RU2802812C2 - Treatment approach designed to treat with a combination of anti-cd19 antibody and venetoclax - Google Patents

Abstract

FIELD: pharmaceuticals and medicine.

SUBSTANCE: 1 object is the use of a combination containing an antibody to CD19 and venetoclax in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukaemia and/or small cell lymphocytic lymphoma, where the specified antibody to CD19 is administered at least 7 days before the first administration of venetoclax. Object 2 - a method for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukaemia and/or small cell lymphocytic lymphoma in a patient, including the introduction of a therapeutically effective amount of the combination.

EFFECT: reducing the risk of developing tumour lysis syndrome (TLS) during combined treatment.

36 cl, 3 dwg, 1 ex

Description

Field of technology to which the invention relates

The present invention provides a therapeutic approach comprising anti-CD19 antibodies and venetoclax for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma. Antibodies to CD19, in particular MOR00208, and venetoclax are administered to patients suffering from non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and/or small lymphocytic lymphoma (SLL) according to a specific treatment approach designed to reduce the effects of therapy associated with tumor lysis syndrome.

State of the art

B cells are lymphocytes that play an essential role in the humoral immune response. They are produced in the bone marrow of most mammals and constitute 5-15% of the circulating lymphocyte pool. The main function of B cells is to produce antibodies to various antigens, and they are an essential element of the adaptive immune system. Because of their critical role in regulating the immune system, B cell dysregulation is associated with a variety of disorders such as lymphomas and leukemia. These include non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SSL).

NHL is a heterogeneous lymphocyte-derived malignancy. In the United States of America (USA), the incidence of the disease is estimated to be approximately 65,000/year, with a mortality rate of approximately 20,000 (according to the American Cancer Society, 2006 and SEER Summary of Cancer Statistics). The disease can occur in all age groups, usually occurring in adults over 40 years of age, with the incidence of the disease increasing with age. NHL is characterized by a clonal proliferation of lymphocytes that accumulate in the lymph nodes, blood, bone marrow, and spleen, although any major organ may be involved. The current classification system used by pathologists and clinicians is the World Health Organization (WHO) tumor classification, which divides NHL into neoplasms of precursor and mature B cells and T cells. For inclusion in clinical trials, the PDQ currently categorizes NHL into indolent or aggressive forms. The group of indolent forms of NHL consists primarily of follicular subtypes, small cell lymphocytic lymphoma, MALT (mucosal lymphoid tissue lymphoma) and marginal zone lymphoma; the indolent form is present in approximately 50% of patients with newly diagnosed B-cell NHL. The aggressive form of NHL includes patients with histologically confirmed diagnoses of primary diffuse large B-cell lymphoma (DLBL, DLBCL or DLCL) (40% of all newly diagnosed patients have diffuse large cells), Burkitt's lymphoma and mantle cell lymphoma.

In addition to NHL, there are several types of leukemia that arise from impaired B cell function.

Chronic lymphocytic leukemia (also known as "chronic lymphoid leukemia" or "CLL") is a type of leukemia in adults caused by an abnormal accumulation of B lymphocytes. In CLL, the malignant lymphocytes may appear normal and mature, but they are unable to effectively fight the infection. CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, age is a key risk factor. Over 75% of new cases of the disease are diagnosed in patients over 50 years of age. More than 10,000 cases are diagnosed annually, and the mortality rate is almost 5,000 per year (according to the American Cancer Society, 2006 and SEER Summary of Cancer Statistics). CLL is an incurable disease but progresses slowly in most cases. Many people with CLL lead normal and active lives for many years. Due to its slow onset in the early stage, CLL is generally not treated, as early intervention for CLL is not thought to prolong survival time or improve quality of life. Instead, the condition is monitored over time. Types of initial treatment for CLL vary depending on the exact diagnosis and progression of the disease. There are dozens of agents used to treat CLL. Combination chemotherapy regimens such as FCR (fludarabine, cyclophosphamide, and rituximab) and BR (ibrutinib and rituximab) are effective for both newly diagnosed CLL and relapsed CLL. Allogeneic bone marrow (stem cell) transplantation is rarely used as first-line therapy for CLL due to the risks associated with it.

Another type of leukemia is small lymphocytic lymphoma (SLL), which is considered a variant of CLL without the clonal lymphocytosis required for the diagnosis of CLL, but otherwise sharing common pathological and immunophenotypic characteristics (Campo et al., 2011). Confirmation of SLL requires the presence of lymphadenopathy and/or splenomegaly. Moreover, the number of B-lymphocytes in the peripheral blood should not exceed 5×10 ⁹ /l. In SLL, the diagnosis should be confirmed by histopathological evaluation of lymph node biopsies, if possible (Hallek et al., 2008). The incidence rate of SLL is approximately 25% of that of CLL in the United States (Dores et al., 2007).

Human CD19 is a structurally distinct cell surface receptor expressed on the surface of human B cells, including but not limited to pre-B cells, early developmental B cells (i.e., immature B cells), mature B cells on the path of terminal differentiation into plasmacytes and malignant B cells. CD19 is expressed by most types of pre-B-cell acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, B-cell chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia, malignant reticuloendotheliosis, common acute lymphocytic leukemia, and some types of acute lymphoblastic leukemia with null cells Nadler et al, J. Immunol., 131: 244-250 (1983), Loken et al, Blood, 70: 1316-1324 (1987), Uckun et al, Blood, 71: 13- 29 (1988), Anderson et al, 1984. Blood, 63:1424-1433 (1984), Scheuermann, Leuk. Lymphoma, 18: 385-397 (1995)). In turn, CD19 expression on plasma cells suggests that it may be expressed on differentiated B cell tumors such as multiple myeloma, plasmacytomas, and Waldenström tumors (Grossbard et al., Br. J. Haematol, 102: 509-15( 1998); Treon et al, Semin. Oncol, 30: 248-52 (2003)).

Therefore, the CD19 antigen is a target for immunotherapy in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma, including each of the subtypes described herein.

