nasal cannula is defined as oxygen delivered at ⁇ 6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute.
• CRS is associated with elevations in a wide array of cytokines, including marked elevations in IFN-y, IL-6, and TNF-a levels. Emerging evidence implicates IL-6, in particular, as a central mediator in CRS. IL-6 is a proinflammatory, multi-functional cytokine produced by a variety of cell types, which has been shown to be involved in a diverse array of physiological processes, including T cell activation. Regardless of the inciting agent, CRS is associated with high IL-6 levels (Nagorsen et al. Cytokine. 25(1 ): 31 -5, 2004; Lee et al. Blood. 124(2): 188-95, 2014); Doesegger et al. Clin. Transl. Immunology.
• IL-6 correlates with the severity of CRS, with subjects who experience a Grade 4 or 5 CRS event having much higher IL-6 levels compared to subjects who do not experience CRS or experience milder CRS (Grades 0-3) (Chen et al. J. Immunol. Methods. 434:1 -8, 2016).
• the method may further comprise administering to the subject one or more additional doses of the IL-6R antagonist to manage the CRS event.
• the subject may be administered a corticosteroid, such as methylprednisolone or dexamethasone if CRS event is not managed through administration of the IL-6R antagonist.
• any of the methods described herein may involve monitoring a subject for additional non-CRS adverse events. Incidence, nature, and severity of physical findings and adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI CTCAE v5.0). Other than CRS, one of the most common adverse events reported in patients undergoing treatment with mosunetuzumab and/or lenalidomide is neutropenia (e.g., febrile neutropenia).
• neutropenia e.g., febrile neutropenia
• Neutropenia is characterized by an abnormally low blood count of neutrophils, which are a type of white blood cells. Neutropenia may lead to an increased risk of infection.
• the generally accepted reference range for absolute neutrophil count (ANC) in adult humans is 1 ,500 to 8,000 cells/pL of blood.
• Mild neutropenia is characterized by ANC between 1 ,000-1 ,500 cells/pL (Grade 1 -2);
• moderate neutropenia is characterized by ANC between 500 and 1 ,000 cells/pL (Grade 3)
• severe neutropenia is characterized by ANC below 500 cells/pL (Grade 4).
• Febrile neutropenia (Grade 3+ neutropenia) is characterized by ANC below 1 ,000 cells/pL in addition to either a single temperature measurement greater than 38.3 °C or sustained temperature measurements greater than 38 °C for more than one hour.
• the invention features a method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day ( ⁇ 1 day) dosing cycle and a second 28-day ( ⁇ 1 day) dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered
• At least one chemo-immunotherapy regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).
• the invention features a method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject: (a) has relapsed or refractory follicular lymphoma (R/R FL) that expresses CD20, and (b) has been previously treated with at least one chemo-immunotherapy regimen; and wherein administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day ( ⁇ 1 day) dosing cycle and eleven subsequent 28-day ( ⁇ 1 day) dosing cycles, wherein: (a) the first do
• each subject has received only one prior line of systemic therapy and either: (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004; 104 (5): 1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) has been refractory to prior anti-CD20 monoclonal antibody treatment, or (c) has disease progression within 24 months after initiation of prior therapy.
• FLIPI Follicular Lymphoma International Prognostic Index
• the FL of each subject is histologically documented as Grade 1 , 2, or 3a, but not 3b according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016; 127:2375-90).
• each subject has not been treated with the anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more) prior to being administered the effective amount of mosunetuzumab and lenalidomide.
• 4 weeks e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, or more
• mosunetuzumab and lenalidomide have a synergistic effect on the R/R FL.
• the synergistic effect is a partial response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the synergistic effect is a complete response, as defined by Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• the methods of the invention features premedication with corticosteroids to reduce adverse effects of mosunetuzumab administration.
• premedication with corticosteroids reduces the rate of cytokine release syndrome (CRS) in subjects treated with mosunetuzumab (e.g., subjects administered a combination of mosunetuzumab and lenalidomide).
• the dosing regimen further comprises administration of a corticosteroid.
• the corticosteroid is administered to the subject during the first dosing cycle.
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the corticosteroid.
• the C1 D1 , the C1 D2, and the C1 D3 of the corticosteroid are administered to the subject on Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subject before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• the corticosteroid used is dexamethasone.
• each dose of dexamethasone is about 10 mg (e.g., about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg). In some embodiments, dexamethasone is administered intravenously.
• the corticosteroid is administered to the subject on the first dosing cycle and not on the second dosing cycle.
• the corticosteroid is administered to the subject on the second dosing cycle.
• the second dosing cycle comprises a single dose (C2D1 ) of the corticosteroid.
• the C2D1 of the corticosteroid is administered to the subject on Day 1 of the second dosing cycle.
• the C2D1 of the corticosteroid is administered to the subject before administration of the C2D1 of mosunetuzumab.
