Phase II Study With Safety run-in of Azacitidine (AZA) Combined With Venetoclax (VEN) in Patients With Higher-risk Chronic Myelomonocytic Leukemia (CMML)
概览
- 阶段
- 2 期
- 干预措施
- Venetoclax
- 疾病 / 适应症
- Chronic Myeloid Leukemia
- 发起方
- Groupe Francophone des Myelodysplasies
- 入组人数
- 44
- 试验地点
- 24
- 主要终点
- Safety run-in
- 状态
- 进行中（未招募）
- 最后更新
- 上个月
概览
简要总结
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
详细描述
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
研究者
入排标准
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
Azacidine+Venetoclax
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.
干预措施: Venetoclax
结局指标
主要结局
Safety run-in
时间窗: 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
Overall response rate
时间窗: 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
次要结局
- 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)
- Overall response rate at best response(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)