WO2018229222A1 - Dosage regimes for the administration of an anti-cd19 adc - Google Patents

Dosage regimes for the administration of an anti-cd19 adc Download PDF

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Publication number
WO2018229222A1
WO2018229222A1 PCT/EP2018/065873 EP2018065873W WO2018229222A1 WO 2018229222 A1 WO2018229222 A1 WO 2018229222A1 EP 2018065873 W EP2018065873 W EP 2018065873W WO 2018229222 A1 WO2018229222 A1 WO 2018229222A1
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WIPO (PCT)
Prior art keywords
adc
dose
administered
treatment
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2018/065873
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English (en)
French (fr)
Inventor
Jay Marshall Feingold
David Rodney UNGAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ADC Therapeutics SA
MedImmune Ltd
Original Assignee
ADC Therapeutics SA
MedImmune Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1709440.0A external-priority patent/GB201709440D0/en
Priority claimed from GBGB1709444.2A external-priority patent/GB201709444D0/en
Priority claimed from GBGB1710494.4A external-priority patent/GB201710494D0/en
Priority claimed from GBGB1710495.1A external-priority patent/GB201710495D0/en
Priority claimed from GBGB1720543.6A external-priority patent/GB201720543D0/en
Priority claimed from GBGB1720542.8A external-priority patent/GB201720542D0/en
Priority claimed from GBGB1802679.9A external-priority patent/GB201802679D0/en
Priority claimed from GBGB1808473.1A external-priority patent/GB201808473D0/en
Priority to JP2019569479A priority Critical patent/JP7145891B2/ja
Priority to PL18732041.1T priority patent/PL3638373T3/pl
Priority to UAA202100090A priority patent/UA127900C2/uk
Priority to EP18732041.1A priority patent/EP3638373B1/en
Priority to AU2018285562A priority patent/AU2018285562B2/en
Priority to BR112019026564-3A priority patent/BR112019026564A2/pt
Priority to US16/622,649 priority patent/US11318211B2/en
Priority to CA3064804A priority patent/CA3064804A1/en
Priority to ES18732041T priority patent/ES2988683T3/es
Priority to NZ759283A priority patent/NZ759283B2/en
Priority to KR1020197037482A priority patent/KR102442736B1/ko
Priority to MX2019015042A priority patent/MX2019015042A/es
Priority to EA202190041A priority patent/EA202190041A1/ru
Application filed by ADC Therapeutics SA, MedImmune Ltd filed Critical ADC Therapeutics SA
Publication of WO2018229222A1 publication Critical patent/WO2018229222A1/en
Priority to ZA2019/07613A priority patent/ZA201907613B/en
Anticipated expiration legal-status Critical
Priority to US17/699,065 priority patent/US11938192B2/en
Priority to JP2022148738A priority patent/JP2022191244A/ja
Priority to US17/938,193 priority patent/US20230106885A1/en
Priority to JP2024195841A priority patent/JP2025024041A/ja
Ceased legal-status Critical Current

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
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    • 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
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07K16/2827—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 B7 molecules, e.g. CD80, CD86
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Definitions

  • CD19 is an important regulator of transmembrane signals in B cells.
  • An increase or decrease in the cell surface density of CD19 affects B cell development and function, resulting in diseases such as autoimmunity or hypogammaglobulinemia.
  • the CD19 complex potentiates the response of B cells to antigen in vivo through cross-linking of two separate signal transduction complexes found on B cell membranes.
  • the two signal transduction complexes, associated with membrane IgM and CD19 activate phospholipase C (PLC) by different mechanisms.
  • PLC phospholipase C
  • CD19 ADC is not rapidly cleared from the bloodstream, with trough levels at the end of each 3-week treatment cycle maintained at a relatively high level, or even gradually increasing with each treatment cycle.
  • the dose is reduced following the first treatment cycle. That is, the starting dose is administered in the first treatment cycle and the reduced dose is administered in the second and subsequent treatment cycles.
  • Dosing regime Taper 6' in Table 1 is an example of such a dosing regime.
  • the dose Is reduced following the second treatment cycle That is, the starting dose is administered in each of the first and second treatment cycles and the reduced dose is administered in each of the third and subsequent treatment cycles.