MOR00208 (formerly called XmAb5574) is a genetically engineered humanized monoclonal Fc antibody that binds CD19. Increased binding of Fc MOR00208 to FcγR due to genetically engineered XmAb mutations significantly enhances in vitro antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and direct cytotoxic effects (apoptosis) on the tumor compared to unmodified antibody. MOR00208 has not been shown to mediate complement-dependent cytotoxicity. In previous studies, MOR00208 was combined with fludarabine, bendamustine, idelalisib, and venetoclax. Synergistic activity was observed for individual partners in the combination MOR00208 (WO 2013/24097, WO 2013/024095, WO 2017/032679 and WO 2018/078123). Additionally, chimeric antigen receptor (CAR) T cells targeting CD19 and ABT-737 and the BCL-2 inhibitor, navitoclax, are used in combination to treat B-cell malignancies (Karlsson et al, Cancer Gene Therapy, vol. 20, no. 7, 2013-06.21, pages 386-393).

MOR00208 has been and is currently undergoing several clinical trials in CLL, ALL and NHL. An ongoing phase II trial (COSMOS) is examining the efficacy and safety of the combination of MOR00208 with venetoclax in patients with relapsed or refractory CLL, SLL. Venetoclax, also known as GDC-0199, ABT-199 and RG7601, is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with a 17p deletion identified by an FDA-approved test who have completed at least one previous therapy. Venetoclax is described in US Patent Nos. 8,546,399 and 9,174,982, all of which are incorporated by reference in their entirety.

However, treatment with antibodies to CD19, as well as treatment with venetoclax, is not without side effects. Tumor lysis syndrome (TLS) is the most significant risk with venetoclax treatment. TLS and associated laboratory abnormalities were reported in 6% of patients with CLL (N=66) with recommended risk stratification, dosing regimen, and prophylaxis. Also, five patients (4%) developed TLS during treatment with MOR00208. Three had ALL (14%), one had NHL (1%), and one had CLL (4%).

Tumor lysis syndrome (TLS) is a metabolic syndrome that is caused by the rapid killing of tumor cells by tumor cell-killing antitumor cells and the subsequent release of cell contents, releasing large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Catabolism of nucleic acids to uric acid leads to hyperuricemia; A marked increase in uric acid excretion may lead to uric acid precipitation in the renal tubules and renal vasoconstriction, impaired autoregulation, decreased renal blood flow, oxidation and inflammation, leading to acute renal failure. Hyperphosphatemia with precipitation of calcium phosphate in the renal tubules can also cause acute renal failure. High concentrations of both uric acid and phosphate increase the risk of acute renal failure because uric acid precipitates more quickly in the presence of calcium phosphate and vice versa, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, uremia, and acute renal failure. This usually occurs in patients with large, rapidly proliferating, responsive tumors (Jagasia et al., Complications of hematopoietic neoplasms. Wintrobe MM, Greer JP, Foerster J, et al. Wintrobe's Clinical Hematology. ^11th ed. Philadelphia, Pa: Lippincott Williams &Wilkins; 2003. Vol II: 1919-44).

However, therapy based on the combination of MOR00208 and venetoclax provides a promising therapeutic approach for use in the treatment of CLL, NHL and/or ALL, but potentially carries an increased risk of developing TLS due to the additive/overlapping cytotoxicity of MOR00208 and venetoclax.

Although most adverse events are tolerable and tolerable, the continued goal is to determine the best tolerated dosage of such therapeutic agents to mitigate the occurrence of side effects such as TLS. Accordingly, it is an object of the present invention to provide a treatment approach comprising a combination of MOR00208 and venetoclax that reduces the risk of an adverse inflammatory response such as TLS, and which can be administered without negatively affecting the efficacy of combination treatment with the combination of MOR00208 and venetoclax.

Short description

The present invention is the first to provide a treatment approach designed to provide combination therapy containing an anti-CD19 antibody, particularly MOR00208, and a BCL-2 inhibitor, particularly venetoclax, which reduces the risk of treatment-related TLS.

The new treatment provides a better safety profile for the combination treatment without delaying the delivery of care to patients in need. To prevent an increased risk of TLS when both drugs are used concomitantly, treatment with MOR00208 is initiated one week before the start of venetoclax treatment with a gradual dose increase, starting with the lowest dose of 20 mg. Administration of MOR00208 in the first week (initial dose on day 1 and loading dose on day 4) significantly reduces the absolute lymphocyte count (ALC) to a value close to or even below the critical threshold of 25 x 10 ⁹ /L for assessing tumor burden described in the guidelines. use of Venclexta®, thereby reducing the risk of developing TLS during subsequent combination treatment of MOR00208 with venetoclax during the weekly venetoclax dose-escalation phase.

According to the Venclexta® prescribing information, the dose of venetoclax is administered according to a weekly tapering schedule over 5 weeks to a recommended daily dose of 400 mg. The 5-week tapered dose regimen, starting on day 8, is designed to gradually reduce tumor mass (shrinkage), resulting in a reduced risk of developing tumor lysis syndrome (TLS).

In one aspect, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in treating a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered for at least 7 days before the first administration of the indicated BCL-2 inhibitor.

In another aspect, the present invention provides the use of a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor in the treatment of patients suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered over at least 7 days. before the first administration of the specified BCL-2 inhibitor.

In another aspect, the present invention provides the use of a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor in the manufacture of a medicament for use in treating a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody CD19 is administered at least 7 days before the first administration of the specified BCL-2 inhibitor.

In another aspect, the present invention provides a method of treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma in a patient, wherein the method comprises administering a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor, wherein said anti-CD19 antibody is administered for at least 7 days before the first administration of the indicated BCL-2 inhibitor.

In one embodiment, the patient is a human.

