Clinical Trial 18858

Cancer Type: Malignant Hematology
Interventions:ALRN-6924

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

  • Lubomir Sokol

Overview

Study Title

A Phase 1/2a Open-Label Study to Determine the Safety and Tolerability of ALRN-6924 in Patients with Advanced Solid Tumors or Lymphomas Expressing Wild-Type p53 Protein

Summary

The goal of this clinical research study is to learn about ALRN-6924 in participants with Peripheral T-cell Lymphoma (PTCL). This study looks at what effects, good and bad, ALRN-6924 has on participants and their tumor.

Objective

The Primary Objectives of the Phase 1 Dose Escalation are to: - Evaluate the safety and tolerability of ALRN-6924 in adult patients with advanced solid tumors, or lymphomas with wild-type (WT) TP53 that are refractory to or intolerant of standard therapy, or for which no standard therapy exists. - Determine the dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) or the optimal biological dose (OBD) of ALRN-6924 in adult patients with advanced solid tumors or lymphomas. The Secondary Objectives are to: - Describe the pharmacokinetics (PK) of ALRN-6924 and its metabolites in blood following single and multiple intravenous (IV) infusions. - Assess potential patient biomarkers (e.g., p53 status, MDM2 and MDMX expression levels), the effect of ALRN-6924 treatment on these biomarkers, and possible correlation between these biomarkers and clinical response. - Assess the effect of ALRN-6924 treatment on potential pharmacodynamic (PD) biomarkers in tumor biopsy samples (including bone marrow aspirates), (e.g., p21, caspase, MDM2) and blood samples (e.g., macrophage inhibitory cytokine-1 [MIC-1]), and assess possible correlation between these biomarkers and clinical response. - Evaluate potential clinical activity of ALRN-6924 in patients with specific tumor types expressing WT TP53 in the dose expansion phase; tumor types will be determined based on results of the dose escalation phase, as well as data from additional nonclinical pharmacology studies. - Investigate the immunogenicity of ALRN-6924. The Exploratory Objectives are to: - Starting at dose level 3: assess the effect of ALRN-6924 treatment on potential PD biomarkers (e.g., p21, p53,caspase) in circulating tumor cells (CTC), where detectable, or in mononuclear blood cells (MNBC). - Assess the effects of ALRN-6924 treatment on cell-free DNA from blood. Study Objectives Phase 2a Dose Expansion in PTCL patients. The Primary Objectives of the Phase 2a Dose Expansion are to: - Assess Overall Response Rate. - Further evaluate the safety and tolerability of ALRN-6924. The Secondary Objectives of the Phase 2a Dose Expansion are to: - Assess Duration of Response. - Assess Progression Free Survival (PFS). - Assess Overall Survival (OS). - Assess PFS and OS at 1 year. - Assess Time to Response. - Assess the effect of ALRN-6924 treatment on potential pharmacodynamic (PD) biomarkers in tumor biopsy samples (including bone marrow aspirates, where clinically indicated) by measuring potential biomarkers such as e.g., p53, p21, caspase, MDM2, MDMX and in blood samples by measuring potential biomarkers such as e.g.,macrophage inhibitory cytokine-1 [MIC-1], and assessing possible correlation between these biomarkers and clinical outcomes. - Investigate the immunogenicity of ALRN-6924.

Inclusion Criteria

  • Males or females age 18 years and older, inclusive, at the time of informed consent
  • Histologically- or cytologically-confirmed malignancy that is metastatic or unresectable and for which standard measures do not exist or are no longer effective (dose escalation phase (DEP)) or a histologically confirmed diagnosis of Peripheral T-cell Lymphoma (PTCL) based on pathology review at the local institution, using the most recent edition of the World Health Organization (WHO) Classification, relapsed or refractory disease after at least one prior systemic anticancer regimen (expansion phase (EXP) in PTCL)
  • Wild-type (WT) the gene that encodes p53 (TP53) status
  • At least one target lesion that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for solid tumors, or IWG 2014 for lymphoma
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • 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

  • Exclusion Criteria

  • Previous treatment with investigational agents that inhibit murine double minute 2 (MDM2) or murine double minute X (MDMX) activity (some MDM2-treated patients may be eligible)
  • Known hypersensitivity to any study drug component
  • Known and untreated brain metastases. Patients with primary central nervous system (CNS) malignancies are excluded.
  • History of coagulopathy, platelet disorder or history of non-drug induced thrombocytopenia
  • History of pulmonary embolism within 6 months prior to the first dose of ALRN-6924 or untreated deep vein thrombosis (DVT)
  • 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
  • A 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
  • Active uncontrolled infection, including HIV/AIDS or Hepatitis B or C
  • Patients with cancers likely to be Human Papilloma Virus (HPV)-positive such as cervical cancers, oropharyngeal cancers or anal cancers must undergo additional screening to determine eligibility
  • Known history of another primary malignancy that has not been in remission for ≥2 years
  • Required use of medications predominantly cleared by hepatobiliary transporters within 48 hours of study drug infusion