• the C2D1 of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C2D1 of mosunetuzumab.
• the dosing regimen further comprises administration of a corticosteroid.
• the corticosteroid is administered to the subjects during the first dosing cycle.
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of the corticosteroid.
• the C1 D1 , the C1 D2, and the C1 D3 of the corticosteroid are administered to the subjects on Days 1 , 8 ( ⁇ 1 day), and 15 ( ⁇ 1 day), respectively, of the first dosing cycle.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered to the subjects before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 - C1 D3 of the corticosteroid is administered to the subjects 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• the corticosteroid is administered to the subjects on the first dosing cycle and not on the second dosing cycle.
• the corticosteroid is administered to the subjects on the second dosing cycle.
• the second dosing cycle comprises a single dose (C2D1 ) of the corticosteroid.
• the C2D1 of the corticosteroid is administered to the subjects on Day 1 of the second dosing cycle.
• the C2D1 of the corticosteroid is administered to the subjects before administration of the C2D1 of mosunetuzumab.
• the C2D1 of the corticosteroid is administered to the subjects 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the C2D1 of mosunetuzumab.
• each additional dosing cycle comprises administering to the subject an additional dose of the corticosteroid. In some embodiments, each additional dose of the corticosteroid is administered on Day 1 of each additional dosing cycle. In some embodiments, each additional dose of the corticosteroid is administered to the subject before administration of each additional dose of mosunetuzumab.
• each additional dose of the corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of each additional dose of mosunetuzumab.
• the corticosteroid is administered intravenously.
• the corticosteroid is dexamethasone.
• each dose of dexamethasone is about 10 mg (e.g., about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg).
• the incidence of an adverse event is not significantly higher than if mosunetuzumab was administered alone to the population of subjects having R/R FL. In some embodiments, the incidence of an adverse event is not significantly higher than if lenalidomide is not administered to the population of subjects. In some embodiments, the incidence rate of an adverse event is not significantly higher in a population of subjects having R/R FL when treated with a combination therapy of mosunetuzumab and lenalidomide in comparison to a population of subjects having R/R FL treated with a monotherapy of mosunetuzumab or lenalidomide alone.
• the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome is less than 45% (e.g., less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., between about 0% to about 50%, between about 5% to about 40%, between about 5% to about 20%, between about 5% to about 10%, between about 20% to about 45%, between about 30% to about 40%, between about 20% to about 40%, between about 15% to about 35%, between about 15% to about 25%, between about 35% to about 45%, or between about 25% to about 45%; e.g., about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%
• the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading") is less than 35%. In some embodiments, the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading”) is less than 25%. In some embodiments, the incidence rate of CRS is about 30%.
• the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading") is less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1 %; e.g., between 0% and 10%, between 0% and 9%, between 0% and 8%, between 0% and 7%, between 0% and 6%, between 0% and 5%, between 0% and 4%, between 0% and 3%, between 0% and 2%, between 0% and 1 %, between 1 % and 3%, between 1 % and 5%, between 1 % and 10%, between 3% and 5%, between 5% and 8%, between 5% and 10%, or between 8% and 10%).
• ASTCT CRS grading is
• the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading”) is less than 5%. In some embodiments, the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading”) is less than 3%.
• the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (“ASTCT CRS grading") is less than 1 %. In some embodiments, the incidence rate of CRS having a grade of 3 or higher is about 0%.
• the incidence rate of neutropenia in a population of patients having R/R FL and treated with combination therapy of mosunetuzumab and lenalidomide is less than 40% (e.g., less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., between about 0% to about 40%, between about 5% to about 40%, between about 5% to about 20%, between about 5% to about 10%, between about 20% to about 40%, between about 30% to about 40%, between about 15% to about 35%, between about 15% to about 25%, between about 35% to about 40%, or between about 25% to about 40%; e.g., about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 3%, about 1%, or about 0%).
• the incidence rate of neutropenia is less than 30%. In some embodiments, the incidence rate of neutropenia is less than 20%. In some embodiments, the incidence rate of neutropenia having Grade of 3 or 4 is about 19%. In some embodiments, the incidence rate of febrile neutropenia is about 0%.
• the methods described herein may result in an acceptable safety profile for subjects having R/R mosunetuzumab being treated with combination therapy of mosunetuzumab and lenalidomide.
• treatment using the methods described herein that result in intravenously administering mosunetuzumab in the context of a fractionated, dose-escalation dosing regimen and oral administration of lenalidomide results in a reduction (e.g., by 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, 50% or greater, 55% or greater, 60% or greater, 65% or greater, 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater; e.g., between 20% and 100%, between 20% and 90%, between 20% and 80%, between 20% and 70%, between 20% and 60%, between 20% and 50%, between 20% and 40%, between 20% and 30%, between 40%
• the invention provides mosunetuzumab, a bispecific antibody that binds to CD20 and CD3, useful for treating relapsed and/or refractory (R/R) follicular lymphoma (FL).