In one embodiment, said anti-CD19 antibody and said BCL-2 inhibitor are administered separately. In one embodiment, said anti-CD19 antibody is administered at least 7 days before the first administration of said BCL-2 inhibitor. In another embodiment, said anti-CD19 antibody is administered at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days before the first administration of said BCL-2 inhibitor.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered once per week, once every two weeks or once a month after the first administration on day 1, and wherein the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose with a weekly dose increase. In a further embodiment, the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months. In a further embodiment, the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months and once every two weeks for the next at least 3 months. In another embodiment, the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then once a month. In another embodiment, the anti-CD19 antibody, after the first dose on day 1, is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then an additional dose is administered once a month on day 4. In an additional embodiment, In an embodiment, an additional dose of anti-CD19 antibody is administered on day 4.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered once per week, once every two weeks, or once a month after the first administration on day 1, and wherein said BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly tapering to 50 mg, 100 mg, 200 mg and 400 mg. In another embodiment, the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose, component 400 mg.

In one embodiment of the present invention, there is provided a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody after the first dose per day 1 is administered once a week for the first 3 months, twice a week for the next 3 months, and then once a month, and wherein said BCL-2 inhibitor is administered for the first time on day 8 at a starting dose of 20 mg , followed by weekly tapering to 50 mg, 100 mg, 200 mg, and 400 mg. In another embodiment, the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose, component 400 mg.

In one embodiment, said BCL-2 inhibitor is venetoclax.

In one embodiment, said anti-CD19 antibody comprises an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3) , the LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), the LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and the LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6).

In another embodiment, said anti-CD19 antibody comprises a heavy chain variable region containing the sequence

and a light chain variable region with the sequence

In another embodiment, said anti-CD19 antibody comprises a heavy chain constant domain containing the sequence

In another embodiment, said anti-CD19 antibody comprises a light chain constant domain containing the sequence

In another embodiment, said anti-CD19 antibody comprises a heavy chain constant domain containing the sequence

and a light chain constant domain containing the sequence

In another embodiment, said anti-CD19 antibody is administered at a concentration of 12 mg/kg.

In another embodiment, the present invention provides a combination for use in the treatment of chronic lymphocytic leukemia, small cell lymphocytic lymphoma, or non-Hodgkin lymphoma, wherein the non-Hodgkin lymphoma is selected from the group consisting of follicular lymphoma, small cell lymphocytic lymphoma, mucosal lymphoma, lymphoma marginal zone, diffuse large B-cell lymphoma, Burkitt's lymphoma and mantle cell lymphoma.

Description of graphic materials

Figure 1 shows a gradual increase in venetoclax dosage.

Figure 2 shows the amino acid sequence of the variable domains of MOR00208.

Figure 3 shows the amino acid sequence of the Fc regions of MOR00208.

Detailed Description of the Present Invention

The term "antibody" means monoclonal antibodies, including any isotype such as IgG, IgM, IgA, IgD and IgE. An IgG antibody consists of two identical heavy chains and two identical light chains, which are linked by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments, called "complementarity determining regions" ("CDRs") or "hypervariable regions", which are primarily responsible for binding to the epitope of the antigen. They are designated CDR1, CDR2 and CDR3, numbered sequentially from the N-terminus. The more highly conserved variable region fragments outside the CDR are called "framework regions". "Antibody fragment" means a fragment of Fv, scFv, dsFv, Fab, Fab', F(ab')2 or other fragment that contains at least one heavy chain variable region or light chain variable region, each of which contains CDRs and frameworks plots.

Bcl-2 (B-cell lymphoma 2) protein, encoded by the BCL2 gene in humans, is a member of the originating family of Bcl-2 regulatory proteins that regulate cell death (apoptosis) by either inducing (proapoptotic) or inhibiting (antiapoptotic) apoptosis . In the NCBI, the Bcl-2 gene is listed as number 596. In particular, Bcl-2 is considered an important anti-apoptotic protein and is therefore classified as an oncogene. Bcl-2 gets its name from B-cell lymphoma 2 because it is the second member of a series of proteins originally described in follicular lymphoma types through chromosomal translocations involving chromosomes 14 and 18. Orthologues (such as Bcl2 in mice) have been identified in many mammals for which whole genome data are available.

“BCL-2 inhibitors” are a class of drugs that exert their effect by inhibiting the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2), resulting in programmed cell death. BCL-2 inhibitors include venetoclax. Venetoclax is marketed by Abbvie and Genentech (trade name VENCLEXTA™, also known as GDC-0199, ABT-199 and RG7601). Venetoclax is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion detected by an FDA-approved test who have received at least one prior therapy.

The formula for venetoclax is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4 -[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide and has the following structure:

"Venetoclax", "AVT" and "AVT-199" are used interchangeably in this document.

Other BCL-2 inhibitors include the following.

Genasens. An antisense oligonucleotide drug, Genesense (G3139), is developed by Genta Incorporated to target Bcl-2. The antisense strand of DNA or RNA is non-coding and complementary to the coding strand (which is the template for the formation of RNA or protein, respectively). An antisense drug is a short sequence of RNA that hybridizes to the mRNA and inactivates it, preventing protein formation. Proliferation of human lymphoma cells (with the t(14;18) translocation) could be suppressed using antisense RNA targeting the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of a gene sense that is complementary to the first 6 codons of Bcl-2 mRNA. It has shown successful results in phase I/II trials in lymphoma. A large-scale phase III trial began in 2004. As of 2016, the drug had not been approved and its developer had gone out of business.

AVT-737 and AVT-263. In the mid-2000s, Abbott Laboratories developed a new inhibitor of Bcl-2, Bcl-xL, and Bcl-w known as ABT-737. This compound is part of a group of small molecule BH3 mimetic inhibitors (SMIs) that target these Bcl-2 family proteins, but not A1 or Mcl-1. ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. In vitro studies have shown that primary cells from patients with B-cell malignancies are sensitive to ABT-737. In animal models, it increases survival, causes tumor regression, and a large percentage of mice are cured. In preclinical studies using patient-derived xenografts, ABT-737 was effective in treating lymphoma and other blood cancers. Due to its unfavorable pharmacological properties, ABT-737 is not suitable for clinical trials, but its derivative ABT-263 has similar activity against small cell lung cancer (SCLC) cell lines and has entered clinical trials.

As used herein, the term "gradual increase" means increasing the dose from a first set point to additional set points over a predetermined period of time.

