Clinical Trial 18876

Cancer Type: Malignant Hematology
Interventions:ALRN-6924; Cytarabine (Cytosine Arabinoside)

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • David Sallman

Overview

Study Title

A Phase 1/1b Open-Label Study to Determine the Safety and Tolerability of ALRN-6924 alone and in Combination with Cytarabine (Ara-C) in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome with Wild-Type TP53

Summary

The purpose of this study is to evaluate safety, tolerability, PK (pharmacokinetics), PD (pharmacodynamics) and anti-tumor effects of ALRN-6924 in participants with acute myeloid leukemia or advanced myelodysplastic syndrome with wild-type (WT) TP53.

Objective

Primary Objectives: - Evaluate the safety and tolerability of ALRN-6924 alone and in combination with cytarabine (Ara-C) in adult patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS) with wild-type (WT) TP53 who are relapsed/refractory to or intolerant of standard therapy, or for whom no standard therapy exists. - Determine the dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) of ALRN-6924 alone and in combination with cytarabine in adult patients with AML or advanced MDS. Secondary Objectives: - Describe the pharmacokinetics (PK) of ALRN-6924 and its metabolite and of cytarabine in blood following single and multiple intravenous (IV) infusions. - Evaluate potential clinical activity of ALRN-6924 alone and in combination with cytarabine in patients with AML or advanced MDS with WT TP53. - Investigate the immunogenicity of ALRN-6924. Exploratory Objectives: - Assess the relationship between clinical outcome and potential biomarkers such as pre-treatment p53,MDM2 and MDMX status in AML and MDS cells in bone marrow and/or peripheral blood. - Assess the effect of ALRN-6924 treatment, alone and in combination with cytarabine, on potential PD biomarkers (e.g., p53, p21, caspase, apoptosis) and TP53 mutation status in AML and MDS cells in bone marrow and/or peripheral blood.

Inclusion Criteria

  • Male or female patients age 18 years and older, inclusive, at the time of informed consent
  • Relapsed or refractory acute myeloid leukemia (AML) or IPSS-R intermediate/high/very high-risk myelodysplastic syndrome (MDS) patients
  • Wild-type TP53 status
  • ECOG (Eastern Cooperative Oncology Group) performance status 0-2
  • Predicted life expectancy of ≥ 3 months
  • Adequate hematologic function
  • Adequate hepatic function
  • Acceptable coagulation profile
  • Recovery from significant toxicities from previous therapies and sufficient time since last dose of previous therapy
  • Negative serum or urine pregnancy test within 7 days prior to the first dose of ALRN-6924 for women of child-bearing potential
  • Ability to understand and willingness to sign a written informed consent document
  • Willing and able to undergo a pre- and subsequent on-treatment bone marrow biopsies

  • Exclusion Criteria

  • Are eligible for available approved standard therapies
  • Patients with a myelodysplastic/myeloproliferative neoplasm
  • Previous treatment with investigational agents that inhibit MDM2 or MDMX activity (some MDM2-treated patients may be eligible)
  • History of allogeneic stem cell transplantation
  • Leukemic blast counts of >25,000/µl
  • Deletion of chromosome 17, or del(17p)
  • Evidence of current central nervous system leukemic involvement
  • Known hypersensitivity to any study drug component
  • History of coagulopathy
  • History of pulmonary embolism within 6 months prior to the first dose of ALRN-6924 or untreated DVT (deep vein thrombosis)
  • Required concurrent use of anti-coagulants or anti-platelet medication, with the exception of aspirin doses ≤81 mg/day, low-dose SC heparin or SC low-molecular-weight heparin for DVT prophylaxis, or heparin flushes to maintain IV catheter patency
  • Pre-existing history of or known cardiovascular risk
  • Clinically significant gastrointestinal bleeding within 6 months prior to the first dose of ALRN-6924
  • Clinically significant third-space fluid accumulation
  • Pregnant or lactating females
  • Evidence of any serious and/or unstable pre-existing medical condition that would interfere with patient safety ability to provide informed consent
  • Active uncontrolled infection, including HIV/AIDS or Hepatitis B or C
  • Known history of another primary malignancy that has not been in remission for ≥1 year
  • Any other condition that may interfere with compliance of the study protocol
  • Required use of medications predominantly cleared by hepatobiliary transporters within 48 hours of study drug infusion