Phase Ib/II Study of Omacetaxine and Venetoclax for Patients With Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 Dose (RP2D) of Omacetaxine in Combination With Venetoclax
研究概览
简要总结
This phase Ib/II trial best dose, possible benefits and/or side effects of omacetaxine and venetoclax in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory) and have a genetic change RUNX1. Drugs used in chemotherapy, such as omacetaxine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving omacetaxine and venetoclax may help to control the disease.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase 1b) II. To determine the efficacy of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase II)
SECONDARY OBJECTIVES:
I. To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS).
II. To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (or biphenotypic or bilineage leukemia including a myeloid component) or myelodysplastic syndrome
- •For myelodysplastic syndrome (MDS) patients, patients must have no response, progression, or relapse following at least 4 cycles of azacytidine or decitabine; and/or intolerance defined as grade >= 3 drug-related toxicity precluding continued therapy
- •Age >= 18 years
- •Subjects must have documented RUNX1 gene mutation
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- •Creatinine < 2 unless related to the disease
- •Direct bilirubin < 2x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
- •Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3x ULN unless considered due to leukemic involvement
- •In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (i.e. immunotherapy) agents. Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI)
- •Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug
- •Willing and able to provide informed consent
排除标准
- •Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
- •Patients with any concurrent uncontrolled clinically significant medical condition including active infection or psychiatric illness, which could place the patient at unacceptable risk of study treatment
- •Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
- •Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
- •Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or known human immunodeficiency virus (HIV) infection
- •Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to meet this criterion.)
- •Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception
- •Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)
研究组 & 干预措施
Ph 1 Arm A (AML) Dose 0
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-10 . Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Omacetaxine Mepesuccinate (Drug)
Ph 1 Arm A (AML) Dose 0
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-10 . Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
Ph 1 Arm B (MDS) Dose 0
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-10 . Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Omacetaxine Mepesuccinate (Drug)
Ph 1 Arm B (MDS) Dose 0
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-10 . Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
Ph 1 Arm A (AML) Dose +1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Omacetaxine Mepesuccinate (Drug)
Ph 1 Arm A (AML) Dose +1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
Ph 1 Arm B (MDS) Dose + 1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Omacetaxine Mepesuccinate (Drug)
Ph 1 Arm B (MDS) Dose + 1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
Ph 2 Arm A (AML) Dose +1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Omacetaxine Mepesuccinate (Drug)
Ph 2 Arm A (AML) Dose +1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
Ph 2 Arm B (MDS) Dose + 1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Omacetaxine Mepesuccinate (Drug)
Ph 2 Arm B (MDS) Dose + 1
Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D) of Omacetaxine in Combination With Venetoclax
时间窗: Up to 30 days
The RP2D will be selected at the end of the Phase 1b portion based on safety data , in Arms A and B independently. Preliminary efficacy and PK data for each dose level may also be considered as appropriate.
Number of Participant to Achieve Complete Remission
时间窗: At day 28, and 3 cycles.
Complete Remission for AML is defined as: Absolute neutrophil count \> 10\^3/UL, platelets . 10\^5/UL, red cell transfusion independence, absence of extramedullary disease, and bone marrow with \< 5% blasts. Complete Remission for MDS is defined as: Absolute neutrophil count \> 10\^3/UL, platelets . 10\^5/UL, hemoglobin \>11 g/dl, and bone marrow with \< 5% blasts. Peripheral dysplasia will be noted.
次要结局
- Event-free Survival (EFS)(Up to Two years, 8 months, 30 days)
- Overall Survival (OS)(Up to Two years, 8 months, 30 days)
- Duration of Response(Up to Two years, 8 months, 30 days)