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)

NCT05182385 | Active Not Recruiting Phase 1 DMC

• 2 other identifiers: GMALL-BLIVEN2021-001384-25
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 17

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.

Conditions

ALL, Recurrent, Adult

Keywords

ALL; acute lymphoblastic leukemia; MRD positive; minimal residual disease; blinatumomab; venetoclax

Outcome Measures

Primary Outcomes (2)

• Phase I/ part 1: Maximum tolerated dose (MTD)

  The primary endpoint of the part I dose escalation part will be maximum tolerated dose (MTD). The combination of Venetoclax and Blinatumomab will be evaluated for tolerability in a 3+3 design. In a 3+3 design, three patients will form a cohort. Each cohort will receive a higher cumulative dose of Venetoclax in pre-defined dose escalation steps (see table below). If one patient experiences dose limiting toxicity (DLT), the cohort will be expanded to six patients. If two or more of these 6 patients experience a DLT, the next lower Venetoclax dose will be defined as maximum tolerated dose (MTD). If 0/3 or \<2/6 patients in a cohort experience a DLT, the next dose escalation cohort will be opened. In case of ≥ 2 DLTs at the dose level 1, dose level -1 will be used as a fallback option. The DLT evaluation period is defined as the first 49 days after initiation of Venetoclax in cycle 1 (i.e. C1D-7 to C1D42)

  through study part I completion, anticipated after 1 year

• Phase II/ part 2: rate of complete molecular remissions (Mol-CR)

  The primary efficacy measure of the part II expansion part will be the rate of complete molecular remissions (Mol-CR) after one cycle of Blinatumomab and Venetoclax. \- Mol-CR is defined as MRD negativity with a sensitivity of at least 10E-04 Disease status will be assessed by bone marrow and peripheral blood analysis at the end of Cycle 1. Bone marrow aspiration is required at any time on study in case peripheral blood analysis is suspicious for progression of disease.

  after one cycle of treatment (up to 43 days)

Secondary Outcomes (11)

• Rate of composite complete remissions (cCR)

  until End of Follow-Up (up to 6 months after EOT)

• Overall response rate (ORR)

  until End of Follow-Up (up to 6 months after EOT)

• Remission duration

  at 1 year and 2 years after EOT

• Event-free survival (EFS)

  at 1 year and 2 years after EOT

• Overall survival (OS)

  at 1 year and 2 years after EOT

Other Outcomes (3)

• Treatment realisation 1

  until end of treatment (up to 1+12 weeks)

• Treatment realisation 2

  until end of treatment (up to 1+12 weeks)

• Treatment realisation 3

  until end of treatment (up to 1+12 weeks)

Study Arms (2)

hematological relapse

EXPERIMENTAL

Diagnosis of Ph-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

Drug: Blinatumomab; Drug: Venetoclax

molecular relapse

EXPERIMENTAL

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

Drug: Blinatumomab; Drug: Venetoclax

Interventions

Blinatumomab DRUG

All patients with hematological relapse will additionally receive Blinatumomab immunotherapy (first cycle: 9 ug/d c.i.v. on d1 until d7 and 28 ug/d c.iv. on d8 until d28; second cycle: 28 ug/d c.iv. on d1 to d28) in six-week cycles (4 weeks on Blinatumomab, 2 weeks off Blinatumomab). All patients with molecular relapse will additionally receive Blinatumomab immunotherapy at 28 ug/d c.iv. on d1 until d28 in six-week cycles (4 weeks on Blinatumomab, 2 weeks off Blinatumomab.) Patients eligible for a second cycle shall not receive Blinatumomab starting dose independent from relapse type.

Also known as: blincyto

hematological relapse; molecular relapse

Venetoclax DRUG

In phase I of the study all eligible patients will receive increasing doses of Venetoclax on days -7 to -1 (Venetoclax dose-titration) in the first cycle and continuous dosing of Venetoclax at a pre-specified target dose (TD, p.o., once daily, d1 to d42) in six-week cycles for a maximum of two cycles. In phase II of the study all eligible patients will receive the recommended phase 2 dose (RP2D) of Venetoclax in six-week cycles for a maximum of two cycles. RP2D will be MTD. Patients eligible for a second cycle shall not receive Venetoclax dose-titration independent from relapse type.

Also known as: Venclyxto

hematological relapse; molecular relapse

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• 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
• 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
• 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
• 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:
• 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

You may not qualify if:

• Patients with diagnosis of Philadelphia positive BCP-ALL according to WHO classifiation
• Patients with diagnosis of Burkitt´s Leukemia according to WHO classification
• Patients with extramedullary relapse; non-bulky lymph node (\< 7.5 cm diameter) involvement will be accepted
• Patients with CNS involvement at relapse (as determined by CSF analysis)
• Patients with suspected or histologically confirmed testicular involvement at relapse
• Current autoimmune disease of any kind or history of autoimmune disease with potential CNS involvement
• Patients with Philadelphia-positive BCP-ALL still receiving TKI
• Prior or concomitant therapy with BH3 mimetics
• Prior therapy with anti CD19 therapy, unless administered in MRD-positive setting (i.e. with bone marrow blasts ≤ 5%)
• 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
• 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
• Presence of Graft-versus-Host Disease (GvHD) and/or on immunosuppressant medication within 2 weeks before start of protocol-specified therapy
• 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.
• Major surgery within 2 weeks of first dose of study drug
• Patients who are pregnant or lactating

Sponsors & Collaborators

• Goethe University: lead
• University Hospital Schleswig-Holstein: collaborator

Study Sites (17)

Universitätsklinikum Tübingen

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

University Hospital of Frankfurt (Main)

Frankfurt am Main, Hesse, 60590, Germany

Location

Universitätsklinikum Dresden

Dresden, Saxony, 01307, Germany

Location

Charité - Campus Benjamin Franklin

Berlin, 12203, Germany

Location

Universitätsklinikum Köln

Cologne, 50937, Germany

Location

University Hospital Düsseldorf

Düsseldorf, 40225, Germany

Location

Universität Erlangen

Erlangen, Germany

Location

Universitätsklinikum Essen

Essen, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

UKSH-Kiel

Kiel, Germany

Location

Universitätsklinik Leipzig

Leipzig, Germany

Location

Klinikum Mannheim

Mannheim, Germany

Location

Klinikum Rechts der Isar der TU München

München, 81675, Germany

Location

Klinikum Oldenburg

Oldenburg, 26133, Germany

Location

Robert - Bosch - Krankenhaus

Stuttgart, Germany

Location

MeSH Terms

Conditions

Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasm, Residual

Interventions

blinatumomab; venetoclax

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplastic Processes

Study Officials

• Nicola Goekbuget, MD

  GMALL-Study-Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 17, 2021
• First Posted: January 10, 2022
• Study Start: December 15, 2021
• Primary Completion: April 30, 2026
• Study Completion: April 30, 2026
• Last Updated: July 25, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

DE (17)