Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer

NCT03654716 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 18-284
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 4

Brief Summary

This research study is studying a novel drug called ALRN-6924 as a possible treatment for resistant (refractory) solid tumor, brain tumor, lymphoma or leukemia. The drugs involved in this study are:

• ALRN-6924
• Cytarabine (for patients with leukemia only)

Conditions

Leukemia; Brain Tumor; Solid Tumor; Lymphoma

Keywords

Leukemia; Solid Tumor; Brain Tumor; Lymphoma; TP53; p53; MDM2; MDMX; PPM1D

Outcome Measures

Primary Outcomes (2)

• Percentage of patients with dose limiting toxicity by CTCAE v.5.0 for each dose level

  2 years

• Percentage of patients with toxicity by CTCAE v.5.0

  2 Years

Secondary Outcomes (3)

• Peak plasma concentration of ALRN-6924

  2 years

• Area under the curve (AUC) of ALRN-6924

  2 years

• Objective response rate

  2 years

Study Arms (3)

ALRN-6924 -- Cohort A

EXPERIMENTAL

* Participants will receive ALRN-6924 monotherapy on days 1, 4 (± 1 day), 8 (± 1 day), and 11 (± 1 day) of a 21-day cycle. * ALRN-6924 will be administered intravenously. * Participants with otherwise unselected TP53 wild type solid tumors and lymphoma will participate in this cohort.

Drug: ALRN-6924

ALRN-6924 -- Cohort B

EXPERIMENTAL

* Participants will receive ALRN-6924 monotherapy on days 1, 4 (± 1 day), 8 (± 1 day), and 11 (± 1 day) of a 21-day cycle. * ALRN-6924 will be administered intravenously. * Participants with solid and CNS tumors and lymphoma with specific diagnoses or molecular features will participate in this cohort.

Drug: ALRN-6924

ALRN-6924 -- Cohort C

EXPERIMENTAL

* Patients will receive ALRN-6924 in combination with cytarabine on days 1, 8 (± 1 day), and 15 (± 1 day) of a 28-day cycle. * Cytarabine is administered intravenously. * ALRN-6924 will be administered intravenously. * Participants with TP53 wild type acute leukemia will participate in this cohort.

Drug: ALRN-6924; Drug: Cytarabine

Interventions

ALRN-6924 DRUG

ALRN-6924 is a drug that blocks certain proteins in tumor cells called MDM2 and MDMX. These proteins may be important in the growth of some cancers. Laboratory experiments and results from studies with adults show that ALRN-6924 may stop tumor growth and, in some cases, may cause tumor cells to die.

ALRN-6924 -- Cohort A; ALRN-6924 -- Cohort B; ALRN-6924 -- Cohort C

Cytarabine DRUG

Cytarabine belongs to the category of chemotherapy called antimetabolites. Antimetabolites are very similar to normal substances within the cell. When the cells incorporate these substances into the cellular metabolism, they are unable to divide

Also known as: Cytosar

ALRN-6924 -- Cohort C

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age \> 1 years and ≤ 21 years at time of enrollment.
• Karnofsky performance status ≥ 50% for patients ≥16 years of age and/or Lansky ≥ 50% for patients \<16 years of age
• For Cohorts A and B
• Participants must have evaluable or measurable disease.
• Must have disease that is relapsed or refractory and for which standard curative or palliative measures do not exist or are no longer effective.
• For Cohort A, participants must have histologically confirmed non-CNS primary solid tumors or lymphoma based upon biopsy or surgery at initial diagnosis and/or relapse/progression. The only exception to histologic confirmation is for patients with retinoblastoma.
• For Cohort B, participants must have one of the following confirmed diagnoses:
• Diagnosis of retinoblastoma
• Histologic diagnosis of hepatoblastoma and WT TP53
• Diagnosis of malignant rhabdoid tumor and WT TP53. For the purposes of this study, a diagnosis of malignant rhabdoid tumor will include histologic diagnosis (CNS atypical teratoid/rhabdoid tumor, rhabdoid tumor of the kidney or rhabdoid tumor of the soft tissue) AND molecular confirmation (loss of INI1 protein staining or BRG1 protein staining by IHC, or documentation of SMARCB1 or SMARCA4 mutation or loss)
• Solid tumor, CNS tumor, or lymphoma with MDM2 amplification or high-copy gain and WT TP53
• Solid tumor, CNS tumor, or lymphoma with MDMX amplification or high-copy gain and WT TP53
• Solid tumor, CNS tumor, or lymphoma with PPM1D amplification, high-copy gain, or PPM1D activating mutation and WT TP53
• Solid tumor or lymphoma with TET2 loss or loss-of-function mutation and WT TP53
• Testing for MDM2, MDMX, TP53, SMARCB1, SMARCA4, PPM1D and TET2 variants must be performed in a laboratory certified to return results for clinical purposes in order to be used to qualify a patient for Cohort B.

You may not qualify if:

• Patients receiving medications within 48 hours of enrollment that are primarily cleared by organic anion transporter polypeptide \[OATP\] members OATP1B1 and OATP1B3
• Pregnant participants will not be entered on this study given that the effects of ALRN-6924 on the developing human fetus are unknown.
• Breastfeeding mothers are not eligible, because there is an unknown risk for adverse events in nursing infants secondary to treatment of the mother with ALRN-6924.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ALRN-6924.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with a known history of HIV, hepatitis B, and/or hepatitis C (testing not required as part of screening).
• Patients with a known personal history of angioedema or known family history of hereditary angioedema.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• TeamConnor Childhood Cancer Foundation: collaborator
• Cookies for Kids' Cancer: collaborator
• Aileron Therapeutics, Inc.: collaborator

Study Sites (4)

UCSF Benioff Children's Hospital

San Francisco, California, 94158, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Texas Children's Hospital, Baylor College of Medicine

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Leukemia; Brain Neoplasms; Lymphoma

Interventions

Cytarabine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• David S Shulman, MD

  Dana-Farber Cancer Institute

  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: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 29, 2018
• First Posted: August 31, 2018
• Study Start: November 1, 2018
• Primary Completion: July 17, 2023
• Study Completion: July 17, 2023
• Last Updated: February 14, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)