  • Dosing regime Taper 3', Taper 4, Taper 5', and Taper T in Table 1 are examples of such a dosing regime.
  • the starting dose is reduced no more than once and the treatment cycle length is increased no more than once during the treatment of a subject.
  • the subject may have, may be suspected or having, or may have been diagnosed with a leukaemia such as Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • a leukaemia such as Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • the subject may have, or have been determined to have Relapsed or Refractory B-cell Lineage Non-Hodgkin Lymphoma (B-NHL).
  • B-NHL B-cell Lineage Non-Hodgkin Lymphoma
  • the present disclosure provides a method of reducing the toxicity and/or side effects associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a tapered and/or elongated dosage regime as defined herein.
  • the present disclosure provides a packaged pharmaceutical product comprising a CD19-ADC as described herein in combination with a label or insert advising that the CD19-ADC should be administered in a tapered and/or elongated dosage regime.
  • the disclosure also provides a kit comprising:
  • the present authors sought an altered dosage regime to improve the efficacy of CD19-ADC treatment.
  • Data collected from a number of different mouse xenograft models of CD19+ proliferative disease indicated that administration of CD19-ADC as a single dose on day 1 of the treatment cycle led to effective treatment, with administration of an identical total dose of AD19-ADC as a series of smaller partial doses resulting in higher mortality levels (see Figures 2 and 3).
  • fractionated dosage regimes are potentially especially advantageous in diseases such as acute leukaemia, where the rapid production of circulating myeloblasts acts as an antigenic sink for the CD19-ADC.
  • This is consistent with the exploration or adoption of fractionated dosage regimes in some other treatments of subjects with leukaemia (Frey F, et al. Abstract 7002. Presented at: AS CO Annual Meeting; June 3-7, 2016; Chicago; Aue G, et al. Haematologica February 2010 95: 329-332; Taksin A, et al. Leukemias (2007) 21 , 66-71. Published online 19 October 2006).
  • the CD19-ADC may be ADCx19 as described herein.
  • fractionated dosage regime is used herein to describe a dosage regime in which the total dose of CD19-ADC administered during the treatment cycle is administered in a series of two or more partial doses during the treatment cycle.
  • 'partial dose' is used herein to denote a dose of ADC that is a fraction of the total dose of ADC to be administered in the treatment cycle. The sum of all partial doses delivered in a treatment cycle equals the total dose.
  • a fractionated dosage regime contrasts with a 'single-dose' dosing regime in which the total dose of CD19-ADC administered in the treatment cycle is administered as a single dose at the start of the treatment cycle.
  • the subject may be human.
  • the subject may have cancer, or may have been determined to have cancer.
  • the subject may have, or have been determined to have, a CD19+ cancer or CD19+ tumour-associated non-tumour cells, such as CD19+ infiltrating cells.
  • the subject has been diagnosed as having the proliferative disease prior to the start of treatment with the CD19-ADC.
  • fractional dosage regime reduces the treatment toxicity or side-effects as compared to a single dose per treatment cycle regime.
  • the fractional dosage regime increases the treatment efficacy as compared to a single dose per treatment cycle regime.
  • the CD19-ADC Is administered intravenously.
  • the present disclosure provides a method of reducing the toxicity and/or side effects associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a fractionated dosage regime as defined herein.
  • the present disclosure provides a CD19ADC as defined herein for use in a method of treatment as described herein.
  • CD19-ADC refers to an ADC in which the antibody component is an anti-CD19 antibody.
  • PBD-ADC refers to an ADC in which the drug component is a pyrrolobenzodiazepine (PBD) warhead.
  • anti-CD 19-ADC refers to an ADC in which the antibody component is an anti-CD19 antibody, and the drug component is a PBD warhead.
  • R 6' , R 7' , R 9' are selected from the same groups as R 6 , R 7 and R 9 respectively;
  • R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • R 21 is selected from OH, OR A and SO z M;
  • Q is selected from 0-R L2 , S-R L2' and NR N -R L2' , and R N is selected from H, methyl and ethyl
  • DC may have the chemical structure:
  • the Ab is a CD19 antibody
  • the DAR is between 1 and 8.
  • the antibody is a fully human monoclonal lgG1 antibody, preferably IgGI . K.
  • tapered dosage regime is used herein to describe a dosage regime in which the total dose of CD19-ADC administered in the first treatment cycle (from hereon in termed the "starting dose") is greater than the total dose of CD19-ADC administered in one or more subsequent treatment cycle.
  • starting dose the total dose of CD19-ADC administered in the first treatment cycle
  • a tapered dosage regime contrasts with a constant dosing regime in which the starting dose is the same as the total dose administered in each subsequent treatment cycle (see 'Constant' in Table 1 , below).
  • each dose reduction reduces the administered dose by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least 95%. In some cases, each dose reduction reduces the administered dose by about 50%.
  • the reduced dose is 60 pg/kg.
  • elongated dosage regime is used herein to describe a dosage regime in which the length of the first treatment cycle (from hereon in termed the "starting length") is shorter than the length of one or more subsequent treatment cycle.
  • An elongated dosage regime contrasts with a constant dosing regime in which the starting length is the same the length of each subsequent treatment cycle (see 'Constant' in Table 2, below).
  • the starting dose is about 120, 150, or 200 pg/kg. . In some cases the starting dose is about 140 to 160 pg/kg. In some cases the starting dose is about 150 pg/kg. In some cases the reduced dose is about 60 pg/kg. In some cases the reduced dose is about 70 to 80 pg/kg. In some cases the reduced dose is about 75 pg/kg. In some cases the starting length is 3 weeks and the increased length is 6 weeks. In some cases the starting dose and starting length are respectively about 120 pg/kg and three weeks and the reduced dose and increased length are respectively about 60 pg/kg and six weeks. In some cases the starting dose and starting length are respectively about 150 pg/kg and three weeks and the reduced dose and increased length are respectively about 60 pg/kg and six weeks.
  • fractionated dosage regime is used herein to describe a dosage regime in which the total dose of CD19-ADC administered during the treatment cycle is administered in a series of two or more partial doses during the treatment cycle.
  • 'partial dose' is used herein to denote a dose of ADC that is a fraction of the total dose of ADC to be administered in the treatment cycle. The sum of all partial doses delivered in a treatment cycle equals the total dose.
  • a fractionated dosage regime contrasts with a 'single-dose' dosing regime in which the total dose of CD19-ADC administered in the treatment cycle is administered as a single dose at the start of the treatment cycle.
  • the amount of CD19-ADC administered in each partial dose may be the same or different. So, for example, a total dose of 100 units of ADC delivered in 3 partial doses may be delivered as (1 x 50 units, 1 x 30 units, and 1 x 20 units) or (3 x 33 1/3 units). Preferably all of the partial doses contain the same amount of CD19-ADC i.e. all of the partial doses are of equal size.
  • the time interval between one partial dose and the next partial dose may be the same as, or different to, the time interval between the one partial dose and the preceding partial dose. Preferably, the time interval between one partial dose and the next partial dose is the same as the time interval between the one partial dose and the preceding partial dose. That is, preferably the administration of the partial doses is regularly spaced throughout the treatment cycle. An example of such regular administration is the administration of 3 partial doses on days 1 , 8, and 15 of a 3-week (i.e. 21 day) treatment cycle.
  • the length of the treatment cycle may vary depending upon the pharmokinetics (PK) of the CD19-ADC and the clinical requirements of the subject.
  • the treatment cycle may be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.
  • the treatment cycle is 3 weeks or 6 weeks, with 3 weeks being particularly preferred.
  • the present disclosure provides a method of therapy comprising administering an ADC which binds CD19 for use in therapy, wherein the method comprises selecting a subject based on expression of CD19.
  • the label may specify that the ADC is administered in a fractionated dosage regime as described herein.
  • the label may specify that the subject has a particular type of cancer, such as leukaemia, optionally wherein the B-ALL is Relapsed or Refractory.
  • leukaemia include Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • B-cell Lineage Acute Lymphoblastic Leukemias B-ALL).
  • the proliferative disease treated by the methods disclosed herein may be CD19+.
  • the antigen in at least some of the cells in the target location (typically a neoplasm) the antigen may be absent, or present on the cell surface at an insignificant level.
  • the target neoplasm only e.g. less than 80, 70, 60, 50, 30, 20%, 10% or 5%of the cells may be CD19 positive.
  • CD19+ may be defined as determination of CD19 expression by >5% of leukemic myeloblast cells within bone marrow (aspirate or biopsy), as assessed at an approved clinical laboratory.
  • the neoplasm or neoplastic cells are malignant. In some cases the neoplasm or neoplastic cells are metastatic.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • gastrointestinal including, e.g. bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin.
  • the level of toxicity is measured as the incidence of Treatment Emergent Adverse Events (TEAE) occurring after one treatment cycle at a given total dose of CD19- ADC.
  • a treatment-emergent AE (TEAE) is defined as any event not present before exposure to the CD19-ADC or any event already present that worsens in either intensity or frequency after exposure to the CD19-ADC.
  • the incidence of AE with the tapered and/or elongated dosage regime may be no more that 95%, such as no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the incidence of AE in the corresponding constant dose level and cycle length regime.
  • Adverse events will be graded according to CTCAE Version 4.0 (v4.03, published June 14, 2010; NIH Publication No. 09-5410).
  • the incidence of DLTs with the tapered and/or elongated regime is 50% of the incidence of DLT in the corresponding constant dose level and cycle length regime.
  • Assessment of response to treatment with ADC may be based on bone marrow samples (aspirate or biopsy if aspirate unattainable) taken toward the end of each treatment cycle. For example, on day 19 ⁇ 3 days in a 21-day treatment cycle.
  • the subject's response to ADC may be categorised as CR, PR, SD, or PD according to the 2014 Lugano Classification Criteria (using the New "Cheson” Criteria), in which: • Complete response (CR) is defined as achieving each of the following: o Nodal Disease ⁇ 1.5 cm in LDi
  • Stable Disease is defined as achieving each of the following:
  • the reduction in toxicity is measured relative to a single-dose dosage regime having the same total dose administered and length of treatment cycle.
  • the total dose of CD19-ADC is administered as a single dose at the start of the treatment cycle.
  • the present disclosure also provides a method of increasing the treatment efficacy associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a fractionated dosage regime as defined herein.
  • o ANC 1.0 x 109/L and platelet count >100 x 109/L
  • subjects are selected for treatment with the fractionated dosage regimes described if they have, are suspected of having, or have been diagnosed with leukaemia
  • the leukaemia may be Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome- positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • HCL Hairy cell leukaemia
  • HCL-v Hairy cell leukaemia variant
  • ALL Acute Lymphoblastic Leukaemia
  • Ph+ALL Philadelphia chromosome-positive ALL
  • Ph-ALL Philadelphia chromosome-negative ALL
  • the level of CD19 expression is used to select a subject as suitable for treatment. Where the level of expression of CD19 is above a threshold level, the subject is determined to be suitable for treatment.
  • a patient is determined to be suitable for if they have increased sensitivity to ADC-induced toxicity.
  • a patient is determined to be suitable for treatment if their disease is relapsed or refractory.
  • the neurologic disorder may be polyradiculopathy (including acute inflammatory demyelinating polyradiculoneuropathy (AIDP)), Guillain-Barre syndrome (GBS), myasthenia gravis, or neurologic disorder that is linked to or is an early indicator of polyradiculitis, GBS, or myasthenia gravis (e.g. ascending (bilateral) sensory loss and/or motor weakness).
  • polyradiculopathy including acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
  • GBS Guillain-Barre syndrome
  • myasthenia gravis e.g. ascending (bilateral) sensory loss and/or motor weakness
  • a subject experiences a > grade 2 neurologic toxicity (e.g. grade 2 polyradiculitis or GBS)
  • treatment with the ADC is permanently discontinued.
  • a selected cell-containing fraction may contain cell types of interest which may include white blood cells (WBC), particularly peripheral blood mononuclear cells (PBC) and/or granulocytes, and/or red blood cells (RBC).
