NCT05768711Active, not recruitingPhase 2
Phase II Study With Safety run-in of Azacitidine (AZA) Combined With Venetoclax (VEN) in Patients With Higher-risk Chronic Myelomonocytic Leukemia (CMML)
Groupe Francophone des Myelodysplasies24 sites in 1 country44 target enrollmentStarted: October 4, 2023Last updated:
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Enrollment
- 44
- Locations
- 24
- Primary Endpoint
- Overall response rate
Study Overview
Brief Summary
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
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, hypomethylating agent-naïve, higher-risk chronic myelomonocytic leukemia patients
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age 18 and older.
- •CMML diagnosis according to ICC 2022 criteria.
- •Intermediate-2 or high risk according to the molecular CMML Prognostic Scoring System (CPSS-mol) 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-mol. In patients with failed or missing cytogenetics or genetics at screening, cytogenetics and genetics at CMML diagnosis will be used to compute CPSS-mol.
- •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) is acceptable. No washout is necessary for those patients but pre-HY WBC will be taken in consideration for CPSS-mol 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-mol at inclusion (WBC prior to HY used to compute CPSS-mol at inclusion in HY-exposed patients) or with a CPSS-mol 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.
Arms & Interventions
Azacidine+Venetoclax
Experimental
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.
Intervention: Venetoclax (Drug)
Outcomes
Primary Outcomes
Overall response rate
Time Frame: after 3 and 6 cycles of treatment of the phase II patients (each cycle is 28 days)
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
Safety run-in
Time Frame: after 2 cycles of treatment of the safety run-in phase patients (each cycle is 28 days)
Determination of dose-limiting toxicities within the first two cycles of treatment
Secondary Outcomes
- Overall response rate at best response(through study completion, an average of 5 years)
- Identification and grading of adverse events(through study completion, an average of 5 years)
- Overall survival(through study completion, an average of 5 years)
- Acute Myeloid Leukemia (AML)-free survival(through study completion, an average of 5 years)
- Event-free survival(through study completion, an average of 5 years)
- Survival censoring at Hematopoietic Stem Cell Transplantation (HSCT)(through study completion, an average of 5 years)
- Survival censoring to subsequent therapy(through study completion, an average of 5 years)
- Duration of response(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(through study completion, an average of 5 years)
- Rate of Hematopoietic Stem Cell Transplantation (HSCT)(through study completion, an average of 5 years)
- Subsequent therapy(through study completion, an average of 5 years)
- Cumulative incidence of AML and cumulative risk of death without AML(through study completion, an average of 5 years)
- Complete remission rate(after 3 and 6 cycles of treatment (each cycle is 28 days))
- Overall response rate after 3 and 6 cycles of treatment(after 3 and 6 cycles of treatment (each cycle is 28 days))
- Progression-free survival(through study completion, an average of 5 years)
Investigators
Study Sites (24)
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