Azacitidine Combined With Venetoclax in Patients With Higher-risk Chronic Myelomonocytic Leukemia (AVENHIR)

Study Overview
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Brief Summary
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Open-label phase II, single arm, multicenter study with safety run-in to evaluate the efficacy and safety of Azacitidine combined with Venetoclax in patients with higher-risk chronic myelomonocytic leukemia

Detailed Description
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AVENHIR trial is an open-label phase II, single arm, multicenter study with safety run-in to evaluate the efficacy and safety of the combination of Azacitidine and Venetoclax in newly diagnosed, hypomethylating agent-naïve, higher-risk chronic myelomonocytic leukemia patients

Official Title
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Phase II Study With Safety run-in of Azacitidine (AZA) Combined With Venetoclax (VEN) in Patients With Higher-risk Chronic Myelomonocytic Leukemia (CMML)

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 and older. CMML diagnosis according to WHO 2016 criteria. Intermediate-2 or high risk according to the CMML Prognostic Scoring System (CPSS) at study entry. In patients treated with HY at screening, the white blood count (WBC) prior to introduction of HY will be used to compute CPSS. In patients with failed or missing cytogenetics at screening, cytogenetics at CMML diagnosis will be used to compute CPSS. No prior treatment with hypomethylaing agents, including Azacitidine, decitabine, SGI-110, AST7227 or CC-486 for CMML or any antecedent condition, including antecedent MDS or auto-immune disease. Prior treatment with Erythropoiesis Stimulating Agents (ESA) is allowed with a > 15 days washout from ESAs. Prior treatment with hydroxyurea (HY) for < 6 weeks is acceptable. No washout is necessary for those patients but pre-HY WBC will be taken in consideration for CPSS computation. Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale. Adequate organ function including the following: total bilirubin < 2 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or due to Gilbert syndrome), alanine transaminase (ALT) and aspartate transaminase (AST) < 3 times ULN, Creatinine clearance > 30 mL/min as estimated by the CKD-EPI equation. Signed Informed Consent Form (ICF). Negative pregnancy and adequate contraception (including in male patients) if relevant. A FCBP (female of childbearing potential) for this study is defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must: Have had 2 negative pregnancy tests as verified by the investigator prior to starting investigational medicinal product (IMP) (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing pregnancy testing during the course of the study and after end of treatment. If sexually active, agree to use, and be able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IMP, during treatment with IMP (including dose interruptions), and for 3 months after the last dose of IMP. Highly effective contraception is defined in this protocol as the following (information also appears in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy. Male subjects must have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 3 months after the last dose of IMP, even if he had undergone a successful vasectomy. Affiliation to a health insurance system. Exclusion Criteria: Myeloproliferative / myelodysplastic syndrome other than CMML. Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%. If both local and central review are available and discrepant, the central review will be used. CMML with t(5;12) or PDGFRbeta rearrangement that may be treated with imatinib. Unavailable CPSS at inclusion (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients) or with a CPSS low or intermediate-1 at study entry. Pregnant or breastfeeding. Serious concomitant systemic disorder, including auto-immune or auto-inflammatory disease requiring > 20 mg/d prednisone equivalent, active bacterial, fungal or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study. Medical condition requiring therapies with CYP3A strong or moderate inducing or inhibiting activity at screening. All strong or moderate CYP3A inducers should be discontinued 7 days prior to the first dose of study drug. All strong or moderate CYP3A inhibitors should be discontinued 3 days prior to the first dose of study drug. A sample list of CYP3A4 inhibitors and inducers is provided in Appendix F. Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years). Known positive test for human immunodeficiency virus (HIV). Note that HIV testing is not required at Screening. Malabsorption syndrome or other condition that precludes an enteral route of administration. Previous therapy with a hypomethylating agent including azacitidine, decitabine, SGI-110, AST7227 or CC-486 for CMML or any antecedent condition, including antecedent MDS or auto-immune disease. Previous therapy with a BH3 mimetic. Antecedent allogeneic stem cell transplantation (HSCT) for CMML or an antecedent of hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial. Subjects referred to in Articles L1121-5 to L1121-8-1 and L1122-1-2 of the Public Health Code.