• the FL may be of Grades 1 , 2, or 3a, but not Grade 3b.
• the invention provides mosunetuzumab that includes an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) an HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6).
• HVRs hypervariable regions
• mosunetuzumab comprises at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively.
• mosunetuzumab comprises an anti-CD20 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b).
• the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO:
• the invention provides mosunetuzumab that includes an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) an HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) an HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) an HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14).
• HVR-H1 comprising the amino acid sequence of NYYIH
• mosunetuzumab comprises at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.
• mosunetuzumab comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).
• the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.
• the invention provides mosunetuzumab that includes (1 ) an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6); and (2) an anti-CD3 arm having a first binding
• mosunetuzumab comprises (1 ) at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR- L1 , FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21 -24, respectively, and (2) at least one (e.g., 1 , 2, 3, or 4) of heavy chain framework regions FR-H1 , FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and/or at least one (e.g., 1 , 2, 3, or 4) of the light chain framework regions FR-L1 , FR-L2, FR-L3, and
• mosunetuzumab comprises (1 ) an anti-CD20 arm comprising a first binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 7; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b), and (2) an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 9
• mosunetuzumab comprises (1 ) a first binding domain comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8 and (2) a second binding domain comprising a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.
• mosunetuzumab has the International Nonproprietary Names for Pharmaceutical Substances (INN) List 117 (WHO Drug Information, Vol. 31 , No. 2, 2017, p. 303), or CAS Registry No. 1905409-39-3, and having (1 ) an anti-CD20 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 33 and 34 , respectively; and (2) an anti-CD3 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 35 and 36, respectively.
• INN International Nonproprietary Names for Pharmaceutical Substances
• mosunetuzumab comprises (1 ) an anti-CD20 arm comprising a first binding domain comprising (a) a heavy chain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 33; (b) a light chain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 34; or (c) a heavy chain as in (a) and a light chain as in (b), and (2) an anti-CD3 arm comprising a second binding domain comprising (a) a heavy chain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,
• mosunetuzumab comprises (1 ) an anti-CD20 arm comprising a first binding domain comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 33 and a light chain comprising an amino acid sequence of SEQ ID NO: 34 and (2) an anti-CD3 arm comprising a second binding domain comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 35 and a light chain comprising an amino acid sequence of SEQ ID NO: 36.
• Mosunetuzumab may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567.
• Lenalidomide is an immunomodulatory (IMiD) imide drug that binds to cereblon, an E3 ubiquitin ligase protein (Gribben et al. 2015).
• IMD immunomodulatory
• the immunomodulatory activity of lenalidomide is not completely understood; however, lenalidomide has been shown to enhance CD4+ and CD8+ T-cell co-stimulation, induce T-cell proliferation, and enhance IL-2 and IFN-y (Haslett et al. 1998; Davies et al. 2001 ).
• Lenalidomide has the CAS Registry Number 191732-72-6 and IUPAC name (3RS)-3-(4-Amino-1 - oxo-1 ,3-d ihydro-2H-isoi ndol-2-yl)piperidine-2, 6-dione.
• Lenalidomide is also known by tradenames including REVLIMID®, linamid, and lenalid.
• Lenalidomide has the DrugBank Accession Number DB00480, PubChem CID 216326, and chemical formula C13H13N3O3.
• the present invention describes additive/synergistic efficacy in the combination of a mosunetuzumab with lenalidomide, as well as potential overlapping toxicity, for which patients are carefully monitored and managed by the dosing regimens and treatment described herein.
• the methods described herein include administering mosunetuzumab and lenalidomide in combination with one or more additional therapeutic agents.
• the one or more additional therapeutic agents may reduce the rate or the severity of cytokine release syndrome (CRS). In some instances, the one or more additional therapeutic agents may prevent symptoms associated with CRS.
• the additional therapeutic agent used to reduce the rate or severity of CRS or prevent symptoms associated with CRS is a corticosteroid (e.g., dexamethasone (CAS#: 50-02-2), prednisone (CAS#: 53-03-2), prednisolone (CAS# 50-42-8), or methylprednisolone (CAS#: 83-43-2)) or an IL-6R antagonist (e.g., tocilizumab, sarilumab, vobarilizumab (ALX-0061 ), satralizumab (SA-237), and variants thereof).
• a corticosteroid e.g., dexamethasone (CAS#: 50-02-2), prednisone (CAS#: 53-03-2), prednisolone (CAS# 50-
• the additional therapeutic agent is tocilizumab. In some instances, the additional therapeutic agent is a corticosteroid. In some instances, a corticosteroid is administered prior to administration of mosunetuzumab. In some instances, the corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of mosunetuzumab. In some instances, the corticosteroid is administered intravenously. In some instances, the corticosteroid is dexamethasone.