"VH" refers to the variable region of the heavy chain of an immunoglobulin antibody or antibody fragment. "VL" refers to the variable region of an immunoglobulin light chain of an antibody or antibody fragment.

The term “CD19” refers to the protein known as CD19, which has the following synonyms: B4, B cell CD19 antigen, B cell surface antigen B4, CVID3, CD19 differentiation antigen, MGC12802, and T cell surface antigen Leu-12.

Human CD19 has the amino acid sequence:

"MOR00208" is an anti-CD19 antibody. The amino acid sequence of the variable domains is presented in Figure 2. The amino acid sequence of the Fc regions of the heavy and light chains of MOR00208 is presented in Figure 3. “MOR00208” and “XmAb 5574” are used as synonyms to describe the antibody shown in Figures 2 and 3. Antibody MOR00208 is described US Patent Application Serial No. 12/377251, which is incorporated by reference in its entirety, describes an antibody called 4G7 H1.52 Hybrid S239D/I332E/4G7 L1.155 (later called MOR00208), as follows:

>4G7 H1.52 hybrid S239D/I332E

>4G7L1.155

Additional antibodies specific for CD19 are described in US Pat. No. 7,109,304 (to Immunomedics), which is incorporated herein by reference in its entirety; US Patent Application Serial No. 11/917,750 (from Medarex), which is incorporated herein by reference in its entirety; US Patent Application Serial No. 11/852106 (from Medimmune), which is incorporated herein by reference in its entirety; US Patent Application Serial No. 11/648505 (from Merck Patent GmbH), which is incorporated herein by reference in its entirety; US Pat. No. 7,968,687 (Seattle Genetics), which is incorporated herein by reference in its entirety; and US Patent Application Serial No. 12/710442 (from Glenmark Pharmaceuticals), which is incorporated herein by reference in its entirety.

"Fc region" means the constant region of an antibody, which in humans may be of the IgG1, 2, 3, 4, or other subclasses. Human Fc region sequences are available on the IMGT website.

"Combination" means more than one component, for example, a compound such as an antibody and venetoclax.

The present invention also relates to combinations, pharmaceutical preparations and pharmaceutical compositions containing the described combinations. The two components in the combination of the present invention, for example, the CD19-specific antibody and venetoclax, can be administered together, simultaneously, separately or sequentially, both physically and temporally.

Venetoclax is currently taken orally and is currently given in a once-daily dose. MOR00208 is currently administered intravenously and is currently administered once a week (“weekly”) or once every two weeks (“biweekly”) or once a month (“monthly”).

Preferably, administration of both drugs allows both drugs to simultaneously be active in the patient. For example, when a dose of MOR00208 is administered once a week and a dose of venetoclax is administered as a daily dose, then the active substance of both drugs is present in the patient's body at the same time. In one embodiment, MOR00208 is administered prior to and/or separately from venetoclax.

"Simultaneously" means that two components are administered at a specific point in time, with both components (drugs) being active in the patient at the same time.

"Administered together" may mean that they are administered at the same time.

The components of the combination can be formulated into various pharmaceutical compositions. The pharmaceutical composition includes an active agent, for example an antibody, for therapeutic use in humans. The pharmaceutical composition may contain suitable carriers or excipients.

“Administered” or “administration” includes, without limitation, delivery through an injectable form, such as, for example, intravenous, intramuscular, intradermal or subcutaneous routes of administration, or through the mucous membrane, such as a nasal spray or inhalation aerosol, or in in the form of a solution, capsule or tablet taken orally.

A "therapeutically effective amount" of a compound or combination refers to an amount sufficient to cure, alleviate, or partially eliminate the clinical manifestations of a given disease or disorder and its complications. The amount that is effective for a particular therapeutic purpose will depend on the severity of the disease or lesion, as well as the body weight and general condition of the subject. It is known that determination of the appropriate dose can be done using routine experiments by constructing a table of values and testing various points in the table; all of these techniques are within the normal skill of a trained physician or clinical scientist.

Embodiments

Because the mechanisms of action of venetoclax and other BCL-2 inhibitors are similar, it is believed that the standard dosing approach described herein should also be effective in reducing the risk of TLS in the treatment of people with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma through a combination of an exemplary anti-CD19 antibody and a BCL-2 inhibitor other than venetoclax.

Because the exemplary anti-CD19 antibody and other anti-CD19 antibodies bind CD19, it is believed that the standard dosing approach described herein should also be effective and reduce the risk of TLS in the treatment of people with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma through the combination of any anti-CD19 antibody and a B-cell lymphoma protein-2 (Bcl-2) inhibitor, wherein the anti-CD19 antibody is described, for example, in US patent application Serial No. 12/377251 (Xencor), WO 2005012493, WO 2010053716 ( Immunomedics); WO 2007002223 (Medarex); WO 2008022152 (Xencor); WO 2008031056 (Medimmune); WO 2007/076950 (Merck Patent GmbH); WO 2009/052431 (Seattle Genetics) and WO 2010095031 (Glenmark Pharmaceuticals), all of which are incorporated herein by reference in their entirety.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered once per week, once every two weeks or once a month after the first administration on day 1, and wherein the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose with a weekly dose increase.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered once per week, once every two weeks or once a month after the first administration on day 1, and wherein the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose for weekly tapering to a daily dose of 400 mg.

In a further embodiment, the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months. In a further embodiment, the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months and once every two weeks for the next at least 3 months. In another embodiment, the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then once a month. In another embodiment, the anti-CD19 antibody, after the first dose on day 1, is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then an additional dose is administered once a month on day 4. In an additional embodiment, In an embodiment, an additional dose of anti-CD19 antibody is administered on day 4.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered once per week, once every two weeks, or once a month after the first administration on day 1, and wherein said BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly tapering to 50 mg, 100 mg, 200 mg, and 400 mg. In another embodiment, the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly tapering to 50 mg, 100 mg, 200 mg and 400 mg followed by a daily dose of 400 mg. In a further embodiment, an additional dose of anti-CD19 antibody is administered on day 4.

