A Phase I/II Study of Venetoclax in Combination With Azacitidine in Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)
概览
- 阶段
- 1 期
- 干预措施
- Azacitidine
- 疾病 / 适应症
- Recurrent Chronic Myelomonocytic Leukemia
- 发起方
- M.D. Anderson Cancer Center
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) (Phase I)
- 状态
- 进行中（未招募）
- 最后更新
- 3个月前
概览
简要总结
This phase I/II trial investigates the side effects and best dose of venetoclax when given together with azacitidine and to see how well it works in treating patients with high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax and azacitidine together may help to control myelodysplastic syndrome or chronic myelomonocytic leukemia.
详细描述
PRIMARY OBJECTIVE: I. To determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of venetoclax in combination with azacitidine in patients with high risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with bone marrow excess blasts \> 5% that are relapsed/refractory to prior hypomethylating agent (HMA) therapy. SECONDARY OBJECTIVES: I. Rate of complete remission (CR). II. Rate of marrow/morphologic complete remission (mCR). III. Rate of hematologic improvement (HI; erythroid/platelet/neutrophil responses). IV. Rate of red blood cell (RBC) transfusion independence. V. Rate of platelet (PLT) transfusion independence. VI. Rate of cytogenetic response. VII. Rate of bone marrow blast response. VIII. Time to transformation to acute myeloid leukemia (AML). IX. Duration of response (DOR). X. Overall survival (OS). XI. Progression-free survival (PFS). XII. Time to next MDS treatment (TTNT). XIII. Event-free survival (EFS). EXPLORATORY OBJECTIVE: I. To investigate the effects of therapy on MDS and to identify biological markers of response to venetoclax and/or its combination with azacitidine. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. Patients receive venetoclax orally (PO) daily on days 1-14 and azacitidine intravenously (IV) over 15 minutes or subcutaneously (SC) on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 30 days and then every 3-6 months for up to 5 years.
研究者
入排标准
入选标准
- •Participants with post HMA-failure high-risk MDS (Int-2 or high risk by the IPSS with overall score \>/=1.5) with excess blasts \>5% with failure defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or progression of disease or relapse at any time after prior response to HMA therapy.
- •Participants with relapsed/refractory chronic myelomonocytic leukemia (CMML) and therapy-related MDS are also eligible.
- •Hydroxyurea is allowed to lower the white cell count \</= 10,000/µl prior to initiation of venetoclax.
- •Adequate hepatic function including total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement, and ALT/AST ≤ 3.0 x ULN unless considered due to leukemic involvement.
- •Adequate renal function as calculated using the modified Cockcroft-Gault equation of ≥ 30ml/min, OR creatinine \< 2x ULN, unless related to the disease.
- •Signed written informed consent.
- •Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment. Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment.
- •Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment.
- •Age \>/= 18 years of age.
排除标准
- •Participants having received any prior BCL2 inhibitor therapy.
- •Participants with MDS with IPSS risk categories Low or Int-1 (overall IPSS score \< 1.5).
- •Participants with known HIV infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). HIV testing will be performed at screening, only if required per local guidelines or institutional standards.
- •Participants known to be positive for hepatitis B or C infection \[HCV Ab indicative of a previous or current infection; and/or positive HBs Ag or detected sensitivity on HBV-DNA PCR test for HBc Ab and/or HBs Ab positivity\] with the exception of those with an undetectable viral load within 3 months of screening. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV \[i.e., HBs Ag-, and anti-HBs+\] may participate.
- •Participants has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
- •Participants has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
- •Participants has a cardiovascular disability status of New York Heart Association Class \>
- •Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
- •Participant has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients of azacitidine that in the opinion of the investigator would adversely affect his/her participating in this study.
- •Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
研究组 & 干预措施
Treatment (venetoclax, azacitidine)
Patients receive venetoclax PO daily on days 1-14 and azacitidine IV over 15 minutes or SC on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Azacitidine
Treatment (venetoclax, azacitidine)
Patients receive venetoclax PO daily on days 1-14 and azacitidine IV over 15 minutes or SC on days 1-5. Cycles repeat every 4-8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax
结局指标
主要结局
Maximum tolerated dose (MTD) (Phase I)
时间窗: Up to 28 days
The MTD is the highest dose level in which \< 2 patients of 6 develop first cycle dose-limiting toxicity (DLT).
Overall response rate (ORR) (Phase II)
时间窗: Up to 5 years post-treatment
ORR is defined as the proportion of patients who had complete remission (CR), partial remission (PR) or marrow CR (mCR) lasting at least 4 weeks, or hematologic improvement (HI) lasting at least 8 weeks. Will estimate the overall response rate for the combination treatment, along with the 95% credible interval.
次要结局
- Overall survival(The time from treatment start till death or last follow-up, assessed up to 5 years post-treatment)
- Progression free survival(The time from treatment to progression or last follow-up, assessed up to 5 years post-treatment)
- Time to transformation to acute myeloid leukemia (AML)(The time from treatment till transformation of AML or last follow-up, assessed up to 5 years post-treatment)
- Rate of hematologic improvement(Up to 5 years post-treatment)
- Rate of CR(Up to 5 years post-treatment)
- Rate of mCR(Up to 5 years post-treatment)
- Rate of red blood cell transfusion independence(Up to 5 years post-treatment)
- Rate of cytogenetic response(Up to 5 years post-treatment)
- Rate of bone marrow blast response(Up to 5 years post-treatment)
- Duration of response(The number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first, assessed up to 5 years post-treatment)
- Event-free survival(The number of days from the date of treatment initiation to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first, assessed up to 5 years post-treatment)
- Rate of platelet transfusion independence(Up to 5 years post-treatment)