• 10 mg of dexamethasone is administered to a subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1 .5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of mosunetuzumab to the subject.
• the corticosteroid is methylprednisolone.
• the corticosteroid is prednisone.
• the one or more additional therapeutic agents may be used in the treatment of neutropenia. In some instances, the additional therapeutic agents may be prevent symptoms associated with neutropenia.
• the additional therapeutic agents may reduce the rate or severity of neutropenia.
• the additional therapeutic agent is granulocyte colony-stimulating factor (G-CSF or GCSF) or colony-stimulating factor 3 (CSF 3).
• G-CSF or GCSF granulocyte colony-stimulating factor
• CSF 3 colony-stimulating factor 3
• the mRNA sequence of human G- CSF/CSF 3 includes, e.g., NCBI RefSeq No. NM_000759, NM_001178147, NM_172219, and NM_172220
• the protein amino acid sequence of human G-CSF/CSF 3 includes, e.g., NCBI RefSeq No. NP 000750, NP 001171618, NP_757373, and NP_757374.
• mosunetuzumab and lenalidomide are formulated, dosed, and administered in a fashion consistent with good medical practice.
• Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
• Mosunetuzumab and lenalidomide need not be, but are optionally formulated with, one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of mosunetuzumab and/or lenalidomide present in the formulation, the type of disorder or treatment, and other factors discussed above.
• Mosunetuzumab and lenalidomide may be suitably administered to the subject over a series of treatments.
• mosunetuzumab and lenalidomide may be administered before, simultaneously with, or after administration of lenalidomide.
• additional therapeutic agents useful in the present invention include therapeutic antibodies, such as alemtuzumab (CAMPATH®), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (BEXXAR®, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
• CAMPATH® alemtuzumab
• AVASTIN® bevacizumab
• cetuximab ERBITUX®, Imclone
• panitumumab VECTIBIX®, Amgen
• rituximab
• Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, o
• Mosunetuzumab and/or lenalidomide described herein can be used in pharmaceutical compositions and formulations.
• Pharmaceutical compositions and formulations of mosunetuzumab, lenalidomide, and/or other agents describe herein can be prepared by mixing one, two, or all three agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
• Lenalidomide may also be formulated according to standard formulation and/or manufacturing practices.
• Dexamethasone may also be formulated according to standard formulation and/or manufacturing practices.
• Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arg
• Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.).
• sHASEGP soluble neutral-active hyaluronidase glycoproteins
• rHuPH20 HYLENEX®, Baxter International, Inc.
• Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968.
• a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
• Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958.
• Aqueous antibody formulations include those described in U.S. Patent No. 6,171 ,586 and W 02006/044908, the latter formulations including a histidine-acetate buffer.
• the formulation herein may also contain more than one active ingredient as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
• an additional therapeutic agent e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above.
• Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
• Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
• colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
• Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules.
• the formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.
• mosunetuzumab is formulated for administration intravenously.
• lenalidomide is formulated for administration orally.
• dexamethasone is formulated for administration intravenously.
• kits or an article of manufacture containing materials useful for the treatment, prevention, and/or diagnosis of the disorders described above.
• the kit or article of manufacture comprises a container and a label or package insert on or associated with the container.
• Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc.
• the containers may be formed from a variety of materials such as glass or plastic.
• the container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be a vial having a stopper pierceable by a hypodermic injection needle).
• At least one active agent in the composition is mosunetuzumab or lenalidomide described herein.
• the label or package insert indicates that the composition is used for treating relapsed and/or refractory (R/R) follicular lymphoma (FL) and further includes information related to at least one of the dosing regimens described herein.
• the label or package insert indicates that the composition is used for treating R/R FL in a patient who is R/R to at least one prior treatment (e.g., a chemo-immunotherapy) that comprised an anti- CD20 antibody (e.g., an anti-CD20 monoclonal antibody; e.g., rituximab or obinutuzumab).
• an anti- CD20 antibody e.g., an anti-CD20 monoclonal antibody; e.g., rituximab or obinutuzumab.
• the kit or article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises mosunetuzumab, lenalidomide, or both mosunetuzumab and lenalidomide; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent.
• the kit or article of manufacture may further comprise a second (or third) container comprising a pharmaceutically- acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
• Example 1 A Phase lb, Open-Label, Non-Randomized, Multicenter Study Evaluating the Safety, Pharmacokinetics, and Efficacy of Mosunetuzumab in Combination with Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma
• Study CO41942 is an ongoing Phase 1 b, open-label, multicenter study evaluating the safety, pharmacokinetics, and efficacy of mosunetuzumab in combination with lenalidomide in patients with relapsed and/or refractory (e.g., R/R or r/r) follicular lymphoma (FL). Patients with r/r FL after at least one prior systemic therapy are eligible to enter the study.
• refractory e.g., R/R or r/r
• FL follicular lymphoma
• Patients with r/r FL after at least one prior systemic therapy are eligible to enter the study.