  • WBC white blood cells
  • PBC peripheral blood mononuclear cells
  • RBC red blood cells
  • methods according to the present disclosure may involve detection of a CD19 polypeptide or nucleic acid in the blood, in white blood cells, peripheral blood mononuclear cells, granulocytes and/or red blood cells.
  • the subject may have, be suspected of having, been identified as being at risk of, or received a diagnosis of leukaemia, such as Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • HCL Hairy cell leukaemia
  • HCL-v Hairy cell leukaemia variant
  • ALL Acute Lymphoblastic Leukaemia
  • Such subjects are preferably treated with a fractionated dosage regime as disclosed herein.
  • the Subject may be undergoing, or have undergone, a therapeutic treatment for that cancer.
  • the subject may, or may not, have previously received ADCx19.
  • the cancer is leukemia or lymphoma, including non-Hodgkin's lymphoma.
  • CD19 expression in the subject is compared to target expression in a control.
  • Controls are useful to support the validity of staining, and to identify experimental artefacts.
  • control may be a reference sample or reference dataset.
  • the reference may be a sample that has been previously obtained from a subject with a known degree of suitability.
  • the reference may be a dataset obtained from analyzing a reference sample.
  • the CD19-ADC and Ibrutinib are administered sequentially.
  • administration of Ibrutinib begins after the completion of CD19-ADC treatment.
  • CD19-ADC In cases where the subject achieves CR following initial treatment with the CD19-ADC and Ibrutinib combination, typically no further CD19-ADC is administered to the subject. In these cases, Ibrutinib administration typically continues for up to 1 year after the completion of CD19-ADC treatment.
  • further CD19-ADC may be administered to the subject.
  • Ibrutinib administration typically continues after the initial treatment with the CD19- ADC and Ibrutinib combination. If the subject has not achieved CR within 3 months after the completion of initial CD19-ADC treatment, further CD19-ADC may be administered to the subject.
  • CD19-ADC in combination with Durvalumab is contemplated, particularly in embodiments where the proliferative disorder is lymphoma.
  • the starting dose is about 90 pg/kg, about 120 pg/kg, or about 150 pg/kg. In some embodiments when administered in combination with Durvalumab, the starting dose of CD19-ADC may be about 140 to 160 pg/kg.
  • the administration of Durvalumab is discontinued on the completion of CD19- ADC treatment. However, typically administration of Durvalumab continues after the completion of CD19-ADC treatment. In some cases, Durvalumab administration continues for up to 1 year after the completion of CD19-ADC treatment.
  • the Durvalumab When administered after the completion of CD19-ADC treatment, the Durvalumab is preferably administered in a Q4W dosage regime. In some embodiments the dose of Durvalumab administered is about 1400 to 1600 mg. The dose of Durvalumab administered is preferably 1500 mg.
  • further CD19-ADC may be administered to the subject.
  • Durvalumab administration typically continues after the initial treatment with the CD19-ADC and Durvalumab combination. If the subject has not achieved CR within 3 months after the completion of initial CD19-ADC treatment, further CD19-ADC may be administered to the subject.
  • CD19-ADC in combination with Cytarabine and Rituximab is contemplated, particularly in embodiments where the proliferative disorder is lymphoma.
  • human G1 m1 , G1 m2, G1 m3, non- G1 m1 [that, is any allotype other than G1 m1], G1 m17, G2m23, G3m21 , G3m28, G3m1 1 , G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1 , A2m2, Km1 , Km2 and Km3) of immunoglobulin molecule.
  • the immunoglobulins can be derived from any species, including human, murine, or rabbit origin.
  • the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816567; and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855).
  • Chimeric antibodies include "primatized” antibodies comprising variable domain antigen-binding sequences derived from a non- human primate (e.g. Old World Monkey or Ape) and human constant region sequences.
  • the dosage regime comprises dosing about 120 pg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 60 pg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration.
  • a reduced dose of about 60 pg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration.
  • the dosage regime comprises dosing about 150 pg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 60 pg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration.
  • a reduced dose of about 60 pg/kg every 6 weeks, beginning 6 weeks after cycle 2 administration.
  • the starting dose of CD19-ADC is about 90 g/kg, about 120 pg/kg, or about 150 pg/kg.
