4530 - A Phase 2a clinical trial combining ALRN-6924 and palbociclib for the treatment of patients with tumors harboring wild-type p53 and MDM2 amplification or MDM2/CDK4 co-amplification

Background

ALRN-6924 is a stabilized, cell-permeating alpha-helical peptide that mimics the p53 tumor suppressor protein to disrupt p53’s interactions with its endogenous inhibitors, MDM2 and MDMX. ALRN-6924 has been evaluated in > 175 cancer patients and demonstrated single-agent activity and a well-tolerated single-agent safety profile. MDM2 amplification is an oncogenic event found in up to 4% of all cancers. Co-amplification of MDM2 and cyclin-dependent kinase 4 (CDK4), which are co-located on chromosome 12q13, provides the rationale for combined use of the MDM2-inhibitor ALRN-6924 and the CDK4/6 inhibitor palbociclib in this population, and is further supported by enhanced combination activity in preclinical models.

Methods

This trial is designed to enroll 25 patients with solid tumors harboring wild-type p53 and MDM2 amplification or MDM2/CDK4 co-amplifications. Patients have exhausted or are not eligible for other treatment options. ALRN-6924 is given at a dose of 3.1 mg/kg as IV infusion on Days 1, 8 and 15, and palbociclib is given as an oral dose of 100 mg/day on Days 1-21 of every 28-day treatment cycle. The first nine patients enrolled were evaluated for safety and tolerability after completion of one treatment cycle (safety lead-in). Anti-tumor activity is evaluated with imaging every 8 weeks.

Results

Patient enrollment started in December 2018. As of April 30, 12 patients were enrolled; tumor types include liposarcoma (N = 10), osteosarcoma and glioblastoma (1 of each); 11/12 patients had tumors that were MDM2 and CDK4 co-amplified. The combination was generally well tolerated with transient, self-resolving Grade 3 and 4 neutropenia (N = 7) emerging as the principal but not dose limiting toxicity. Other Grade 3 and 4 adverse events include thrombocytopenia, leukopenia, increased ALT, pulmonary embolism, and fall. An interim analysis of activity and safety (N = 15 patients with ≥2 post baseline CT scans) is scheduled for early September 2019 and the results will be presented.

Conclusions

The combination of ALRN-6924 and palbociclib at pharmacologically relevant doses is feasible and generally well tolerated.

Clinical trial identification

NCT02909972.

Editorial acknowledgement

Legal entity responsible for the study

Aileron Therapeutics, Inc.

Funding

Aileron Therapeutics, Inc.

Disclosure

F. Meric-Bernstam: Honoraria (self): Sumitomo Dainippon Pharma; Dialectica; Advisory / Consultancy: Genentech; Advisory / Consultancy: Inflection Biosciences; Advisory / Consultancy: Pieris; Advisory / Consultancy: Darwin Health; Advisory / Consultancy: Samsung bioepis; Advisory / Consultancy: Aduro; Advisory / Consultancy: Spectrum; Advisory / Consultancy: OrigiMed; Advisory / Consultancy: Debio; Advisory / Consultancy: Xencor; Advisory / Consultancy: Jackson Laboratory; Advisory / Consultancy: Mersana; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Kolon Life Sciences; Advisory / Consultancy: Parexel International; Research grant / Funding (institution): Novartis; AstraZeneca; Taiho; Genentech; Calithera; Debio; Bayer; PUMA; CytoMx; Research grant / Funding (institution): Aileron; Zymeworks; Curis; Pfizer; eFFECTOR; Abbvie; Guardant Health; Daiichi Sankyo; GSK; Travel / Accommodation / Expenses: Taiho; Genentech; Debio; Pfizer. S.G. DuBois: Advisory / Consultancy: Loxo Oncology; Travel / Accommodation / Expenses: Loxo Oncology; Travel / Accommodation / Expenses: Genentech. G.I. Shapiro: Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Merck KGaA/EMD Serono; Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Sierra Oncology; Advisory / Consultancy, Research grant / Funding (institution), Advisory Board: Pfizer; Research grant / Funding (institution): Array BioPharma; Advisory / Consultancy, Advisory Board: G1 Therapeutics; Advisory / Consultancy, Advisory Board: Roche; Advisory / Consultancy, Advisory Board: Bicycle Therapeutics; Advisory / Consultancy, Advisory Board: Fusion Pharmaceuticals; Advisory / Consultancy, Advisory Board: Astex; Advisory / Consultancy, Advisory Board: Almac; Advisory / Consultancy, Advisory Board: Ipsen; Advisory / Consultancy, Advisory Board: Bayer; Advisory / Consultancy, Advisory Board: Angiex; Advisory / Consultancy, Advisory Board: Daiichi Sankyo; Licensing / Royalties, Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition: Patent pending (work) on palbociclib. M.R. Patel: Research grant / Funding (institution): Aileron Therapeutics, Inc. T. Bauer: Advisory / Consultancy: Ignyta; Guardant Health; Loxo; Pfizer; Moderna Therapeutics; Pfizer; Speaker Bureau / Expert testimony, Speaker’s bureau: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Medpacto; Incyte; Mirati; MedImmune; Abbvie; AstraZeneca; Leap Therapeutics; Research grant / Funding (institution): MabVax; Stemline Therapeutics; Merck; Lilly; GSK; Novartis; Pfizer; Research grant / Funding (institution): Genentech/Roche; Deciphera; Merrimack; Immunogen; Millennium; Ignyta; Calithera; Kolltan; Research grant / Funding (institution): Principa; Peleton, Immunocore; Roche; Aileron; BMS; Amgen; Moderna; Research grant / Funding (institution): Sanofi; Boehrnger Ingelheim; Astellas; Five Prime; Jacobio; top Alliance; Loxo; Janssen; Clovis; Research grant / Funding (institution): Takeda; Karyopharm; Onyx; Phosplatin; Foundation Medicine; ARMO; Travel / Accommodation / Expenses: Astellas; AstraZeneca; Celgene; Clovis; EMD Serono; Genentech; Lilly; Travel / Accommodation / Expenses: Merck; Novartis; Pharmacyclics; Sysmex. D. Pinchasik: Full / Part-time employment, former Aileron employee: Aileron Therapeutics, Inc. A. Annis: Shareholder / Stockholder / Stock options: Aileron Therapeutics, Inc.; Full / Part-time employment: Aileron Therapeutics, Inc. M. Aivado: Shareholder / Stockholder / Stock options: Aileron Therapeutics, Inc.; Full / Part-time employment: Aileron Therapeutics, Inc. V. Vukovic: Full / Part-time employment: Aileron Therapeutics, Inc. All other authors have declared no conflicts of interest.