• mosunetuzumab in combination with lenalidomide is the only active treatment combination in Study CO41942, therefore this study focuses on the mosunetuzumab plus lenalidomide combination only.
• the study design is summarized in FIGS. 1 A and 1 B.
• the study includes an initial dose-escalation phase, comprising a dose-escalation cohort, designed to determine the recommended Phase 2 dose (RP2D) of mosunetuzumab.
• the initial dose-escalation phase is followed by an expansion phase in which the RP2D for mosunetuzumab is given.
• Study treatment is administered for 12 cycles; the duration of Cycle 1 is 21 days, and the duration of Cycle 2-12 is 28 days.
• Mosunetuzumab is administered intravenously: in Cycle 1 (21 - day cycle), patients receive 1 mg on Day 1 (C1 D1 dose); 2 mg on Day 8 (C1 D2 dose); and 30 mg on Day 15 (C1 D3 dose).
• Cycles 2-12 (28-day cycles) patients receive 30 mg on Day 1 (C2D1 - C12D1 doses).
• Lenalidomide is administered orally (PO) 20 mg once daily on Days 1 -21 of Cycles 2-12 (28-day cycles). Lenalidomide is not administered on the last 7 days of each of the 28-day Cycles 2-12.
• Patient Eastern Cooperative Oncology Group (ECOG) status was 0 for 81.3% (13/16 patients) and 1 for 18.8% (3/16 patients).
• the median duration of treatment was 1 .8 months (range: 0-7 months).
• the median number of treatment cycles was 3 (range: 1 -9); the median number of doses received was 5 (range: 1 -11 ); and the median cumulative dose received was 93 mg (range: 1 .0-273.0).
• the median duration of treatment was 1 .9 months (range: 0-6 months).
• the median number of treatment cycles was 3 (range: 1 -5); the median number of doses received was 37 (range: 1 -151 ); and the median of cumulative dose received was 740 mg (range: 20.0- 3020.0).
• the safety-evaluable population (N 16) included all patients who were enrolled in the study and received at least one dose of study treatment.
• the percentage of patients who reported at least one event considered related to study treatment was 81 .3% (13/16 patients).
• the percentage of patients who reported at least one event considered related to mosunetuzumab or lenalidomide treatment was 81 .3% and 50.0%, respectively.
• the percentage of patients who reported at least one event that led to dose modification/interruption of study treatment was 37.5% (6/16 patients). Of these, 2 patients had dose interruption of mosunetuzumab and 6 patients had dose interruption of lenalidomide treatment.
• AEs including AEs considered related to mosunetuzumab, SAEs and AESIs were similar in this study as a related study with monotherapy mosunetuzumab administered with similar doses.
• AE adverse event
• AESI adverse event of special interest
• SOC System Organ Class
• AEs considered related to study treatment (e.g., related to mosunetuzumab or lenalidomide) are shown in FIG. 2.
• Percentages are based on N in the column headings. For frequency counts by preferred term, multiple occurrences of the same SAE in an individual are counted only once. For frequency counts of “Total number of events” rows, multiple occurrences of the same SAE in an individual are counted separately. Adverse Events with missing Common Terminology Criteria for Adverse Events (CTCAE) grades are excluded.
• CTCAE Common Terminology Criteria for Adverse Events
• AESIs include events that are considered to be of overlapping toxicities between the study treatments, and are summarized in Table 8. Overall, the percentage of patients who reported at least one AESI was 43.8%(7/16 patients). The most commonly reported AESIs were CRS (31 .3%; 5/16 patients), and neutropenia (25.0%; 4/16 patients). One patient (6.3%) reported an event of Grade 1 thrombocytopenia that had not resolved at the time of CCOD; no intervention was taken.
• Percentages are based on N in the column headings.
• CRS events Five patients (31 .3%) had a CRS event, considered related to mosunetuzumab treatment, as assessed by the Investigator, including 4 patients (25.0%) with ASTCT Grade 1 , and one patient (6.3%) with Grade 2 (Table 9). All 5 patients had onset of first CRS event between Day 1 of Cycle 1 and Day 7 of Cycle 1 (FIG. 5). One patient (6.3%; 1/14) had a subsequent Grade 1 event between Day 15 of Cycle 1 and Day 21 of Cycle 1 during mosunetuzumab monotherapy treatment, and another patient (6.3%; 1/14) had a subsequent Grade 1 event in C2 during mosunetuzumab and lenalidomide combination treatment. Table 9. CRS Events by Dose Cycle for Safety-Evaluable Patients as of CCOD of April 5, 2021.
• the efficacy evaluable population included all patients who had been assessed for response at any time on study, who had withdrawn from treatment or study prior to reaching their first response assessment, or who had been on study long enough to have reached their first scheduled response assessment, planned per protocol for Cycle 3, D15-21 .
• the response was assessed by the Investigator per Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• mosunetuzumab PK is similar when administered in combination with lenalidomide as compared to monotherapy, where the observed concentration measurements fell generally within the popPK model simulated 5th to 95 th prediction intervals.
• NCT04246086 Phase lb study evaluating the safety and activity of combination therapy of mosunetuzumab and lenalidomide in R/R FL patients who have received at least one prior line of therapy.
• Cytokine release syndrome was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• CRS events were Grade 1 (7/8 patients) or Grade 2 (1/8 patients). For most patients (6/8), CRS events occurred in Cycle 1 ; 2 patients experienced Grade 1 CRS events in Cycle 2. Median time to CRS onset was 1 day after first study drug administration (range: 1 -28 days), median CRS duration was 3 days (range: 2-5 days). All CRS events resolved without sequelae. No patient required tocilizumab, ICU admission, high flow oxygen, or vasopressor support. Five patients (19%) reported 14 events of Grade 3-4 neutropenia; all neutropenia events occurred between Day 41 and Day 218, with a duration of 6-16 days. All neutropenia events resolved, with 1 patient receiving primary granulocyte colony-stimulating factor (G-CSF) prophylaxis and 2 patients receiving G-CSF treatment. No febrile neutropenia events occurred.
• G-CSF primary granulocyte colony-stimulating factor
• the efficacy-evaluable population included all patients who had been assessed for response at any time on study, who had withdrawn from treatment or study prior to reaching their first response assessment, or who had been on study long enough to have reached their first scheduled response assessment, planned per protocol for Days 15-21 of Cycle 3.
• Objective response rate in the 13 patients who were efficacy evaluable at data cut-off was 92%, with complete metabolic response observed in 10 patients (77%), partial metabolic response (PMR) in 2 patients (15%), and stable disease in 1 patient (8%).
• PMR partial metabolic response
• Example 3 Preliminary Safety and Efficacy for Mosunetuzumab in Combination with Lenalidomide in Patients with Relapsed/Refractory Follicular Lymphoma: Initial Results from a Phase lb Study
• NCT04246086 Phase lb study (NCT04246086) (described in Example 2 above) evaluating the safety and activity of combination therapy of mosunetuzumab and lenalidomide in R/R FL patients who have received at least one prior line of therapy.
• Lenalidomide (20 mg orally) was administered on Days 1 -21 of Cycles 2-12.
• Corticosteroid pre-medication was administered to the patients during Cycles 1 and 2 and was optional from Cycle 3 onwards.
• 10 mg of dexamethasone was administered intravenously to the patients prior to each dose of mosunetuzumab.
• Corticosteroid pre-medication may additionally be deemed optional on Cycle 2 depending on further safety data evaluation. No hospitalization was mandated by the protocol.
• the primary objective was to evaluate the safety of combination therapy of mosunetuzumab and lenalidomide; secondary objectives include assessment of response and longterm efficacy outcomes.
• Cytokine release syndrome was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014; 32:1 -9).
• Cytokine release syndrome (CRS) events observed in the safety-evaluable patients are summarized below in Table 1 1 .
• CRS events were Grade 1 (7/8 patients) or Grade 2 (1/8 patients). For most patients (6/8), CRS events occurred in Cycle 1 ; 2 patients experienced Grade 1 CRS events in Cycle 2. Median time to CRS onset was 1 day after first study drug administration (range: 1 -28 days), median CRS duration was 3 days (range: 2-5 days). All CRS events resolved by data cut-off date (September 13, 2021 ). No patient received tocilizumab, and no patient required ICU admission, high flow oxygen, or vasopressor support. No immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred. A summary of CRS events by dosing cycle and dose is shown in FIG. 8.
• Anti-tumor activity in evaluable patients is shown in FIG. 10.
• objective response rate in the 29 patients at data cut-off was 89.7%, with complete metabolic response observed in 65.5% of patients (see FIG. 11 ).
• 3/3 patients with history of POD24, 9/9 patients with anti-CD20 refractory disease, and 7/7 patients with double-refractory disease all exhibited responses as measured by PET-CT. Duration of response in all 29 patients as of the data cut-off date of September 13, 2021 , is summarized in FIG. 12.
• a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject:
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject, wherein the subject:
• lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a subject, wherein the subject:
• (c) has disease progression within 24 months after initiation of prior therapy.
• mosunetuzumab for use or use of embodiment 7 or 8, wherein mosunetuzumab and lenalidomide are not to be administered to the subject for at least 4 weeks after the subject has received treatment with an anti-CD20 monoclonal antibody.
• administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg, the C1 D2 is between 0.05 mg to 20.0 mg, and the C1 D3 is between 0.2 mg to 50.0 mg; and
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab, wherein the C2D1 is equal to or greater than the C1 D3 and is between 0.2 mg to 50 mg.
