Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Recurrence

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Neoplasm, Residual

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Antineoplastic Agents

All Drugs and Chemicals

Blinatumomab

Antibodies

Venetoclax

Immunomodulating Agents

Immunoglobulins

Immunoglobulins, Intravenous

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

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

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.

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.

GMALL Study Center

Christoph Faul, Dr.

Andreas Viardot, Dr.

Nicola Gökbuget, Dr. med.

Lisa Heberling, Dr.

Stefan Schwartz, Dr.

Kathrin Nachtkamp, Dr

Bernd Spriewald, Prof

Maher Hanoun, Dr

Walter Fiedler, Prof. Dr.

Simon Raffel, Dr.

Lars Fransecky, Dr.

Boris Böll, Prof. Dr.

Vladan Vucinic, Dr.

Daniela Heidenreich, Dr.

Folker Schneller, Dr.

Andreas Voß

Sonja Martin, Dr.

Nicola Goekbuget, MD

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.

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)

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)

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.

rate of composite complete remissions (cCR) including CR without complete hematologic regeneration (CRh) and CR with incomplete recovery of peripheral blood counts (CRi) after one treatment cycle

* CR is defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (i.e. platelets ≥ 100.000/μl, and ANC

  ≥ 1.000/μl), and no evidence of (extramedullary) disease
* CRh is defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (i.e. 50.000/μl \< platelets \< 100.000/μl, and 500/μl \< ANC \< 1.000/μl), and no evidence of (extramedullary) disease
* CRi is defined as having ≤ 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts (i.e. platelets ≥ 50.000/μl or ANC ≥ 1.000/μl, and no evidence of (extramedullary) disease

overall response rate (ORR), including rate of CR, CRh, CRi, and rate of partial remission (PR)

median and probability of Remission duration at 1 year and 2 years

o EFS time will be calculated from the time of starting on-protocol therapy (C1D-7) until the date of (a) disease assessment indicating relapse after having achieved CR/CRh/CRi or (b) disease assessment indicating refractory disease after one or two cylces or (c) death, whichever occurs first. All subjects failing to achieve CR/CRh/CRi after the first cycle will be reassessed after two cycles if applicable.

Subjects alive and relapse-free at the time of analysis will be censored on their last disease assessment date.

median OS times will be calculated from the time of starting on-protocol therapy (C1D-7) until death due to any cause. Subjects still alive at the time of analysis will be censored at the date last known to be alive.

including CR, CRh, CRi and partial remission (PR)

o PR is defined as having 5% \< blasts \< 20% in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (i.e. platelets \> 50.000/μl, and ANC \> 500/μl)

CR rates in comparson with historical cohorts treated with Blinatumomab alone with inverse probability of treatment weighting (IPTW) using the propensity score

Probability of continuous MRD response and complete MRD response and duration of MRD response

Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ-5D) at different time-points during treatment

Proportion of patients who undergo allogeneic stem cell transplantation

Frequency of different relapse localisations in proportion to total hematological relapses

University Hospital Schleswig-Holstein

Goethe University

Principal Investigator

Neoplastic Processes

Patients will receive four cycles of treatment, unless criteria for treatment discontinuation apply. The duration of one cycle is 6 weeks, including a four week continuous intravenous infusion and a two week infusion free interval, which may be extended by a maximum of 7 days.

Patients entered with MRD level \<10-4 (non quantifiable/MolNE1, quantifiable/MolNE2) or positive MRD, non quantifiable (MolNE3) will receive up to two cycles of Blinatumomab.

Transfer of patients to alloHSCT after one cycle or after subsequent cycles is considered as per protocol discontinuation and as premature treatment discontinuation In case of hematological or extramedullary relapse, the study treatment will be permanently discontinued.

Patients will receive blinatumomab at a dose of 28 µg/day as continuous intravenous infusion at constant flow rate for four weeks, followed by a two-week infusion free interval, defined as one treatment cycle. Up to of four cycles will be performed.

In case of defined toxicities, the dose of blinatumomab may be reduced to 9µg/day.

Patients with an MRD relapse may qualify to receive additional treatment with blinatumomab.

This study is designed to confirm the efficacy, safety, and tolerability of blinatumomab in patients with MRD of B- precursor ALL in complete hematological remission including patients with relapse after SCT. The study aims to expand experience generated in previous trials in patients with MRD positive ALL with a focus on additional specific questions.

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

In case of hematological or extramedullary relapse, the study treatment will be permanently discontinued.

There will be a safety follow-up visit at 30 days after end of the last infusion. There will be efficacy follow-up until 18 months after treatment start. In patients scheduled for SCT the 30-day safety-visit may be performed at the latest time point possible before initiation of subsequent treatment.

Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia

A Multicenter, Single-arm Study to Assess the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (Blast Successor Trial)

realisation rate calculated as scheduled total dose/delivered total dose

Proportion of patients who achieve complete MRD response after one cycle of treatment with blinatumomab in patients with and without prior SCT

Probability of continuous complete remission (remission duration) at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Probability of hematological relapse-free survival rate at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Probability of overall survival at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Frequency of different relapse localisations in proportion to total hematological relapses (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Biological evaluation of hematological and extramedullary relapses including CD19 expression (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Overall incidence and severity of adverse events in patients with and without prior SCT (CTCAE 4.0) (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Proportion of patients who achieve MRD response after one or two cycles of treatment with Blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Proportion of patients who achieve complete MRD response after two cycles of treatment with blinatumomab in patients with and without prior SCT (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Probability of continuous MRD response and complete MRD response and duration of MRD response at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Time to MRD response measured by time-point of first achievement (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Evaluation of GvHD as part of AE documentation and according to Glucksberg Criteria, grade and localisation. (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Evaluation of overall survival, remission duration, relapse-free survival and treatment related mortality (at day 100 and later) in patients with SCT in complete remission after blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Evaluation of overall survival, remission duration, relapse-free survival and treatment related mortality in patients without SCT in complete remission after blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ-5D) at different time-points during treatment (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	ALL, Recurrent,...	Blinatumomab Venetoclax	18 Years -	Goethe University
Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia	NCT03109093	ALL, Recurrent,...	Blinatumomab	18 Years -	Goethe University

Spots Global Cancer Trial Database for all, recurrent, adult