In one embodiment of the present invention, there is provided a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody after the first dose per day 1 is administered once a week for the first 3 months, twice a week for the next 3 months, and then once a month, and wherein said BCL-2 inhibitor is administered for the first time on day 8 at a starting dose of 20 mg , followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg. In another embodiment, the BCL-2 inhibitor is administered for the first time on day 8 at a starting dose of 20 mg, followed by weekly dosing gradually increasing the dose to 50 mg, 100 mg, 200 mg and 400 mg, followed by a daily dose of 400 mg. In a further embodiment, an additional dose of anti-CD19 antibody is administered on day 4.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma, wherein said anti-CD19 antibody is administered weekly, every other weeks or monthly after the first administration on day 1, and wherein said BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 10, 15 or 20 mg followed by weekly dose increases to 20, 25, 30, 35, 40, 45 or 50 mg, 50, 55, 60, 65, 70, 75, 80, 85 90, 95 or 100 mg, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg and 200, 250 , 300, 350 or 400 mg. In another embodiment, the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly dose increases to 20, 25, 30, 35, 40, 45, or 50 mg, 50, 55, 60. 65, 70, 75, 80, 85, 90, 95 or 100 mg, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg followed by a daily dose of 200, 250 , 300, 350 or 400 mg. In a further embodiment, an additional dose of anti-CD19 antibody is administered on day 4.

In one embodiment, the present invention provides a combination comprising an anti-CD19 antibody and a BCL-2 inhibitor for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody, after first administration, day 1 is administered weekly for the first 3 months, every two weeks for the next 3 months, and monthly thereafter, with said BCL-2 inhibitor first administered on day 8 at an initial dose of 10, 15, or 20 mg, followed by a weekly dose increase to 20 , 25, 30, 35, 40, 45 or 50 mg, 50, 55, 60, 65, 70, 75, 80, 85 90, 95 or 100 mg, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg and 200, 250, 300, 350 or 400 mg. In another embodiment, the BCL-2 inhibitor is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly dose increases to 20, 25, 30, 35, 40, 45, or 50 mg, 50, 55, 60. 65, 70, 75, 80, 85, 90, 95 or 100 mg, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg followed by a daily dose of 200, 250 , 300, 350 or 400 mg.

In another embodiment, said anti-CD19 antibody is administered at a concentration of 12 mg/kg.

In embodiments, the BCL-2 inhibitor is venetoclax.

In embodiments, the components of the combination, anti-CD19 antibody and venetoclax, are administered separately. In one embodiment, venetoclax is administered before the anti-CD19 antibody is administered.

In embodiments, the components of the combination are administered at a specific point in time, with both components (drugs) being active in the patient at the same time. By "synergy" we mean that both drugs are active in the patient at the same time. In some embodiments, the components of the combination are administered together, simultaneously, separately, or sequentially, both physically and temporally. In some embodiments, the components of the combination are administered simultaneously.

In embodiments, the combination is a pharmaceutical composition. In some embodiments, the composition contains a suitable carrier. In some embodiments, the combination is administered in an effective amount.

In some embodiments, the non-Hodgkin's lymphoma is follicular lymphoma. In some embodiments, the non-Hodgkin lymphoma is a small cell lymphocytic lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a mucosal lymphoid tissue lymphoma. In some embodiments, the non-Hodgkin's lymphoma is marginal zone lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is Burkitt's lymphoma. In some embodiments, the non-Hodgkin lymphoma is a mantle cell lymphoma.

In one aspect, the present invention provides a combination comprising the antibody MOR00208 and venetoclax for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein MOR00208 after the first administration on day 1 is administered once a week in for the first 3 months, once every two weeks for the next 3 months, and then an additional dose of tMOR00208 is administered once a month on day 4, and where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by administration with weekly gradual dose increases to 50 mg, 100 mg, 200 mg and 400 mg. In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. . In one embodiment, MOR00208 is administered at a concentration of 12 mg/kg.

In one aspect, the present invention provides a combination comprising an anti-CD19 antibody and venetoclax for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody, after the first administration on day 1, is administered alone once a week for the first 3 months, once every two weeks for the next 3 months, and then an additional dose is administered once a month on day 4, and where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg , followed by weekly tapering to 50 mg, 100 mg, 200 mg, and 400 mg. In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. .

In one embodiment, said anti-CD19 antibody comprises an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3) , the LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), the LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and the LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6).

In another embodiment, said anti-CD19 antibody comprises a heavy chain variable region containing the sequence

and a light chain variable region with the sequence

In another embodiment, said anti-CD19 antibody comprises a heavy chain constant domain containing the sequence

In another embodiment, said anti-CD19 antibody comprises a light chain constant domain containing the sequence

In another embodiment, said anti-CD19 antibody comprises a heavy chain constant domain containing the sequence

and a light chain constant domain containing the sequence

In one aspect, the present invention provides a combination comprising an anti-CD19 antibody and venetoclax for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody, after the first administration on day 1, is administered alone once a week for the first 3 months, once every two weeks for the next 3 months, and then an additional dose is administered once a month on day 4, and where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg , followed by weekly titrations to 50 mg, 100 mg, 200 mg and 400 mg, wherein said anti-CD19 antibody contains a heavy chain constant domain containing a specific sequence.

and a light chain constant domain containing the sequence

In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. .

In one aspect, the present invention provides a combination comprising an anti-CD19 antibody and venetoclax for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered on day 1, on day 4 , on day 8 and once a week for the first 3 months, once every two weeks for the next 3 months, and then once a month, and where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly tapering to 50, 100, 200 and 400 mg. In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. .

In another aspect, the present invention provides the use of a combination comprising an anti-CD19 antibody and venetoclax in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody, after the first administration on day 1, is administered once per week for the first 3 months, once every two weeks for the next 3 months, and then an additional dose is administered once a month on day 4, and where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, with followed by weekly gradual dose increases to 50 mg, 100 mg, 200 mg and 400 mg. In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. .

In another aspect, the present invention provides the use of a combination comprising an anti-CD19 antibody and venetoclax in the manufacture of a medicament for use in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody after the first administration on day 1 is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then an additional dose is administered once a month on day 4, and where venetoclax is administered for the first time on day 8 an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg and 400 mg. In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. .

