Venetoclax in Addition to Blinatumomab in Adult Patients With Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL)

An Open Label, Phase I/II Study of Venetoclax in Addition to Blinatumomab Immunotherapy in Adult Patients With Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL)

This study is designed to determine the feasibility, safety, tolerability and maximum tolerated dose of Venetoclax in combination with Blinatumomab and to evaluate the response in patients treated with the combination of Venetoclax and Blinatumomab in in patients with hematological relapse or molecular relapse.

Transfer of patients to alloHSCT after one cycle or after a subsequent cycle is considered as per protocol discontinuation and as premature treatment discontinuation.

There will be a safety follow-up visit at 30 days after end of the last infusion. There will be efficacy follow-up until 6 months after end of therapy. In patients scheduled for SCT the 30-day safety-visit may be performed at the latest time point possible before initiation of subsequent treatment.

Inclusion Criteria:

1. Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure

2. Age ≥ 18 years

3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

4. Availability of patient-specific molecular MRD markers of immunoglobulin/T-cell receptor gene rearrangementsas assessed by PCR with a sensitivity of at least 10E-04

5. Diagnosis of Philadelphia negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:

   • Refractory BCP-ALL to primary induction therapy, including at least three cycles of standard chemotherapy
   • Untreated first relapse of BCP-ALL with first remission duration < 12 months or
   • Second or greater relapse of BCP-ALL or refractory relapse or
   • Relapse of BCP-ALL any time after allogeneic HSCT or

6. Positivity of MRD marker of immunoglobulin/T-cell receptor gene rearrangements of greater than 0.01% if in first or second remission of BCP-ALL

7. Negative pregnancy test < 7 days before first study drug in women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfil at least one of the following criteria:

   1. Post-menopausal (i.e. 12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml
   2. Post-operative after bilateral ovariectomy with or without hysterectomy
   3. Continuous and correct application of a contraception method with a Pearl index of < 1% (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 3 months after the last dose of study drug. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
   4. Sexual abstinence
   5. Vasectomy of the sexual partner

8. Ability to understand and willingness to sign a written informed consent

9. Willingness to participate in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion Criteria:

1. Patients with diagnosis of Philadelphia positive BCP-ALL according to WHO classifiation

2. Patients with diagnosis of Burkitt´s Leukemia according to WHO classification

3. Patients with extramedullary relapse; non-bulky lymph node (< 7.5 cm diameter) involvement will be accepted

4. Patients with CNS involvement at relapse (as determined by CSF analysis)

5. Patients with suspected or histologically confirmed testicular involvement at relapse

6. Current autoimmune disease of any kind or history of autoimmune disease with potential CNS involvement

7. Patients with Philadelphia-positive BCP-ALL still receiving TKI

8. Prior or concomitant therapy with BH3 mimetics

9. Prior therapy with anti CD19 therapy, unless administered in MRD-positive setting (i.e. with bone marrow blasts ≤ 5%)

10. Treatment with any of the following within 7 days prior to the first dose of study drug: strong cytochrome P450 3A (CYP3A) inhibitors, moderate or strong CYP3A inducers

11. Intake of any of the following within 3 days prior to the first dose of study drug: grapefruit, grapefruit products, Seville oranges or star fruit

12. Presence of Graft-versus-Host Disease (GvHD) and/or on immunosuppressant medication within 2 weeks before start of protocol-specified therapy

13. Radiation, chemotherapy (with the exception of prephase therapy), or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day 1.

14. Major surgery within 2 weeks of first dose of study drug

15. Patients who are pregnant or lactating

16. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety

17. Unstable cardiovascular function:

    • Symptomatic ischemia, or
    • Uncontrolled clinically significant conduction abnormalities (1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
    • Congestive heart failure (CHF) of NYHA Class ≥3, or
    • Myocardial infarction (MI) within 3 months

18. Evidence of clinically significant uncontrolled condition(s) including, but not limited to: Uncontrolled and/or active systemic infection (viral, bacterial or fungal), chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti- HBs antibody (anti-HBs) positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) or blood transfusions may participate.

19. Known human immunodeficiency virus (HIV) infection (HIV testing is not required)

20. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment

21. Adequate hepatic function per local laboratory reference range as follows: Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN, Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)

22. Severe renal dysfunction: estimated creatinine clearance of < 20 mL/min, measured in 24 hour urine or calculated using the formula of Cockroft and Gault

23. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. History of CNS leukemia that is controlled at relapse may be enrolled in this study.

24. History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:

    • Malignancy treated with curative intent and with no known active disease present for 2 years before enrollment and felt to be at low risk for recurrence by the treating physician including
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Adequately treated breast ductal carcinoma in situ without evidence of disease
    • Prostatic intraepithelial neoplasia without evidence of prostate cancer.

25. Current autoimmune disease or history of autoimmune disease with potential CNS involvement

26. Live vaccination within 2 weeks before the start of study treatment

27. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation

28. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.

29. Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study(s). Thirty days is calculated from day 1 of protocol-specified therapy

30. Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject's and Investigator's knowledge.

31. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

32. Woman of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfil at least one of the following criteria:

    • Post-menopausal (i.e. 12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml
    • Post-operative after bilateral ovariectomy with or without hysterectomy
    • Continuous and correct application of a contraception method with a Pearl index of < 1% (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 3 months after the last dose of study drug. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
    • Sexual abstinence
    • Vasectomy of the sexual partner

33. Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving protocol-specified therapy and for at least an additional 3 months after the last dose of protocol-specified therapy