TY - JOUR
T1 - Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53
AU - Saleh, Mansoor N.
AU - Patel, Manish R.
AU - Bauer, Todd M.
AU - Goel, Sanjay
AU - Falchook, Gerald S.
AU - Shapiro, Geoffrey I.
AU - Chung, Ki Y.
AU - Infante, Jeffrey R.
AU - Conry, Robert M.
AU - Rabinowits, Guilherme
AU - Hong, David S.
AU - Wang, Judy S.
AU - Steidl, Ulrich
AU - Naik, Gurudatta
AU - Guerlavais, Vincent
AU - Vukovic, Vojislav
AU - Allen Annis, D.
AU - Aivado, Manuel
AU - Meric-Bernstam, Funda
N1 - Funding Information:
M.R. Patel reports other support from Aileron during the conduct of the study. T.M. Bauer reports grants from Aileron during the conduct of the study; as well as personal fees from Pfizer, Lilly, Bayer, and BMS outside the submitted work. G.S. Falchook reports grants from AIleron during the conduct of the study. G.S. Falchook also reports royalties from Wolters Kluwer; advisory role grants (to institution) from Fujifilm, Silicon, Navire, and Turning Point; advisory role grants (self) from EMD Serono; travel expenses from Bristol Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speakers honorarium from Total Health Conferencing and Rocky Mountain Oncology Society; and research funding (to institution) from 3-V Biosciences, Abbisko, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, RasCal, Regeneron, Rgenix, Ribon, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, and Xencor outside the submitted work. G.I. Shapiro reports other support from Aileron during the conduct of the study. G.I. Shapiro also reports grants from Eli Lilly and Merck & Co.; grants and personal fees from Merck KGaA/EMD Serono and Sierra Oncology; personal fees from Pfizer, G1 Therapeutics, Roche, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, and Blueprint Medicines outside the submitted work. G.I. Shapiro also has a patent for dosage regimen for sapacitabine and seliciclib pending and issued to Cyclacel Pharmaceuticals and Geoffrey Shapiro and compositions and methods for predicting response and resistance to CDK4/6 inhibition pending to L. Cornell and G.I. Shapiro. J.R. Infante reports other support from Aileron Therapeutics during the conduct of the study, as well as personal fees from Janssen Pharmaceuticals outside the submitted work. G. Rabinowits reports other support from Castle, Sanofi-Genzyme, Regeneron, EMD Serono, Pfizer, and Merck outside the submitted work. D.S. Hong reports grants from AbbVie, Adaptimmune, Adlai Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, EMD Serono, Erasca, Fate Therapeutics, Genentech, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, LOXO, Merck, Medimmune, Millennium, Mirati, miRNA, Molecular Templates, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics, Verstatem, and VM Oncology during the conduct of the study. D.S. Hong also reports other support from AACR, ASCO, Celgene, Eli Lilly, Genmab, GlaxoSmithKline, LOXO, miRNA, Phillips, SITC, Molecular Match, OncoResponse, Presagia Inc., and AstraZeneca; personal fees and other support from Amgen, Bayer, Genentech, Janssen, Pfizer, and Takeda; and personal fees from Alpha Insights, Acuta, Axiom, Adaptimmune, Baxter, Boxer Capital, COG, Ecor1, Genentech, GLG, Group H, Guidepoint, HCW Precision, Infinity, Merrimack, Medscape, Numab, Prime Oncology, Seattle Genetics, ST Cube, Tavistock, Trieza Therapeutics, and WebMD outside the submitted work. J.S. Wang reports other support from Florida Cancer Specialists during the conduct of the study, as well as other support from Syndax, H3 Biomedicine, AstraZeneca, Phoenix Molecular Designs, Olema, LSK BioPartners, Taiho, Celgene, Teneobio, Prelude, Acerta, Portola, LOXO, Forty Seven, Nurix, Novartis, Aevi Genomics, Ignyta, Hutchinson MediPharma, BioNTech, Stemline, GlaxoSmithKline, Agenus, Boehringer Ingelheim, Moderna, TopAlliance, Macrogenics, Jacobio, Merck, Birdie, CytomX, Janssen, Klus, Revolution, Kymab, Bicycle, Cyteir, Daiichi Sankyo, Qilu Puget Sound, Vigeo, Black Diamond, Xencor, Clovis, Ribon, Synthorx, Relay, Vedanta, StingThera, ORIC, Artios, Genentech, Treadwell, Mabspace, IGM, PureTech, Erasca, and BioTheryX outside the submitted work. U. Steidl reports grants from Bayer; personal fees from Celgene/BMS, Pieris, Vor Biopharma, and Trillium Therapeutics; grants and personal fees from Aileron and Novartis; and personal fees and other support from Stelexis outside the submitted work. V. Vukovic reports employment with Aileron Therapeutics Inc. D.A. Annis reports personal fees from Aileron Therapeutics, Inc. during the conduct of the study. M. Aivado reports other support from Aileron Therapeutics during the conduct of the study, as well as other support from Aileron Therapeutics outside the submitted work; M. Aivado also has a patent for peptidomimetic macrocycles and uses thereof issued. F. Meric-Bernstam reports grants from Aileron Therapeutics during the conduct of the study; F. Meric Bernstam also reports personal fees from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, OrgiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks, Black Diamond, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Mersana Therapeutics, Puma Biotechnology, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, and Chugai Pharmaceuticals, as well as grants from AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX, Daiichi Sankyo, Debiopharm, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology, and Taiho outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Purpose: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. Patients and Methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. Results: Seventy-one patients were enrolled: 41 in arm A (0.16–4.4 mg/kg) and 30 in arm B (0.32–2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. Conclusions: ALRN-6924 was well tolerated and demonstrated antitumor activity.
AB - Purpose: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. Patients and Methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. Results: Seventy-one patients were enrolled: 41 in arm A (0.16–4.4 mg/kg) and 30 in arm B (0.32–2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. Conclusions: ALRN-6924 was well tolerated and demonstrated antitumor activity.
UR - http://www.scopus.com/inward/record.url?scp=85115834624&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-0715
DO - 10.1158/1078-0432.CCR-21-0715
M3 - Article
C2 - 34301750
AN - SCOPUS:85115834624
SN - 1078-0432
VL - 27
SP - 5236
EP - 5247
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -