A Phase 1b/2 Study of PCM-075 (Onvansertib) in Combination With Either Low-Dose Cytarabine or Decitabine in Subjects With Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 72
- 试验地点
- 9
- 主要终点
- Number of Participants Who Experienced Dose Limiting Toxicities (DLT)
研究概览
简要总结
The purpose of the phase 1b/2 study is to determine whether Onvansertib given orally daily for 5 consecutive days every 28 days is safe and tolerable in adult patients who have relapsed/refractory Acute Myeloid Leukemia (AML), or are ineligible for intensive induction therapy, and to determine the maximum tolerated dose and recommended phase 2 dose of Onvansertib in combination with decitabine or Onvansertib in combination with low-dose cytarabine. In the phase 2 portion of the study, Onvansertib in combination with decitabine will be studied to provide further data on the safety profile of the combination and to preliminarily assess the activity of the chosen combination in patients with untreated AML who are not candidates for aggressive induction therapy, or who have received one prior treatment for their AML.
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
- •Disease Status and Prior Therapy:
- •Histologically confirmed AML with >20% blasts
- •Phase 1b: Participants with AML who are refractory to or have relapsed after initial treatment for their disease, with no more than three prior lines of therapy. Participants who have received prior treatment with cytarabine or decitabine are not excluded.
- •i. Participants with AML who are refractory to, or have relapsed after, initial treatment for their disease, with no more than one prior line of therapy, and are judged not to be candidates for re-induction therapy that includes hematopoietic cell transplantation. Participants who have received prior cytarabine or decitabine are not excluded.
- •ii. Participants with newly diagnosed, untreated AML ineligible for, or who have refused, standard intensive induction therapy
- •Age ≥18 years
- •ECOG performance status ≤2
- •Participants must be willing and able to review, understand, and provide written consent before starting any study-specific procedures or therapy.
- •All men and women must agree to practice effective contraception during the entire study period and after discontinuing study drug, unless documentation of infertility exists
- •Sexually active, fertile women must use two effective forms of contraception (abstinence, intrauterine device, oral contraceptive, or double barrier device) from the time of informed consent and until at least 6 months after discontinuing study drug
- •Sexually active men and their sexual partners must use effective contraceptive methods from the time of participant informed consent and until at least 3 months after discontinuing study drug
排除标准
- •Treatment-related AML or acute promyelocytic leukemia (APL)
- •Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death
- •Clinical evidence of active central nervous system leukemia at the time of screening
- •Alanine aminotransferase and/or aspartate aminotransferase ≥2.5 x upper limit of normal (ULN)
- •Total bilirubin > 2.0 mg/dL (or > 3.0 mg/dL in participants with documented Gilbert syndrome)
- •Serum creatinine ≥2.0 mg/dL
- •New York Heart Association Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic condition
- •Myocardial infarction in the previous 12 weeks (from the start of treatment)
- •Resting left ventricular ejection fraction <50% at the time of screening
- •QT (Interval from the beginning of the QRS complex to the end of the T wave on an electrocardiogram) interval with Fridericia's correction [QTcF] >450 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during screening and that result may be used to determine eligibility.
- •Active and uncontrolled disease (other than AML) or infection as judged by the treating physician
- •Treatment with systemic therapy for the primary disease within 14 days (except for hydroxyurea or isolated doses of cytarabine or decitabine for white blood cell control)
- •Grade 2 or greater toxicities from prior therapy, except for Grade 2 toxicities that are not expected to resolve and that in the judgment of the Investigator do not pose a significant safety risk to subject participation.
- •Participants with any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the participant's ability to sign the informed consent form or his/her ability to cooperate and participate in the study, or to interfere with the interpretation of the results.
研究组 & 干预措施
Phase 1b: Onvansertib + low-dose cytarabine
Onvansertib, administered in escalating doses orally Day 1 through Day 5 every 28 days (1 cycle) in combination with cytarabine, which will be administered in all cohorts as 20 mg/m^2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle). Onvansertib administration, in combination with cytarabine, will be initiated at a starting dose of 12 mg/m^2 orally, daily for 5 days. Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved.
干预措施: Onvansertib (Drug)
Phase 1b: Onvansertib + low-dose cytarabine
Onvansertib, administered in escalating doses orally Day 1 through Day 5 every 28 days (1 cycle) in combination with cytarabine, which will be administered in all cohorts as 20 mg/m^2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle). Onvansertib administration, in combination with cytarabine, will be initiated at a starting dose of 12 mg/m^2 orally, daily for 5 days. Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved.
干预措施: Cytarabine (Drug)
Phase 1b: Onvansertib + decitabine
Onvansertib will be administered in escalating doses orally, Day 1 through Day 5 every 28 days (1 cycle) in combination with decitabine, administered consistently in all cohorts as 20 mg/m^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle). Onvansertib administration, in combination with decitabine, will be initiated at a starting dose of 12 mg/m^2 orally, daily for 5 days (Day 1 through Day 5). Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved.
干预措施: Onvansertib (Drug)
Phase 1b: Onvansertib + decitabine
Onvansertib will be administered in escalating doses orally, Day 1 through Day 5 every 28 days (1 cycle) in combination with decitabine, administered consistently in all cohorts as 20 mg/m^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle). Onvansertib administration, in combination with decitabine, will be initiated at a starting dose of 12 mg/m^2 orally, daily for 5 days (Day 1 through Day 5). Onvansertib dose will be escalated in successive cohorts until the recommended phase 2 dose is achieved.
干预措施: Decitabine (Drug)
Phase 2: Onvansertib + decitabine
Onvansertib recommended phase 2 dose, orally Day 1 through Day 5 every 28 days (1 cycle) and decitabine, administered consistently as 20 mg/m^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle), with treatment modifications or delays based on return of hematopoietic function to baseline or Grade ≤1 toxicity for optimal subject management.
干预措施: Onvansertib (Drug)
Phase 2: Onvansertib + decitabine
Onvansertib recommended phase 2 dose, orally Day 1 through Day 5 every 28 days (1 cycle) and decitabine, administered consistently as 20 mg/m^2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle), with treatment modifications or delays based on return of hematopoietic function to baseline or Grade ≤1 toxicity for optimal subject management.
干预措施: Decitabine (Drug)
结局指标
主要结局
Number of Participants Who Experienced Dose Limiting Toxicities (DLT)
时间窗: Up to Day 28 of Cycle 1
Dose-limiting toxicities were defined as events related to onvansertib that were considered an adverse reaction or suspected adverse reaction during the first cycle of therapy and that fulfilled one of the following: Hematologic (persistent pancytopenia resistant to current standards of care that continues for ≥42 days and is not related to leukemic infiltration or another cause unrelated to study therapy) or Non-Hematologic (any Grade 3 abnormalities that persist \>7 days without decreasing in severity despite standards of care, are clinically significant, or that are Grade 4 and symptomatic).
Number of Participants With Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status
时间窗: Baseline and end of study (approximately up to up to 27 months)
ECOG performance status was determined using 6-point scale from 0-5, with 0 meaning a participant was fully active/able to carry on all pre-disease activities without restriction and 5 meaning the participant was deceased.
Phase 2: Number of Participants Who Achieved a Complete Response (CR)
时间窗: Up to 27 months
Complete Response also includes Complete Response with Incomplete Blood Count Recovery (CRi). Complete response is defined by the following criteria: Morphologic leukemia-free state plus: * Subject is independent of transfusions * Absolute neutrophil count of \>1000/mm3 * Platelets of ≥100,000/mm3 Complete response with incomplete blood count recovery meets all criteria for CR except for either neutropenia (ANC \<1000/mm3) or thrombocytopenia (\<100,000/mm3) but must include transfusion independence.
Number of Participants With Adverse Events (AEs)
时间窗: Baseline up to 30 days after last dose of study drug (up to 27 months)
Any clinically significant change in electrocardiogram (ECG), physical examination findings, body weight, vital signs, and laboratory parameters were recorded as Adverse Events.
次要结局
- Pharmacokinetic Parameter: Area Under the Curve Over the First 24 Hours AUC(0-24) for Onvansertib(Cycle 1: Days 1 and 5)
- Phase 2: Number of Participants Who Achieved a Morphologic Leukemia-free (MLF) State(Up to 27 months)
- Phase 2: Number of Participants With Partial Response (PR)(Up to 27 months)
- Phase 2: Duration of Response (DOR)(Up to 27 months)
- Phase 2: Event-free Survival (EFS)(12 Months)
- Phase 2: Overall Survival (OS)(12 Months)
- Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) for Onvansertib(Cycle 1: Days 1 and 5)
- Pharmacokinetic Parameter: Plasma Terminal Elimination Half-life (t1/2) for Onvansertib(Cycle 1: Days 1 and 5)
- Pharmacokinetic Parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib(Cycle 1: Days 1 and 5)