A Phase I Pilot Study of Minnelide, A Novel Heat Shock Protein 70 Inhibitor, in Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 主要终点
- Safety Profile of Minnelide: Rate of Toxicity in Study Participants
研究概览
简要总结
Minnelide, a water-soluble disodium salt variant of triptolide, is a diterpenoid heat shock protein 70 (HSP70) inhibitor. Studies using AML cell lines, primary patient samples, and mouse transplant models demonstrate that Minnelide has potent cell killing effects. Minnelide has already been developed for human use and given to patients in a phase I trial for gastrointestinal (GI) cancers. Given the clinical safety profile and preliminary activity described in human GI cancers, the low-nanomolar anti-leukemic potency of triptolide in vitro, and that minnelide doses predicted to be significantly below the maximum tolerated dose (MTD) in human GI cancers decreased leukemia burden in animal models, the investigators propose a phase I trial in acute myeloid leukemia (AML).
详细描述
This is a Phase 1, open label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic pilot study of minnelide given to adult patients with relapsed or refractory AML.
The patient population will consist of adults previously diagnosed with relapsed/refractory AML for whom standard curative or life-prolonging treatment is unavailable or is no longer effective. Patients who are on hydroxyurea may be included in the study and may continue on hydroxyurea while participating in this study.
Once enrolled into the study, patients will be administered Minnelide via a 30-minute IV infusion. Each 28-day treatment cycle is composed of 5 consecutive daily doses of Minnelide followed by a 2-day rest period, repeating for 21 days, followed by a 7-day rest period.
Minnelide therapy may be administered for up to at least 12 cycles provided that the patient tolerates treatment and there is evidence of clinical benefit. If patients are still receiving clinical benefit, treatment may continue beyond 12 cycles, depending on drug availability and drug manufacturer (Minneamrita®) agreement. Study drug may be discontinued early if a patient experiences study drug related toxicities. Patients may discontinue therapy at any time. Patients will attend an End-of-Study visit 30 (+/- 10) days after receiving their last dose of study drug.
To determine the MTD of minnelide, an approach using traditional "3+3" escalation rules will be used. Dose-limiting toxicity (DLT) will be defined as events that are considered by the investigator to be related to therapy with minnelide. Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 of treatment will influence decisions regarding dose escalation. The initial minnelide dose will be 0.53 mg/m2 per dose; (3 dose levels will be explored; 0.53 mg/m2, 0.67 mg/m2, and 0.80 mg/m2). If more than 1 DLT occurs at Dose Level 1, then the next dose to be evaluated (Dose Level -1) will be 0.40 mg/m2. If more than 1 DLT occurs at Dose Level -1, the investigators will consider stopping the study. More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing dose level are all permissible at the discretion of the investigator, if such measures are needed for patient safety or for a better understanding of the dose-related toxicity, exposure, or pharmacodynamics of minnelide.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Relapsed or refractory Acute Myeloid Leukemia (AML) as defined by International Working Group (IWG) criteria. (Therapy-related AML and/or secondary AML evolving from an antecedent hematologic disorder are not excluded).
- •Adult patients 18 years of age or older
- •Ability to understand the investigational nature, potential risks and benefits of the research study and to provide valid written informed consent.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- •Patients must satisfy the following laboratory criteria:
- •Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin is ≤ 2 x upper limit of normal of direct bilirubin.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 2.5 × ULN
- •Creatinine 1.5 x ULN or calculated creatinine clearance > 50ml/min
- •White blood cell (WBC) count < 50,000/µL before administration of Minnelide on Cycle 1 Day
- •Note: Hydroxyurea may be used to suppress the WBC to < 50,000/µL to qualify patients for the study, during the study hydroxyurea may be used for the first 28 days of treatment according to the investigator's discretion.
- •Suitable venous access to allow for all study related blood sampling (safety and research)
- •Estimated life expectancy, in the judgment of the Investigator, which will permit receipt of at least six weeks of treatment
- •Able to understand and willing to sign written informed consent and HIPAA documents
- •Female patients who are postmenopausal for at least one year before the screening visit OR surgically sterile OR of childbearing potential.
- •Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
- •Male patients, even if surgically sterilized (i.e., status postvasectomy), who agree to practice effective barrier contraception during the entire study treatment period and through four months after the last dose of study drug (female and male condoms should not be used together), OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
- •Able to undergo bone marrow aspiration or biopsy at screening
排除标准
- •Therapy with any investigational products, systemic anti-neoplastic therapy, or radiotherapy within 14 days prior to Cycle 1 Day
- •Patients actively receiving hydroxyurea are eligible and may continue to receive hydroxyurea during protocol treatment.
- •Candidates for standard and/or potentially curative treatments. (A candidate is defined as a patient that is both eligible and willing to have these treatments.)
- •Major surgery within 28 days prior to Cycle 1 Day 1
- •New York Heart Association Class III or IV heart failure, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG
- •Baseline corrected QT interval (QTc) exceeding 480 msec using the Fridericia formula and/or patients receiving class 1A or class III antiarrythmic agents.
- •Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
- •Known, active HIV, Hepatitis A, B or C infection (prior Hepatitis C infection that has been treated and determined to be cured is allowed)
- •Female patients who are pregnant or breast feeding. (Confirmation that the patient is not pregnant will require a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women.)
- •Females of child bearing potential who refuse to either practice two effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through four months after the last dose of study drug
- •Males of child bearing potential who either refuse to practice effective barrier contraception or abstain from heterosexual intercourse during the entire study treatment period and through four months after the last dose of study drug. (Includes surgically sterilized males - i.e., status post vasectomy)
- •Female patients who are both lactating and breastfeeding, or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
- •Female patients who intend to donate eggs (ova) during the course of this study or within four months after receiving their last dose of study drug(s)
- •Male patients who intend to donate sperm during the course of this study or within four months after receiving their last dose of study drug(s)
- •Significant medical or psychiatric disorder likely in the judgment of the Investigator to interfere with compliance to protocol treatment/research
- •Symptomatic central nervous system (CNS) involvement with leukemia
- •A concurrent second active and non-stable malignancy. Patients with a concurrent second active but stable malignancy are eligible.
- •Known hepatic cirrhosis or severe pre-existing hepatic impairment
研究组 & 干预措施
Minnelide 0.40 (Dose Level -1)
Dose Level -1: 25% decrease from prior dose level
- 0.40 mg/m2 administered intravenously on days 1-5, 8-12, and 15-19 of a 28 day cycle
干预措施: Minnelide (Drug)
Minnelide 0.53 (Dose Level 1)
Starting Dose Level 1:
- 0.53 mg/m2 administered intravenously on days 1-5, 8-12, and 15-19 of a 28 day cycle
干预措施: Minnelide (Drug)
Minnelide 0.67 (Dose Level 2)
Dose Level 2: 25% increase from Dose Level 1
- 0.67 mg/m2 administered intravenously on days 1-5, 8-12, and 15-19 of a 28 day cycle
干预措施: Minnelide (Drug)
Minnelide 0.80 (Dose Level 3)
Dose Level 3: 25% increase from Dose Level 2
- 0.80 mg/m2 administered intravenously on days 1-5, 8-12, and 15-19 of a 28 day cycle
干预措施: Minnelide (Drug)
结局指标
主要结局
Safety Profile of Minnelide: Rate of Toxicity in Study Participants
时间窗: From first dose of therapy to within 30 days after final dose; assessed up to 13 months
Rate of toxicity in study participants including serious adverse events (SAEs), grade 3 or higher adverse events (AEs), and dose limiting toxicities (DLTs) by treatment dose level cohorts. Toxicity will be assessed in terms of nature, grade and attribution to treatment, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03. * Evaluable for Safety: Study participants who receive at least one dose of Minnelide therapy. * Evaluable for DLT: Study participants who either experience a DLT during Cycle 1 or receive at least 12 (80%) of scheduled doses of minnelide during Cycle 1 without a DLT. Missed doses will not be made up. Eligible patients who discontinue minnelide therapy, miss more than 3 doses of Minnelide, or require a dose reduction in minnelide during Cycle 1 for reasons other than DLT will not be evaluable for DLT and will be replaced.
Maximum Tolerate Dose (MTD) of Minnelide
时间窗: During Cycle 1, up to 28 days
The MTD will be defined as highest dose level below or at the maximally administered dose for which ≤ 1 out of 6 patients experiences a dose-limiting toxicity (DLT). To determine the MTD of Minnelide, an approach using traditional "3+3" escalation rules will be used. Dose-limiting toxicity (DLT) will be defined as events that are considered by the investigator to be related to therapy with minnelide. Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 of treatment will influence decisions regarding dose escalation.
Recommended Phase 2 Dose (RP2D) of Minnelide
时间窗: During Cycle 1, up to 28 days
Following the proposed dose escalation and expansion cohort, the RP2D of Minnelide will be established as the highest dose level tested for which no more than 2 out of 12 patients experiences a dose-limiting toxicity.
次要结局
- Efficacy of Minnelide Therapy: Overall Response Rate (ORR)(Disease assessment at Baseline, Cycle 2 Day 1, afterwards on Day 1 of each/every other 28-day cycle at investigator discretion, End of Study; Assessed up to 13 months)
- Pharmacokinetics (PK): Area Under the Curve (AUC) of Plasma Concentration of Minnelide(Cycle 1 Days 1, 2, 8 and 9)
- Pharmacokinetics (PK): Maximum (Peak) Plasma Concentration (Cmax) of Minnelide(Cycle 1 Days 1, 2, 8 and 9)
- Pharmacokinetics (PK): Time to maximum plasma concentration (Tmax) of Minnelide(Cycle 1 Days 1, 2, 8 and 9)
- Pharmacokinetics (PK): Terminal Phase Half Life (t1/2) of Plasma Concentration of Minnelide(Cycle 1 Days 1, 2, 8 and 9)
- Pharmacokinetics (PK): total body clearance (CL/F)(Cycle 1 Days 1, 2, 8 and 9)
- Pharmacokinetics (PK): Apparent Volume of Distribution (Vd/F)(Cycle 1 Days 1, 2, 8 and 9)
- Pharmacodynamics (PD): Expression and Activity Levels of HSP70, PI3K/Akt/mTOR, MAPK/ERK pathway and other relevant markers(Assessed up to 12 months)
研究者
Justin Watts
Assistant Professor of Medicine
University of Miami