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacidine+Venetoclax<br>Azacitidine will be administered subcutaneously at the standard dose of 75 mg/m²/d either on days 1-7 or using a 5-2-2 schedule of the 28 day-cycles. Patiens will be exposed to Venetoclax during the first 7 or 14 days of the 28 day-cycles (number of days of Venetoclax determined during the safety run-in phase). At cycle 1, Venetoclax will be given orally with 3-day ramp-up, at 100 mg on day 1, 200 mg on day 2 and 400 mg on days 3 to 7 or 14 of the cycle. At all subsequent cycles, Venetoclax will be given orally at 400 mg on days 1 to 7 or 14 of the cycle. Treatment duration will be 24 months. | Drug: Venetoclax<br>* Combination of Azacitidine and Venetoclax<br>* Other names: ABT-199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in | Determination of dose-limiting toxicities within the first two cycles of treatment | after 2 cycles of treatment of the safety run-in phase patients (each cycle is 28 days) | 
| Overall response rate | Overall response encompasses complete remission, partial remission, marrow response and clinical benefit according to protocol-defined criteria modified from MDS/MPN IWG criteria after 3 and 6 cycles of treatment | after 3 and 6 cycles of treatment of the phase II patients (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate | Complete remission according to protocol-defined criteria modified from MDS/MPN IWG criteria after 3 and 6 cycles of treatment | after 3 and 6 cycles of treatment (each cycle is 28 days) | 
| Overall response rate at best response | Overall response (complete remission, partial remission, marrow response, clinical benefit) according to protocol-defined criteria modified from MDS/MPN IWG criteria at best response | through study completion, an average of 5 years | 
| Overall response rate after 3 and 6 cycles of treatment | Overall response (complete remission, partial remission, marrow response, clinical benefit) according to the DACOTA trial response criteria after 3 and 6 cycles of treatment | after 3 and 6 cycles of treatment (each cycle is 28 days) | 
| Duration of response | Duration of response defined as the time interval between the first date of achievement of any response according to MDS/MPN IWG criteria to progressive disease | through study completion, an average of 5 years | 
| Identification and grading of adverse events | Safety profile, both hematological and non-hematological of treatment (Venetoclax combined with Azacitidine) including identification and grading of adverse events based on NCI CTCAE version 5.0 | through study completion, an average of 5 years | 
| Overall survival | Overall survival defined as the time from inclusion until death or end of follow-up | through study completion, an average of 5 years | 
| Acute Myeloid Leukemia (AML)-free survival | AML-free survival defined as the time from inclusion to transformation to AML according to WHO 2016 criteria, death or end of follow-up, whichever occurs first | through study completion, an average of 5 years | 
| Progression-free survival | Progression-free survival defined as the time from inclusion to progressive disease according to MDS/MPN IWG criteria, transformation to AML, death or end of follow-up, whichever occurs first | through study completion, an average of 5 years | 
| Event-free survival | Event-free survival defined as the time from inclusion to failure to achieve any response according to MDS/MPN IWG criteria at the 6-cycle evaluation, occurence of progressive disease according to MDS/MPN IWG criteria, transformaion to AML, or death, whichever occurs first | through study completion, an average of 5 years | 
| Cumulative incidence of AML and cumulative risk of death without AML | Cumulative incidence of AML and cumulative risk of death without AML, considering death and transformation to AML as competing risk | through study completion, an average of 5 years | 
| Cumulative incidence of progressive disease or transformation to AML and cumulative risk of death without progression or AML | Cumulative incidence of progressive disease or transformation to AML and cumulative risk of death without progression or AML | through study completion, an average of 5 years | 
| Rate of Hematopoietic Stem Cell Transplantation (HSCT) | Rate of Hematopoietic Stem Cell Transplantation (HSCT) and post-HSCT ovrall survival and AML-free survival | through study completion, an average of 5 years | 
| Survival censoring at Hematopoietic Stem Cell Transplantation (HSCT) | Overall survival, AML-free survival and progressive-free survival censoring at Hematopoietic Stem Cell Transplantation (HSCT) | through study completion, an average of 5 years | 
| Subsequent therapy | Rate and description of subsequent therapy | through study completion, an average of 5 years | 
| Survival censoring to subsequent therapy | Overall survival, AML-free survival and progressive-free survival censoring at subsequent therapy | through study completion, an average of 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMML, Azacitidine, Venetoclax