  • the Durvalumab is preferably administered concurrently with the CD19-ADC in a Q3W regime.
  • the dose of Durvalumab is preferably about 1500 mg.
  • the administration of Durvalumab continues after the completion of CD19-ADC treatment.
  • the Durvalumab is preferably administered in a Q4W dosage regime.
  • the dose of Durvalumab administered is preferably about 1500 mg.
  • the administration of Durvalumab continues after the completion of CD19-ADC treatment. If the subject has not achieved CR within 3 months after the completion of initial CD19-ADC treatment, preferably further CD19-ADC is administered to the subject.
  • the CD19-ADC is preferably administered in a dosing regime comprising dosing about 150 pg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 75 pg/kg every 3 weeks, beginning 3 weeks after cycle 2 administration.
  • the Rituximab is preferably administered concurrently with the CD19-ADC in a Q3W regime; for example, both on day 1 of each treatment cycle.
  • the dose of Rituximab is about 325 to 425 mg/m 2 .
  • the dose of Rituximab is preferably about 375 mg/m 2 .
  • the CD19-ADC is administered in combination with Cytarabine
  • the CD19-ADC is administered in a dosing regime comprising dosing about 140 to 160 pg/kg every 3 weeks for 2 cycles, then continuing treatment with the third and subsequent cycles at a reduced dose of about 7o to 80 pg/kg every 3 weeks, beginning 3 weeks after cycle 2 administration.
  • the Rituximab is preferably administered concurrently with the CD19-ADC in a Q3W regime.
  • the dose of Rituximab is about 325 to 425 mg/m 2 .
  • the dose of Rituximab is preferably about 375 mg/m 2 .
  • the Rituximab is administered on day 1 of each Q3W treatment cycle.
  • the cytarabine is preferably administered concurrently with the CD19-ADC in a Q3W regime.
  • the cytarabine is administered as 5 equal, partial doses spread one partial dose per day on days 1 to 5 of each cycle.
  • the partial dose level may be about 100 mg/m 2 , about 200 mg/m 2 , about 300 mg/m 2 , or about 400 mg/m 2 per partial dose.
  • each partial dose is 40 to 60 pg/kg, such as 45 to 55 pg/kg. In particularly preferred cases each partial dose is 50 pg/kg.
  • the proliferative disease is a leukaemia, such as Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • HCL Hairy cell leukaemia
  • HCL-v Hairy cell leukaemia variant
  • ALL Acute Lymphoblastic Leukaemia
  • the use of this type of fractionated dosage regime to treat haematological cancers such as ALL are embodiments of particular interest.
  • the ALL is CD19+, and may be relapsed or refractory types.
  • a method of treating a proliferative disease in a subject comprising administering to a subject a CD19-ADC, wherein the CD19-ADC comprises a conjugate of f rmula L - (D L ) P , where D L is of formula I or II:
  • R 12 is selected from the group consisting of:
  • Y and Y' are selected from O, S, or NH;
  • R 6' , R 7 , R 9' are selected from the same groups as R 6 , R 7 and R 9 respectively;
  • R 11a is selected from OH, OR A , where R A is CM alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
  • R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • CD19-ADC optionally wherein about 150 pg/kg of CD19-ADC are administered for two, 3-week treatment cycles
  • CD19- ADC is about 90 pg/kg, about 120 pg/kg, about 140 to 160 pg/kg, or about 150 pg/kg.
  • a non-Hodgkin's Lymphoma such as diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), or Mantle Cell lymphoma (MCL).
  • DLBCL diffuse large B-cell lymphoma
  • FL Follicular Lymphoma
  • MCL Mantle Cell lymphoma
  • the dose of Rituximab administered is 375 mg/m 2 .
  • the dose of CD19- ADC is about 90 pg/kg, about 120 pg/kg, about 140 to 160 pg/kg, or about 150 pg/kg.
  • the tapered and/or elongated dosage regime has greater efficacy than a dosage regime having constant dosage level and cycle length, optionally wherein the constant dose level and cycle length of the comparator regime is the same as the starting dose and starting length of the tapered and/or elongated regime.