In another aspect, the present invention provides a method of treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma in a patient, wherein the method comprises administering a combination comprising an anti-CD19 antibody and venetoclax, wherein said anti-CD19 antibody, after the first administration on day 1, is administered alone once a week for the first 3 months, twice a week for the next 3 months, and then an additional dose is administered once a month on day 4, and where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg followed by with a weekly gradual increase in dose to 50, 100, 200 and 400 mg. In another embodiment, venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg, and 400 mg, followed by a daily dose of 400 mg. .

Examples

Study

This is a phase II, multicenter, open-label study of MOR00208 in combination with venetoclax for the treatment of adult patients with relapsed/refractory (R/R) CLL or R/R SLL who have been pretreated with a BTK inhibitor as a single agent or as part of combination therapy. A total of 120 patients were included in this study in Europe and the USA. The primary objective of the study is to determine the safety and effectiveness of the combination of MOR00208 and venetoclax.

The study will include a run-in phase to assess safety, including 10-12 patients per treatment combination. MOR00208 will be administered at a dose of 12.0 mg/kg by intravenous (IV) infusion, and venetoclax will be administered as oral tablets at a daily dose of 400 mg.

To reduce the risk of TLS, treatment with venetoclax is initiated after initial treatment with MOR00208 at a dose of 20 mg from cycle 1 day 8 (C1D8) for 7 days, followed by a weekly titration schedule to the recommended daily dose of 400 mg.

The run-in phase for safety assessment concludes with assessment of safety data from all treated patients after 10 patients have completed at least 5 weeks of combination treatment. All 10 to 12 patients will be dosed sequentially at least one week apart.

A safety assessment will be conducted by IDMC after the first 10 patients complete at least 5 weeks of combination treatment. The assessment will be carried out by IDMC as already described. It is important to note that all patients who participate in the safety run-in phase will be hospitalized on the day of the first two venetoclax dose increases (C1D8 and C1D15).

Criteria for assessing the safety of combination therapy are outlined in the trial's safety monitoring plan.

The study begins when the outcome of the relevant run-in phase for safety assessment is known. If the safety assessment results in a reduction in the recommended dose of venetoclax, the clinical trial sponsor will review the dosage and make appropriate changes to the protocol.

An interim analysis will be performed for each arm in the trial to test futility and safety. While the interim analysis is being conducted, patients are no longer included in this eligible group. This interim analysis will be based on the response and safety data of enrolled patients up to the interim analysis, which is defined as 3 months after the 40th patient started treatment.

As soon as 40 patients are recruited, recruitment will be suspended for the duration of the discussion with the customer. Then the recruitment will be resumed at the customer's discretion after an interim analysis.

In the study, MOR00208 was administered via infusion at a dose of 12.0 mg/kg over 28-day cycles. From cycle 1 to 3, each cycle consists of weekly infusions (on day 1, day 8, day 15 and day 22). In Cycle 1, an additional loading dose is administered on Day 4. From Cycles 4 to 6, MOR00208 is administered once every two weeks via infusion on Day 1 and Day 15 of each cycle. Thereafter, MOR00208 is administered on day 1 of each cycle, starting with cycle 7 of day 1.

Venetoclax is self-administered starting on cycle 1 day 8 and day 1 of each cycle. Venetoclax treatment may be modified by tapering or discontinuation based on clinical and laboratory data. In the event that treatment with venetoclax is discontinued due to side effects believed to be related to venetoclax, the patient may continue treatment with MOR00208.

Tumor scores used to determine the primary end point (ORR) and secondary efficacy outcomes are assessed through a central review of radiological study and clinical data by an independent Radiology/Clinical Review Committee (TRC).

Discontinuation of the study drug will be required if disease progression occurs. Patients who discontinue treatment due to disease progression will be followed for survival every 3 months for up to and including 3 years after EOT. Patients who discontinue treatment for reasons other than disease progression or withdrawal of consent will undergo tumor evaluation before PD occurs. They will then be monitored for survival every 3 months.

Patients who benefit from treatment are allowed to continue treatment with MOR00208 beyond cycle 24 at the discretion of the investigator. The total duration of the study is limited to 5 years from the date of the first visit to the first patient. Depending on the time of inclusion relative to the start of the study, the duration of study participation varies for each patient.

Patient inclusion criteria

Diagnosis/Group included in trial

1. Age≥18 years

2. Chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL):

a) a history of a diagnosis of CLL or SLL that meets the diagnostic criteria for IWCLL

b) histologically confirmed diagnosis of SLL through lymph node biopsy and documented in the medical record

c) indications for treatment in accordance with IWCLL recommendations

3. Patients must have both of the following:

a) relapsed ¹ or refractory ² disease while taking a BTK inhibitor (for example, ibrutinib) or intolerance to such therapy

b) treatment with a single agent or combination treatment with a BTK inhibitor for at least one month must represent the patient's most recent prior anticancer therapy

¹ recurrent disease is defined as progressive disease in subjects who previously achieved a PR or CR prior to the most recent BTK inhibitor therapy

² refractory disease is defined as progressive disease in subjects who had not previously achieved a PR or CR before the most recent BTK inhibitor therapy, or stable disease as the best response after 12 months of the most recent BTK inhibitor therapy

4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

5. Patients with a history of autologous or allogeneic stem cell transplantation must demonstrate complete hematologic recovery without any evidence of active graft-versus-host disease before enrollment in the study.