• mosunetuzumab for use or use of any one of embodiments 2-8 and 10-14, wherein the mosunetuzumab is to be administered to the subject according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg, the C1 D2 is between 0.05 mg to 20.0 mg, and the C1 D3 is between 0.2 mg to 50.0 mg; and
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab, wherein the C2D1 is equal to or greater than the C1 D3 and is between 0.2 mg to 50 mg.
• the C1 D1 is between 0.4 mg to 4.0 mg, the C1 D2 is between 1 .0 mg to 20.0 mg, and the C1 D3 is between 3.0 mg to 50.0 mg;
• the C2D1 is between 3.0 mg to 50.0 mg.
• the C1 D1 is between 0.8 mg to 3.0 mg
• the C1 D2 is between 1 .0 mg to 6.0 mg
• the C1 D3 is between 3.0 mg to 45.0 mg
• the C2D1 is between 3.0 mg to 45.0 mg. 18.
• the C1 D1 is 1 .0 mg
• the C1 D2 is 1 .0 mg
• the C1 D3 is 3.0 mg
• the C2D1 is 30.0 mg
• the C1 D1 is 1 .0 mg, the C1 D2 is 2.0 mg, and the C1 D3 is 30.0 mg, and the C2D1 is 30.0 mg.
• each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab.
• each additional dose of mosunetuzumab is to be administered on Day 1 of each of the one or more additional dosing cycles.
• 34. The method of any one of embodiments 1 -13, wherein administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising twelve dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg, the C1 D2 is between 0.05 mg to 20.0 mg, and the C1 D3 is between 0.2 mg to 50.0 mg; and
• the second to twelfth dosing cycles each comprises a single dose (C2D1 -C12D1 ) of mosunetuzumab, wherein each single dose C2D1 -C12D1 are equivalent in amount, is equal to or greater than the C1 D3, and is between 0.2 mg to 50 mg.
• mosunetuzumab for use or use of any one of embodiments 1 -13, wherein the mosunetuzumab is to be administered to the subject according to a dosing regimen comprising twelve dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab, wherein the C1 D1 and the C1 D2 are each no greater than the C1 D3, and wherein the C1 D1 is between 0.02 mg to 4.0 mg, the C1 D2 is between 0.05 mg to 20.0 mg, and the C1 D3 is between 0.2 mg to 50.0 mg; and
• the second to twelfth dosing cycles each comprises a single dose (C2D1 -C12D1 ) of mosunetuzumab, wherein each single dose C2D1 -C12D1 are equivalent in amount, is equal to or greater than the C1 D3, and is between 0.2 mg to 50 mg.
• the C1 D1 is between 0.4 mg to 4.0 mg, the C1 D2 is between 1 .0 mg to 20.0 mg, and the C1 D3 is between 3.0 mg to 50.0 mg;
• each single dose C2D1 -C12D1 is between 3.0 mg to 50.0 mg.
• the C1 D1 is between 0.8 mg to 3.0 mg
• the C1 D2 is between 1 .0 mg to 6.0 mg
• the C1 D3 is between 3.0 mg to 45.0 mg
• each single dose C2D1 -C12D1 is between 3.0 mg to 45.0 mg.
• the C1 D1 is 1 .0 mg, the C1 D2 is 1 .0 mg, and the C1 D3 is 3.0 mg, and each single dose C2D1 -C12D1 is 30.0 mg; or (c) the C1 D1 is 1 .0 mg, the C1 D2 is 2.0 mg, and the C1 D3 is 30.0 mg, and each single dose C2D1 -C12D1 is 30.0 mg.
• mosunetuzumab for use or use of any of the preceding embodiments, wherein mosunetuzumab is to be administered intravenously.
• mosunetuzumab for use or use of any one of embodiments 14-53, wherein lenalidomide is to be administered daily.
• mosunetuzumab for use or use of any one of embodiments 47-55, wherein lenalidomide is to be administered daily on the first 14 days of each dosing cycle comprising administration of lenalidomide.
• mosunetuzumab for use or use of any one of embodiments 56-59, wherein lenalidomide is not to be administered on the last 7 days of each dosing cycle comprising administration of lenalidomide.
• mosunetuzumab for use or use of any one of embodiments 14-61 , wherein lenalidomide is to be administered at a dose of 20 mg.
• a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab intravenously administered on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises orally administering 20 mg lenalidomide daily on Days 1 -21 of the second dosing cycle.
• Mosunetuzumab for use in combination with lenalidomide for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab in combination with lenalidomide for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg
• C2D1 is 30 mg
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab intravenously administered on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises orally administering 20 mg lenalidomide daily on Days 1 -21 of each dosing cycle.
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab intravenously administered on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises orally administering 20 mg lenalidomide daily on Days 1 -14 of the second dosing cycle.
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• mosunetuzumab Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab intravenously administered on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises orally administering
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:
• mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody.
