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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
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.
Universitätsklinikum Tübingen
Tübingen, Baden-Wurttemberg, Germany
Universitätsklinikum Ulm
Ulm, Baden-Wurttemberg, Germany
University Hospital of Frankfurt (Main)
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)
Time frame: 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.
Time frame: after one cycle of treatment (up to 43 days)
Rate of composite complete remissions (cCR)
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
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Frankfurt am Main, Hesse, Germany
Universitätsklinikum Dresden
Dresden, Saxony, Germany
Charité - Campus Benjamin Franklin
Berlin, Germany
Universitätsklinikum Köln
Cologne, Germany
University Hospital Düsseldorf
Düsseldorf, Germany
Universität Erlangen
Erlangen, Germany
Universitätsklinikum Essen
Essen, Germany
Universitätsklinikum Hamburg-Eppendorf
Hamburg, Germany
...and 7 more locations
Time frame: until End of Follow-Up (up to 6 months after EOT)
Overall response rate (ORR)
overall response rate (ORR), including rate of CR, CRh, CRi, and rate of partial remission (PR)
Time frame: until End of Follow-Up (up to 6 months after EOT)
Remission duration
median and probability of Remission duration at 1 year and 2 years
Time frame: at 1 year and 2 years after EOT
Event-free survival (EFS)
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.
Time frame: at 1 year and 2 years after EOT
Overall survival (OS)
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.
Time frame: at 1 year and 2 years after EOT
Overall response rate (ORR)
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)
Time frame: after one cycle of treatment (up to 43 days)
CR rates in comparson to Blinatumomab monotherapy
CR rates in comparson with historical cohorts treated with Blinatumomab alone with inverse probability of treatment weighting (IPTW) using the propensity score
Time frame: after one cycle of treatment (up to 43 days)
Duration of MRD response
Probability of continuous MRD response and complete MRD response and duration of MRD response
Time frame: until End of Follow-Up (up to 6 months after EOT)
Measurement of Quality of Life
Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ-5D) at different time-points during treatment
Time frame: until End of Follow-Up (up to 6 months after EOT)
Rate of allogeneic stem cell transplantation
Proportion of patients who undergo allogeneic stem cell transplantation
Time frame: until End of Follow-Up (up to 6 months after EOT)
Relapse localisations
Frequency of different relapse localisations in proportion to total hematological relapses
Time frame: until End of Follow-Up (up to 6 months after EOT)