Philadelphia negative, CD19-positive B-precursor acute lymphoblastic leukemia: -Refractory BCP-ALL to primary induction therapy -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 MedDRA version: 21.1 Level: L
Conditions
Interventions
Product Name: Venclyxto
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VENETOCLAX
CAS Number: 1257044-40-8
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration num
Sponsors
Goethe-Universität, vertreten durch den Präsidenten, dieser vertreten durch die LKP (bevollmächtigt durch den Sponsor)
Eligibility
Sex/Gender
All
Inclusion 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 =65 years) yes F.1.3.1 Number of subjects for this age range 4
Exclusion criteria
Exclusion criteria: 1. Patients with diagnosis of Philadelphia positive BCP-ALL 2. Patients with diagnosis of Burkitt´s Leukemia 3. Patients with extramedullary relapse 4. Patients with CNS involvement at relapse 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 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 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, or -CHF of NYHA Class =3, or -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 HBV or HCV requiring treatment 19. Known HIV infection 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: AST and 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the part I dose escalation part will be to determine feasibility, safety, and tolerability of Venetoclax in combination with Blinatumomab. The primary objective of the part II expansion part will be to evaluate the response in patients treated with the combination of Venetoclax and Blinatumomab.;Secondary Objective: To evaluate additional efficacy and safety of Venetoclax in combination with Blinatumomab and to improve quality of life of patients treated with Venetoclax/Blinatumomab combination. The exploratory objectives of this trial are: - Explore biological features predicting mol-CR - Describe venetoclax-induced changes in gene and protein expression of leukemic blasts isolated from patients - Compare baseline protein expression of leukemic blasts among patients and correlate to response - Determine the effects of the combination treatment of venetoclax and blinatumomab on the composition of human T-lymphocytes.;Primary end point(s): The primary endpoint of the part I dose escalation part will be maximum tolerated dose (MTD). 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.;Timepoint(s) of evaluation of this end point: - maximum tolerated dose (MTD) after day -7 until day -1 in phase I-patients - rate of complete molecular remissions (Mol-CR) after each cycle of treatment (4 weeks of treatment) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - 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 o 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 o 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 50.000/µl, and ANC > 500/µl) - To compare CR rates with historical cohorts treated with Blinatumomab alone with inverse probability of treatment weighting (IPTW) using the propensity score - Early mortality during induction therapy - Duration of MRD response and complete MRD response - Rate of allogeneic stem cell transplantation - Relapse localisation - Quality of life of patients - Safety and tolerability of induction and consolidation therapy - Treatment realisation (interruptions, dose reductions, treatment discontinuation);Timepoint(s) of evaluation of this end point: at the end of each treatment cycles and until end of follow-up-period | — |
Countries
Germany
Contacts
Public ContactGMALL-Studienzentrale
Universitätsklinik Frankfurt, Med. Klinik II
Outcome results
None listed