6. Patients must meet the following laboratory criteria at screening:

• Adequate bone marrow function as follows:

a) absolute neutrophil count (ANC)≥1.0×10 ⁹ /l

b) platelet count ≥ 30×10 ⁹ /l in the absence of clinically significant signs of bleeding

c) hemoglobin ≥8.0 g/dl

• Adequate liver and kidney function as follows:

d) total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in cases of documented CLL liver disease (for patients with Gilbert's disease, serum bilirubin up to 3 × ULN is allowed provided direct bilirubin is normal)

e) ALT and AST ≤ 2.5 × ULN or < 3 × ULN in cases of documented CLL liver disease

f) serum creatinine clearance, calculated using the standard Cockcroft-Gault formula, should be: ≥50 ml/min

Other inclusion criteria

7. Women of childbearing potential (FCBP; see Appendix F) should:

a) not be pregnant, which when screened by a negative serum test and urine pregnancy test prior to initiation of study therapy

b) refrain from breastfeeding and donating blood or eggs during the course of the study and for 3 months after the last dose of the study drug (note: All patients are prohibited from donating blood during the above period of time)

c) agree to ongoing pregnancy tests during the study and up to 3 months after the end of therapy. This also applies even if the patient practices complete and prolonged sexual abstinence.

d) agree to continue abstinence from heterosexual intercourse if this is consistent with her lifestyle, or they agree to use and be able to comply with highly effective contraception without interruption during the study and for 3 months after the last dose of the study drug

f) FCBPs using hormonal contraceptives should add a barrier method as a second form of contraception as it is currently unknown whether idelalisib or venetoclax may interfere with the effectiveness of hormonal contraceptives.

8. Men should use a highly effective method of contraception without interruption if the patient is sexually active with FCBP, refrain from donating blood or sperm while participating in the study and for 3 months after the last dose of study drug

Study Treatment

In this open-label study, treatment comprising MOR00208 and venetoclax is administered as scheduled until disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever occurs first.

Each investigator is responsible for ensuring that shipments of investigational medicinal products and other investigational materials from the customer and other medicinal products from relevant customers are correctly received, recorded, processed and safely and properly stored in accordance with all applicable regulatory guidelines and used in accordance with this protocol. The researcher may delegate these tasks to another person (subject to local laws and regulations). Medication record forms are kept at each study site and are reviewed during follow-up visits. All doses prescribed to the patient and all dose changes during the study must be recorded in the eCRF.

The investigational drug must be handled and/or obtained as described in the Investigational Drug Preparation Guide, the Investigator Brochure (IB) for MOR00208, and other safety documents (e.g., prescribing information issued by the US FDA for treatment with venetoclax).

MOR00208

The MOR00208 finished dosage form (DP) should be stored refrigerated at 2 to 8°C in the original packaging in an appropriate storage area accessible only to the pharmacist(s), investigator or duly designated person.

DP MOR00208 is a yellowish lyophilisate supplied in 20 ml single-use glass vials. Each vial contains 200 mg of MOR00208 for reconstitution with 5 ml of water for injection (WFI). Diluted to 40 mg/mL MOR00208 in 25 mM sodium citrate, 200 mM trehalose, and 0.02% (w/v) polysorbate 20 pH 6.0. Each product vial is designed to deliver 200 mg of MOR00208 in 5 mL of reconstituted solution. The solution after dissolution is colorless to slightly yellow and contains virtually no foreign particles; it may contain some white or off-white particles associated with the product.

To administer, MOR00208 is diluted with sodium chloride injection in a commercially available 250 mL infusion container with 0.9% (w/v).

MOR00208 is administered intravenously at a dose of 12.0 mg/kg. During the first 3 months (3 cycles) of the study, each cycle will consist of an infusion of MOR00208 on day 1, day 8, day 15, and day 22 of the cycle. In addition, a loading dose is administered on day 4 of cycle 1. Thereafter, MOR00208 is administered once every two weeks (every 14 days) with infusions on days 1 and 15 of each cycle from cycle 4 to 6 and once monthly on day 1 of each cycle from cycle 7 days 1.

A single infusion of MOR00208 is prepared aseptically and administered at the study site in accordance with the customer's instructions in the Investigational Drug Preparation Guide. In general, the MOR00208 vial should be used as soon as possible after reconstitution with WFI. Any amount of solution remaining in the vial must be discarded. Once reconstituted for infusion, MOR00208 should be administered as soon as possible.

For the first infusion, the intravenous (IV) infusion rate should be 70 mL/hour for the first 30 minutes and then increased to a rate of 125 mL/hour; the total duration of infusion should not exceed 2.5 hours. All subsequent infusions of MOR00208 are administered intravenously at a constant rate of 125 ml/hour over a period of approximately 2 hours. MOR00208 should not be administered by intravenous (IV) bolus or bolus injection.

Venetoclax

Venetoclax tablets commercially available for oral administration are supplied as pale yellow film-coated tablets that contain 10 or 100 mg venetoclax as the active ingredient, or beige film-coated tablets that contain 50 mg venetoclax as the active ingredient. . They should be stored at or below 30°C (86°F).

The dose of venetoclax should be administered according to a weekly dose escalation schedule over 5 weeks to a recommended daily dose of 400 mg. Figure 1 shows this initial dose escalation. The dosing schedule for the tapered phase is as follows: daily dose of venetoclax: week 1 of combination treatment, 20 mg, week 2 - 50 mg, week 3 - 100 mg, week 4 - 200 mg and week 5 - 400 mg onwards. A 5-week tapered dose regimen starting at C1D8 is designed to gradually reduce (reduce) tumor burden and reduce the risk of developing tumor lysis syndrome (TLS). An assessment of patient-specific factors regarding the level of risk for TLS and TLS prophylaxis should be performed prior to administration of the first dose of venetoclax.

For the first 4 weeks of treatment, venetoclax is provided in blisters containing the corresponding venetoclax tablets according to a gradual dose escalation schedule. After completion of the tapering phase, the 400 mg dose is provided using 100 mg tablets supplied in vials.

