A Phase I/II, Open-label, Single Arm, Multicenter Dose-finding Study Assess the Safety and Preliminary Efficacy of Oral Azacitidine CC-486 (ONUREG) in Combination With Venetoclax (VENCLYXTO) in Previously Untreated Higher-risk Myelodysplastic Syndromes Ineligible for Allogenic Transplantation
概览
- 阶段
- 1 期
- 干预措施
- Onureg + Venetoclax
- 疾病 / 适应症
- Untreated Myelodysplastic Syndrome
- 发起方
- Groupe Francophone des Myelodysplasies
- 入组人数
- 36
- 试验地点
- 25
- 主要终点
- Dose-limiting toxicity
- 状态
- 进行中（未招募）
- 最后更新
- 上个月
概览
简要总结
This phase I/II open-label, dose-finding, multi-center study will assess safety and primary efficacy of Onureg and Venetoclax combination, to define the optimal biological dose and optimal treatment duration of Onureg to be used along with Venetoclax for further studies in previously untreated patients with higher-risk myelodysplastic syndromes (HR-MDS) not eligible to transplant.
详细描述
During phase I, three dose features of Onureg will be tested in combination with a fixed dose of Venetoclax to define the optimal biological dose for phase II. The phase II will assess safety and primary efficacy of Onureg and Venetoclax combination, to define the optimal biological dose and optimal treatment duration of Onureg to be used along with Venetoclax for further studies in previously untreated patients with HR-MDS not eligible to transplant.
研究者
入排标准
入选标准
- •Subjects must understand and voluntarily sign and date an ICF indicating the investigational nature of the study, approved by an independent EC/IRB, prior to the initiation of any screening or study-specific procedures.
- •Age ≥ 18 years at the date of signing the ICF.
- •Diagnosis of MDS according to the 2016 WHO classification (13) (Appendix 1), with presence of \< 20% bone marrow blasts per bone marrow aspirate at screening, confirmed by local investigator with HR-MDS, based on the revised International Prognostic Scoring System (IPSS-R) \>3 (intermediate, high or very high) (14) (Appendix 2) and a blast percentage of 5 or more.
- •Previously untreated HR-MDS: no prior therapy for MDS with any hypomethylating agents (azacitidine or decitabine), chemotherapy, allo-Hematopoietic Stem Cell Transplantation (HSCT) or experimental agent. All other treatments are not considered prior therapy.
- •Not immediately eligible for allo-HSCT or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤
- •Total white blood cell (WBC) count ≤ 10 G/L; Treatment with hydroxyurea is permitted to lower the WBC to reach this inclusion criterion and will be stopped at least 48 hours before treatment initiation.
- •Adequate liver functions as demonstrated by:
- •Serum alanine transaminase (ALT) \< 3.0 × upper limit of normal \[ULN\];
- •Serum aspartate transaminase (AST) \< 3.0 × ULN;
排除标准
- •Previous treatment for MDS, any approved or investigational antineoplastic agents or radiotherapy.
- •Previous diagnosis of:
- •MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)
- •MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
- •Participant has an active, uncontrolled systemic fungal, bacterial, or viral infection. The participant should be afebrile and off antibiotics for at least 72 hours and off antifungals for 7 days. In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on Investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the patient at a higher risk of receiving investigational treatment.
- •History of clinically significant medical conditions, laboratory abnormality, psychiatric illness or any other reason that the investigator determines would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug or predisposes the participant to high risk of noncompliance with the protocol.
- •History of active malignancy within the past year prior to screening, with the exception of:
- •Adequately treated carcinoma in situ of the uterine cervix
- •Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
- •Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy.
研究组 & 干预措施
Onureg + Venetoclax
Onureg (CC-486, oral azacitidine) will be administered orally at 200 or 300 mg once daily for 7 or 14 consecutive days, beginning on Day 1 of repeated 28-day cycles. Venetoclax will be administered orally at 400 mg once daily for 14 consecutive days on days 1 to 14, beginning on Day 1 of repeated 28-day cycles. Patients will be treated up to 4 cycles and for a maximum of 24 cycles.
干预措施: Onureg + Venetoclax
结局指标
主要结局
Dose-limiting toxicity
时间窗: at day 28 of cycle 1
Dose-limiting toxicities according to CTCAE (common terminology criteria for adverses events) 5.0 occurring within the first cycle of treatment
Overall response
时间窗: at day 28 of cycle 1
Overall response measured after the first cycle of treatment according to modified IWG-MDS (International Working Group-Myelodysplastic Syndromes) 2006
次要结局
- Time to next treatment(at end of study (an average of 5 years))
- Transfusion independence(at end of study (an average of 5 years))
- Patient-reported outcomes according to FACIT-AN(at end of treatment (an average of 4 years))
- Time to response(at end of treatment (an average of 4 years))
- Duration of response(at end of study (an average of 5 years))
- Progression to acute myeloid leukemia (AML)(at end of treatment (an average of 4 years))
- Survival(at end of study (an average of 5 years))
- Early mortality(at day 28)
- Patient-reported outcomes according to EQ-5D-5L(at end of treatment (an average of 4 years))
- Patient-reported outcomes according to PGIC(at end of treatment (an average of 4 years))
- Patient-reported outcomes according to PGIS(at end of treatment (an average of 4 years))
- Best response(after 6 cycles of treatment (each cycle is 28 days))
- Hematological improvement(at end of treatment (an average of 4 years))
- Duration of transfusion independence(at end of study (an average of 5 years))
- Identification and grading of adverse events(at end of treatment (an average of 4 years))