  • neurologic disorder or neurological toxicity is polyradiculopathy, acute inflammatory demyelinating (AIDP), Guillain-Barre syndrome (GBS), myasthenia gravis, or a neurologic disorder that is linked to or is an early indicator of polyradiculitis, GBS, or myasthenia gravis, such as ascending sensory loss and/or motor weakness.
  • AIDP acute inflammatory demyelinating
  • GBS Guillain-Barre syndrome
  • myasthenia gravis or a neurologic disorder that is linked to or is an early indicator of polyradiculitis, GBS, or myasthenia gravis, such as ascending sensory loss and/or motor weakness.
  • a method of increasing the treatment efficacy associated with administration of a CD19-ADC to a subject comprising administering the CD19-ADC according to the method of any preceding statement.
  • tissue of interest is lymphoid tissue or tumour tissue.
  • a packaged pharmaceutical product comprising a CD19-ADC as defined in any one of statements 1 to 5, in combination with a label or insert advising that the CD19-ADC should be administered according to the method of any one of statements 1 to 92.
  • a kit comprising:
  • a first medicament comprising a CD19-ADC as defined in any one of statements 1 to 6; and, optionally,
  • a package insert or label comprising instructions for administration of the CD19-ADC according to the method of any one of statements 1 to 136.
  • a method of treating a proliferative disease in a subject comprising administering to a subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a fractionated dosage regime, and;
  • CD19-ADC comprises a conjugate of formula L - (D L ) P , where D L is of formula I or II:
  • R 12 is selected from the group consisting of:
  • R 21 , R 22 and R 23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
  • R 25a and R 25b are H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
  • R 24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
  • R 12 is , where R 26a and R 26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C1-4 alkyl ester;
  • R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR', nitro, Me 3 Sn and halo;
  • Y and Y' are selected from O, S, or NH;
  • R 6 , R 7' , R 9' are selected from the same groups as R 6 , R 7 and R 9 respectively;
  • R 1 1' is a linker for connection to the antibody (Ab);
  • R 11a is selected from OH, OR A , where R A is C1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
  • R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • R 20 is selected from H and R c , where R c is a capping group
  • R 21 is selected from OH, OR A and SO z M;
  • each of R 11 , R 12 and R 13 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
  • R 14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
  • R 22 is of formula Ilia, formula lllb or formula lllc:
  • A is a C5-7 aryl group
  • R C1 , R C2 and R C3 are independently selected from H and unsubstituted C1-2 alkyl;
  • Q is selected from 0-R L2' , S-R L2' and NR N -R L2' , and R N is selected from H, methyl and ethyl
  • X is selected from the group
  • R' 2' is a linker for connection to the antibody (Ab);
  • R 10 and R 1 1 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • R 10 is H and R 11 is selected from OH, OR A and SO z M;
  • R 30 is H and R 31 is selected from OH, OR A and SO z M.
  • the Ab is a CD19 antibody
  • the DAR is between 1 and 8.
  • Ab comprises a heavy chain having sequences of SEQ ID NO. 13 and a light chain having the sequences of SEQ ID NO. 14.
  • the method according to any preceding statement wherein the partial dose is 81 to pg/kg. .
  • the method according to any preceding statement wherein the partial dose is 91 to0 pg/kg. .
  • the method according to any preceding statement wherein the partial dose is 101 to0 pg/kg. 0.
  • the method according to any preceding statement wherein the partial dose is 1 1 1 to0 pg/kg. 1.
  • the method according to any preceding statement wherein the partial dose is 121 to0 pg/kg. 2.
  • the method according to any preceding statement wherein the partial dose is 131 to0 pg/kg. 3.
  • the method according to any preceding statement wherein the partial dose is 141 to0 pg/kg. 4.
  • the proliferative disease is non-Hodgkin's Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Waldenstroms Microglobulinemia, Burkitt's lymphoma, and Marginal Zone B-cell lymphoma (MZBL), and leukemias such as Hairy cell leukaemia (HCL), Hairy cell leukaemia variant (HCL-v), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome- positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MCL Mantle Cell lymphoma
  • CLL chronic lymphatic lymphoma
  • MZBL Marginal Zone B-cell lymphoma
  • leukemias such
  • each partial dose is 8 mg.
