Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Safety Study of ALRN-6924 in Patients With Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome

Summary: Phase I, open label, multi-center dose escalation (DEP) and dose expansion (EXP) study designed to evaluate safety, tolerability, PK (pharmacokinetics), PD (pharmacodynamics) and anti-tumor effects of ALRN-6924 in patients with acute myeloid leukemia or advanced myelodysplastic syndrome with wild-type (WT) TP53.

Detailed description: Phase I, open label, multi-center dose escalation (DEP) and dose expansion (EXP) study designed to evaluate safety, tolerability, PK (pharmacokinetics), PD (pharmacodynamics) and anti-tumor effects of ALRN-6924 in patients with acute myeloid leukemia or advanced myelodysplastic syndrome with wild-type (WT) TP53. ALRN-6924 is a stapled peptide designed to disrupt integration between the p53 tumor suppression protein and inhibition by murine double minute 2 (MDM2) and murine double minute X (MDMX).
  Men and women 18 years of age and older with relapsed or refractory acute myeloid leukemia or advanced myelodysplastic syndrome and for which standard treatment(s) are not available or are no longer effective can be enrolled. Treatment of patients in the DEP and EXP phases will continue in the study until documentation of disease progression, unacceptable toxicity, or patient or physician decision to discontinue study participation is made.

Eligibility: Inclusion Criteria:
  -  Male or female patients age 18 years and older, inclusive, at the time of informed consent
  -  Relapsed or refractory acute myeloid leukemia or IPSS-R intermediate/high/very high-risk 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:
  -  Patients 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)
  -  Patients with history of allogeneic stem cell transplantation
  -  Leukemic blast counts of >25,000/µl
  -  Deletion of chromosome 17, or del(17p)
  -  Patients with 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
  -  Patients with 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

Relevance to patient case: not relevant