Spots Global Cancer Trial Database for Minnelide in Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia

Study Description

Brief Summary: 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).

Detailed Description: 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. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. Adverse events (AEs) will be assessed, and laboratory values, vital signs, and electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of minnelide. Serial blood samples for determination of the plasma concentration of minnelide will be obtained during Cycle 1 at pre-specified time points. Assessment of disease response will follow the criteria outlined in the recommendations of the International Working Group (IWG) for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in myeloid malignancies \[21, 22\]. Circulating leukemic blasts will be assayed for pharmacodynamic marker levels before and at pre-defined time points after minnelide administration to characterize the extent and duration of the biological effects of minnelide in leukemic cells. Exploratory analyses of potential relationships between measures of plasma drug exposure and pharmacodynamic effects of minnelide may be performed as permitted by the data.

Keywords

Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: ALL

Healthy Volunteers: No

Locations

Contact Details

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