  • a method of reducing the toxicity and/or side effects associated with administration of a CD19-ADC to a subject comprising administering the CD19-ADC according to the method of any preceding statement.
  • a method of increasing the treatment efficacy associated with administration of a CD19-ADC to a subject comprising administering the CD19-ADC according to the method of any preceding statement.
  • a method of selecting a subject for treatment by a method according to any one of statements 1 to 141 which method comprises selecting for treatment subjects that express CD19 in a tissue of interest.
  • a packaged pharmaceutical product comprising a CD19-ADC as defined in any one of statements 1 to 5, in combination with a label or insert advising that the CD19-ADC should be administered according to the method of any one of statements 1 to 151 .
  • a kit comprising:
  • a first medicament comprising a CD19-ADC as defined in any one of statements 1 to 5; and, optionally,
  • a package insert or label comprising instructions for administration of the CD19-ADC according to the method of any one of statements 1 to 151.
  • a pharmaceutical composition comprising a CD19-ADC as defined in any one of statements 1 to 5, optionally in combination with a pharmaceutically acceptable excipient, for use in a method of any one of statements 1 to 151 .
  • the three initial patients received either 2 or 3 cycles of ADCTx19 before side effects necessitated dose delay which eventually led to removal from the study since the toxicities were slow to resolve.
  • the trough levels at the end of Cycle 1 appear to be in the range of 500-1000 ng/ml.
  • B. 150 pg/kg Dosing every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 pg/kg q6weeks, beginning 6 weeks after Cycle 2 infusion.
  • C. 200 yq/kq Dosing every 6 weeks for 2 cycles. For patients with at least SD 6 weeks after Cycle 2, continue treatment at a reduced dose of 60 pg/kg q6weeks, beginning 6 weeks after Cycle 2 infusion.

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US16/622,649 US11318211B2 (en) 2017-06-14 2018-06-14 Dosage regimes for the administration of an anti-CD19 ADC
PL18732041.1T PL3638373T3 (pl) 2017-06-14 2018-06-14 Schematy dawkowania dla podawania ADC anty-CD19
ES18732041T ES2988683T3 (es) 2017-06-14 2018-06-14 Pautas posológicas para la administración de un CAF anti-CD19
NZ759283A NZ759283B2 (en) 2018-06-14 Dosage regimes for the administration of an anti-cd19 adc
KR1020197037482A KR102442736B1 (ko) 2017-06-14 2018-06-14 항-cd19 adc의 투여를 위한 투약량 체제
CA3064804A CA3064804A1 (en) 2017-06-14 2018-06-14 Dosage regimes for the administration of an anti-cd19 adc
JP2019569479A JP7145891B2 (ja) 2017-06-14 2018-06-14 抗ｃｄ１９ ａｄｃを投与するための投与レジメ
EA202190041A EA202190041A1 (ru) 2018-05-23 2018-06-14 Схемы дозирования для введения adc к cd19
MX2019015042A MX2019015042A (es) 2017-06-14 2018-06-14 Regimen de dosificacion.
UAA202100090A UA127900C2 (uk) 2017-06-14 2018-06-14 Схема дозування для введення adc до cd19
EP18732041.1A EP3638373B1 (en) 2017-06-14 2018-06-14 Dosage regimes for the administration of an anti-cd19 adc
AU2018285562A AU2018285562B2 (en) 2017-06-14 2018-06-14 Dosage regimes for the administration of an anti-CD19 ADC
BR112019026564-3A BR112019026564A2 (pt) 2017-06-14 2018-06-14 regimes de dosagem para a administração de um adc anti-cd19
ZA2019/07613A ZA201907613B (en) 2017-06-14 2019-11-18 Dosage regimes for the administration of an anti-cd19 adc
US17/699,065 US11938192B2 (en) 2017-06-14 2022-03-18 Dosage regimes for the administration of an anti-CD19 ADC
JP2022148738A JP2022191244A (ja) 2017-06-14 2022-09-20 抗ｃｄ１９ ａｄｃを投与するための投与レジメ
US17/938,193 US20230106885A1 (en) 2017-06-14 2022-10-05 Dosage regime
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