Clinical trial NCT05182385: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: ALL, Recurrent, Adult
Keywords: ALL
acute lymphoblastic leukemia
MRD positive
minimal residual disease
blinatumomab
venetoclax
Lead sponsor: Goethe University
Sponsor class: OTHER
Collaborators: name: University Hospital Schleswig-Holstein
First posted: 2022-01-10
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase I/ part 1: Maximum tolerated dose (MTD)
timeFrame: through study part I completion, anticipated after 1 year
measure: Phase II/ part 2: rate of complete molecular remissions (Mol-CR)
timeFrame: after one cycle of treatment (up to 43 days)
Secondary outcomes:
measure: Rate of composite complete remissions (cCR)
timeFrame: until End of Follow-Up (up to 6 months after EOT)
measure: Overall response rate (ORR)
timeFrame: until End of Follow-Up (up to 6 months after EOT)
measure: Remission duration
timeFrame: at 1 year and 2 years after EOT
measure: Event-free survival (EFS)
timeFrame: at 1 year and 2 years after EOT
measure: Overall survival (OS)
timeFrame: at 1 year and 2 years after EOT
measure: Overall response rate (ORR)
timeFrame: after one cycle of treatment (up to 43 days)
measure: CR rates in comparson to Blinatumomab monotherapy
timeFrame: after one cycle of treatment (up to 43 days)
measure: Duration of MRD response
timeFrame: until End of Follow-Up (up to 6 months after EOT)
measure: Measurement of Quality of Life
timeFrame: until End of Follow-Up (up to 6 months after EOT)
measure: Rate of allogeneic stem cell transplantation
timeFrame: until End of Follow-Up (up to 6 months after EOT)
measure: Relapse localisations
timeFrame: until End of Follow-Up (up to 6 months after EOT)
Other outcomes:
measure: Treatment realisation 1
timeFrame: until end of treatment (up to 1+12 weeks)
measure: Treatment realisation 2
timeFrame: until end of treatment (up to 1+12 weeks)
measure: Treatment realisation 3
timeFrame: until end of treatment (up to 1+12 weeks)
Locations:
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Württemberg
city: Frankfurt (Main)
country: Germany
facility: University Hospital of Frankfurt (Main)
state: Hessen
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
state: Sachsen
city: Berlin
country: Germany
facility: Charité - Campus Benjamin Franklin
city: Düsseldorf
country: Germany
facility: University Hospital Düsseldorf
city: Erlangen
country: Germany
facility: Universität Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Kiel
country: Germany
facility: UKSH-Kiel
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Leipzig
country: Germany
facility: Universitätsklinik Leipzig
city: Mannheim
country: Germany
facility: Klinikum Mannheim
city: München
country: Germany
facility: Klinikum Rechts der Isar der TU München
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Stuttgart
country: Germany
facility: Robert - Bosch - Krankenhaus
Study officials:
affiliation: GMALL-Study-Group
name: Nicola Goekbuget, MD
role: PRINCIPAL_INVESTIGATOR
References: