Minnelide in Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT03347994 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 20170643
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia; AML; Refractory AML; Relapsed AML; Refractory Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• Safety Profile of Minnelide: Rate of Toxicity in Study Participants

  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.

  From first dose of therapy to within 30 days after final dose; assessed up to 13 months

• Maximum Tolerate Dose (MTD) of Minnelide

  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.

  During Cycle 1, up to 28 days

• Recommended Phase 2 Dose (RP2D) of Minnelide

  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.

  During Cycle 1, up to 28 days

Secondary Outcomes (8)

• 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

Study Arms (4)

Minnelide 0.40 (Dose Level -1)

EXPERIMENTAL

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

Drug: Minnelide

Minnelide 0.53 (Dose Level 1)

EXPERIMENTAL

Starting Dose Level 1: * 0.53 mg/m2 administered intravenously on days 1-5, 8-12, and 15-19 of a 28 day cycle

Drug: Minnelide

Minnelide 0.67 (Dose Level 2)

EXPERIMENTAL

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

Drug: Minnelide

Minnelide 0.80 (Dose Level 3)

EXPERIMENTAL

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

Drug: Minnelide

Interventions

Minnelide DRUG

Minnelide therapy may be administered for up to 12 cycles of 28 days are planned. If patients are receiving clinical benefit, treatment can continue beyond 12 cycles.

Also known as: Minnelide for Injection

Minnelide 0.40 (Dose Level -1); Minnelide 0.53 (Dose Level 1); Minnelide 0.67 (Dose Level 2); Minnelide 0.80 (Dose Level 3)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 1. 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.

You may not qualify if:

• Therapy with any investigational products, systemic anti-neoplastic therapy, or radiotherapy within 14 days prior to Cycle 1 Day 1. 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

Sponsors & Collaborators

• Justin Watts: lead
• Minneamrita Therapeutics LLC: collaborator

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

14-O-phosphonooxymethyltriptolide disodium salt; Injections

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Justin Watts, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: Dose escalation

Study Record Dates

• First Submitted: November 15, 2017
• First Posted: November 20, 2017
• Study Start: April 1, 2018
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2022
• Last Updated: March 6, 2018

Record last verified: 2018-03