| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with a hematological relapse or a molecular relapse of an Acute Lymphoblastic Leukemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066104 |
| E.1.2 | Term | Precursor B-lymphoblastic leukaemia acute |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 in women of childbearing potential
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) |
|
| E.4 | Principal 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 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 and is not willing to use a highly effective method of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment.
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 |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | 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) |
|
| E.5.2 | 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 < platelets < 100.000/μl, and 500/μl < ANC < 1.000/μl), and no evidence of (extramedullary) disease
o 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)
- Remission duration (median and probability at 1 year and 2 years)
- Event-free survival (EFS) (median and probability at 1 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 cycles 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.
- Overall survival (OS) (median and probability at 1 and 2 years)
o 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.
- 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)
- 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at the end of each treatment cycles and until end of follow-up-period |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| dose-finding study for a product with marketing authorisation in a different disease entity |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
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