Venetoclax should be administered orally once daily until disease progression or unacceptable toxicity is observed. Venetoclax tablets should be taken with food and water at approximately the same time each day. The tablets should be swallowed whole and should not be chewed, crushed or crushed before swallowing. If a patient misses a dose within 8 hours of when it would normally be taken, the patient should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a patient misses a dose for more than 8 hours, the patient should not take the missed dose and should resume their regular dosing schedule the next day. If the patient vomits after a dose is administered, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

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LIST OF SEQUENCES

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Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 9

<211> 213

<212> PROTEIN

<213> Artificial sequence

<220>

<223> RefMab33 light chain

<400> 9

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Arg Val Gly Tyr Met

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr

35 40 45

Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp

65 70 75 80

Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210> 10

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<223> synthetic construction

<400> 10

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Ser Ser Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 11

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> synthetic construction

<400> 11

Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Lys Ser Leu Gln Asn Val

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Asn Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Met Gln His

85 90 95

Leu Glu Tyr Pro Ile Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 12

<211> 330

<212> PROTEIN

<213> Artificial sequence

<220>

<223> synthetic construction

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20

25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35

40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50

55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85

90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100

105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Asp Val Phe Leu Phe Pro Pro 115

120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130

135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165

170 175

Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val 180

185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195

200 205

Lys Ala Leu Pro Ala Pro Glu Glu Lys Thr Ile Ser Lys Thr Lys Gly 210

215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245

250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260

265 270

Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe 275

280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290

295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330

<210> 13

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> synthetic construction

<400> 13

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 14

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<223> synthetic construction

<400> 14

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Ser Ser Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Gly Thr Tyr Tyr Tyr Gly Thr Arg Val Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe

290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Glu

325 330 335

Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 15

<211> 219

<212> PROTEIN

<213> Artificial sequence

<220>

<223> synthetic construction

<400> 15

Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Lys Ser Leu Gln Asn Val

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Asn Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Met Gln His

85 90 95

Leu Glu Tyr Pro Ile Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<---

Claims (58)

1. The use of a combination containing an anti-CD19 antibody and venetoclax in the treatment of a patient suffering from non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma, wherein said anti-CD19 antibody is administered at least 7 days before the first administration of venetoclax, and where the antibody to CD19 contains a heavy chain variable region containing the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 10), light chain variable region with sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 11); heavy chain constant domain containing the sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVV HQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 12), and light chain constant domain containing the sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 13). 2. Use according to claim 1, wherein the anti-CD19 antibody is administered once a week, once every two weeks or once a month after the first administration on day 1, and wherein venetoclax is first administered on day 8. 3. Application according to any one of paragraphs. 1 or 2, where the anti-CD19 antibody after the first dose on day 1 is administered once a week for the first 3 months. 4. Use according to claim 3, wherein the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months and once every two weeks for the next at least 3 months. 5. Use according to claim 4, wherein the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then once a month. 6. Application according to any one of paragraphs. 1-5, where an additional dose of anti-CD19 antibody is administered on day 4. 7. Application according to any one of paragraphs. 1-6, where venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg and 400 mg, possibly followed by a daily dose, component 400 mg. 8. Application according to any one of paragraphs. 1-7, wherein said anti-CD19 antibody and venetoclax are administered separately. 9. Application according to any one of paragraphs. 1-8, where the anti-CD19 antibody is administered at a dose of 12 mg/kg. 10. Application according to any one of paragraphs. 1-9 in the treatment of non-Hodgkin's lymphoma. 11. Use according to claim 10, wherein the non-Hodgkin's lymphoma is follicular lymphoma. 12. Use according to claim 10, wherein the non-Hodgkin's lymphoma is a lymphoma from the lymphoid tissue of the mucous membranes. 13. Use according to claim 10, wherein the non-Hodgkin's lymphoma is marginal zone lymphoma. 14. Use according to claim 10, wherein the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma. 15. Use according to claim 10, wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma. 16. Use according to claim 10, wherein the non-Hodgkin's lymphoma is a mantle cell lymphoma. 17. Application according to any one of paragraphs. 1-9 in the treatment of chronic lymphocytic leukemia. 18. Application according to any one of paragraphs. 1-9 in the treatment of small cell lymphocytic lymphoma. 19. A method of treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or small cell lymphocytic lymphoma in a patient, comprising administering a therapeutically effective amount of a combination containing an anti-CD19 antibody and venetoclax, wherein said anti-CD19 antibody is administered at least 7 days before the first administration of venetoclax, and wherein the anti-CD19 antibody comprises a heavy chain variable region containing the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 10), light chain variable region with sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 11); heavy chain constant domain containing the sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVV HQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 12), and light chain constant domain containing the sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 13). 20. The method of claim 19, wherein the anti-CD19 antibody is administered once a week, once every two weeks, or once a month after the first administration on day 1, and wherein venetoclax is first administered on day 8. 21. Method according to any one of paragraphs. 19 or 20, wherein the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months. 22. The method of claim 21, wherein the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months and once every two weeks for the next at least 3 months. 23. The method of claim 22, wherein the anti-CD19 antibody, after the first administration on day 1, is administered once a week for the first 3 months, once every two weeks for the next 3 months, and then once a month. 24. Method according to any one of paragraphs. 19-23, where an additional dose of CD19 antibody is administered on day 4. 25. Method according to any one of paragraphs. 19-23, wherein venetoclax is administered for the first time on day 8 at an initial dose of 20 mg, followed by weekly titrations to 50 mg, 100 mg, 200 mg and 400 mg, possibly followed by a daily dose, component 400 mg. 26. Method according to any one of paragraphs. 19-25, wherein said anti-CD19 antibody and venetoclax are administered separately. 27. Method according to any one of paragraphs. 19-26, where the anti-CD19 antibody is administered at a dose of 12 mg/kg. 28. Method according to any one of paragraphs. 19-27, where the patient has non-Hodgkin's lymphoma. 29. The method of claim 28, wherein the non-Hodgkin's lymphoma is follicular lymphoma. 30. The method according to claim 28, where the non-Hodgkin lymphoma is a lymphoma from the lymphoid tissue of the mucous membranes. 31. The method of claim 28, wherein the non-Hodgkin's lymphoma is marginal zone lymphoma. 32. The method of claim 28, wherein the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma. 33. The method of claim 28, wherein the non-Hodgkin's lymphoma is Burkitt's lymphoma. 34. The method of claim 28, wherein the non-Hodgkin lymphoma is mantle cell lymphoma. 35. Method according to any one of paragraphs. 19-27, where the patient has chronic lymphocytic leukemia. 36. Method according to any one of paragraphs. 19-27, where the patient has small cell lymphocytic lymphoma.