Abstract 4530
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.
Resources from the same session
4294 - The Patient Voice: An Irish Survey of Nutrition Attitudes & Access to Dietetic Care Throughout the Cancer Journey
Presenter: Erin Stella Sullivan
Session: Poster Display session 1
Resources:
Abstract
1925 - Homcology: home chemotherapy delivery in a simultaneous care project for frail advanced cancer patients
Presenter: Claudio Chini
Session: Poster Display session 1
Resources:
Abstract
4701 - Treatment-related adverse events and tolerability in patients with advanced non-squamous non-small cell lung cancer treated with first-line checkpoint inhibitors in combination with chemotherapy
Presenter: Ruth D'cunha
Session: Poster Display session 1
Resources:
Abstract
2985 - Clinical utility of a systematic toxicity assessment form (STAF) in patients with breast cancer receiving adjuvant or neoadjuvant therapy.
Presenter: Jwa Hoon Kim
Session: Poster Display session 1
Resources:
Abstract
2358 - Physicians’ satisfaction with Health-related quality of life (HRQoL) assessment in daily clinical practice using electronic patient-reported outcome (ePRO) for cancer patients.
Presenter: Guillaume Mouillet
Session: Poster Display session 1
Resources:
Abstract
5172 - Predictors of Survival in Patients with Incurable Cancer
Presenter: Erin Stella Sullivan
Session: Poster Display session 1
Resources:
Abstract
2281 - Patients and Physicians' Satisfaction with Telemedicine (TM) in Cancer Care and Factors that Correlate with a Positive Patient’s Experience
Presenter: Hurria Gondal
Session: Poster Display session 1
Resources:
Abstract
2193 - Adherence to ESMO 2014 guidelines on bone-targeting agent (BTA) initiation for breast and prostate cancer patients: real-world insights from practicing European physicians
Presenter: Alex Rider
Session: Poster Display session 1
Resources:
Abstract
2200 - Use of skeletal-related events preventive agents in patients with solid tumours and bone metastases in central Denmark
Presenter: Anders Boysen
Session: Poster Display session 1
Resources:
Abstract
2504 - Inadequacy of current definition and staging system of Medication-Related Osteonecrosis of Jaw (MRONJ) released by AAOMS : a Computed Tomography study in 151 cancer and myeloma patients
Presenter: Vittorio Fusco
Session: Poster Display session 1
Resources:
Abstract