• mosunetuzumab for use or use of any one of embodiments 93-95, wherein mosunetuzumab and lenalidomide are not to be administered to the subject for at least 4 weeks after the subject has received treatment with an anti-CD20 monoclonal antibody.
• a method of treating a population of subjects comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab intravenously administered on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises orally administering 20 mg lenalidomide daily on Days 1 -21 of the second dosing cycle.
• Mosunetuzumab for use in combination with lenalidomide for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab in combination with lenalidomide for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 28-day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg
• C2D1 is 30 mg
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of the second dosing cycle.
• a method of treating a population of subjects comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprises a single dose (C2D1 -C12D1 ) of mosunetuzumab intravenously administered on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises orally administering 20 mg lenalidomide daily on Days 1 -21 of each dosing cycle.
• Mosunetuzumab for use in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and (c) the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 28-day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -21 of each dosing cycle.
• a method of treating a population of subjects comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab intravenously administered on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and (c) the second dosing cycle further comprises orally administering 20 mg lenalidomide daily on Days 1 -14 of the second dosing cycle.
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• mosunetuzumab in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• mosunetuzumab Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21 -day dosing cycle and a second 21 -day dosing cycle, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second dosing cycle comprises a single dose (C2D1 ) of mosunetuzumab to be administered intravenously on Day 1 of the second dosing cycle, wherein the C2D1 is 30 mg, and
• the second dosing cycle further comprises daily doses of 20 mg lenalidomide to be administered orally on Days 1 -14 of the second dosing cycle.
• a method of treating a population of subjects comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein each subject:
• administering the effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab intravenously administered on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprises a single dose (C2D1 -C12D1 ) of mosunetuzumab intravenously administered on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises orally administering 20 mg lenalidomide daily on Days 1 -14 of each dosing cycle.
• Mosunetuzumab for use in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein: (a) the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and (c) the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a population of subjects, wherein each subject in the population:
• mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising a first 21 -day dosing cycle and eleven subsequent 21 -day dosing cycles, wherein:
• the first dosing cycle comprises a first dose (C1 D1 ), a second dose (C1 D2), and a third dose (C1 D3) of mosunetuzumab to be administered intravenously on Days 1 , 8, and 15, respectively, of the first dosing cycle, wherein the C1 D1 is 1 mg, the C1 D2 is 2 mg, and the C1 D3 is 30 mg,
• the second to twelfth dosing cycles each comprise a single dose (C2D1 -C12D1 ) of mosunetuzumab to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1 -C12D1 is 30 mg, and
• the second to twelfth dosing cycles each further comprises daily doses of 20 mg lenalidomide to be administered on Days 1 -14 of each dosing cycle.
• chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody.
• FLIPI Follicular Lymphoma International Prognostic Index
• (c) has disease progression within 24 months after initiation of prior therapy.
• mosunetuzumab for use or use of any one of embodiments 102-129, wherein mosunetuzumab and lenalidomide are not to be administered to each subject for at least 4 weeks after said subject has received treatment with an anti-CD20 monoclonal antibody.
• ASTCT CRS grading The method, mosunetuzumab for use, or use of embodiment 137, wherein the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome ("ASTCT CRS grading") is less than 35%.
• ASTCT CRS grading The method, mosunetuzumab for use, or use of embodiment 138, wherein the incidence rate of cytokine release syndrome as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome ("ASTCT CRS grading") is less than 25%.
• ASTCT CRS grading The method, mosunetuzumab for use, or use of any one of embodiments 102-139, wherein the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome ("ASTCT CRS grading") is less than 10%.
• cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome ("ASTCT CRS grading") is less than 5%.
• ASTCT American Society of Transplantation and Cellular Therapy
• ASTCT CRS grading The method, mosunetuzumab for use, or use of embodiment 141 , wherein the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome ("ASTCT CRS grading") is less than 3%.
• telomere length a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome (ASTCT CRS grading) is less than 1 %.
• ASTCT CRS grading the incidence rate of cytokine release syndrome having a grade of 3 or higher as defined by the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine-Release Syndrome
• mosunetuzumab for use or use of any one of embodiments 1 -101 , wherein the subject exhibits a reduction in tumor burden after being treated with mosunetuzumab and lenalidomide.
• CT computed tomography
• mosunetuzumab for use, or use of embodiment 165 wherein at least 75% of subjects in the population exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.
• CT computed tomography
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered or is to be administered to the subject before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each single dose C1 D1 -C1 D3 of the corticosteroid is administered or is to be administered to the subjects before administration of the C1 D1 -C1 D3, respectively, of mosunetuzumab.
• each additional dosing cycle comprises administration of an additional dose of the corticosteroid.
• each additional dose of the corticosteroid is administered or is to be administered to the subject before administration of each additional dose of mosunetuzumab.

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