Minnelide in Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia

• Status: Withdrawn
• Trial end date: 2022-04-01
• Target enrollment: 0
• Participant gender: All

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).

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Justin Watts
• Collaborator: Minneamrita Therapeutics LLC
• Treatments: 14-O-phosphonooxymethyltriptolide disodium salt

Criteria

Inclusion Criteria:

1. 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).

2. Adult patients 18 years of age or older

3. Ability to understand the investigational nature, potential risks and benefits of the research study and to provide valid written informed consent.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

5. Patients must satisfy the following laboratory criteria:

1. 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.

2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 2.5 × ULN

3. Creatinine 1.5 x ULN or calculated creatinine clearance > 50ml/min

4. 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.

6. Suitable venous access to allow for all study related blood sampling (safety and research)

7. Estimated life expectancy, in the judgment of the Investigator, which will permit receipt of at least six weeks of treatment

8. Able to understand and willing to sign written informed consent and HIPAA documents

9. Female patients who are postmenopausal for at least one year before the screening visit OR surgically sterile OR of childbearing potential.

10. 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.

11. 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.

12. Able to undergo bone marrow aspiration or biopsy at screening

Exclusion Criteria:

1. 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.

2. 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.)

3. Major surgery within 28 days prior to Cycle 1 Day 1

4. 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

5. Baseline corrected QT interval (QTc) exceeding 480 msec using the Fridericia formula and/or patients receiving class 1A or class III antiarrythmic agents.

6. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy

7. Known, active HIV, Hepatitis A, B or C infection (prior Hepatitis C infection that has been treated and determined to be cured is allowed)

8. 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.)

9. 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

10. 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)

11. 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

12. 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)

13. 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)

14. Significant medical or psychiatric disorder likely in the judgment of the Investigator to interfere with compliance to protocol treatment/research

15. Symptomatic central nervous system (CNS) involvement with leukemia

16. A concurrent second active and non-stable malignancy. Patients with a concurrent second active but stable malignancy are eligible.

17. Known hepatic cirrhosis or severe pre-existing hepatic impairment