PMID- 35635631 OWN - NLM STAT- MEDLINE DCOM- 20220824 LR - 20221213 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 40 IP - 5 DP - 2022 Oct TI - Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study. PG - 1051-1065 LID - 10.1007/s10637-022-01253-3 [doi] AB - BACKGROUND: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naive metastatic melanoma. METHODS: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T+/-D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. RESULTS: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T+/-D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. CONCLUSION: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T+/-D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T+/-D did not confer additional clinical benefit. CI - (c) 2022. The Author(s). FAU - Moschos, Stergios J AU - Moschos SJ AUID- ORCID: 0000-0002-8943-0845 AD - Department of Medicine, Division of Medical Oncology, The University of North Carolina at Chapel Hill and the Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. moschos@med.unc.edu. FAU - Sandhu, Shahneen AU - Sandhu S AD - Department of Medical Oncology, Peter MaCallum Cancer Center and the University of Melbourne, Melbourne, VIC, Australia. FAU - Lewis, Karl D AU - Lewis KD AD - Division of Medical Oncology, Anschultz Medical Campus, University of Colorado, Denver, CO, USA. FAU - Sullivan, Ryan J AU - Sullivan RJ AD - Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. FAU - Puzanov, Igor AU - Puzanov I AD - Department of Medicine, Vanderbilt University Medical Center and Ingram Cancer Center, Nashville TN, USA. FAU - Johnson, Douglas B AU - Johnson DB AD - Department of Medicine, Vanderbilt University Medical Center and Ingram Cancer Center, Nashville TN, USA. FAU - Henary, Haby A AU - Henary HA AD - Medical Affairs, Amgen Inc, Thousand Oaks, CA, USA. FAU - Wong, Hansen AU - Wong H AD - Clinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, CA, USA. FAU - Upreti, Vijay V AU - Upreti VV AD - Clinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, CA, USA. FAU - Long, Georgina V AU - Long GV AD - Melanoma Institute Australia, The University of Sydney and Royal North Shore, and Mater Hospitals, Sydney NSW, Australia. FAU - Flaherty, Keith T AU - Flaherty KT AD - Developmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220530 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid) RN - 0 (Acetates) RN - 0 (Piperidones) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) SB - IM MH - Acetates MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/pharmacokinetics MH - Humans MH - *Melanoma/drug therapy/genetics/pathology MH - Nausea/chemically induced MH - Piperidones MH - Protein Kinase Inhibitors/adverse effects MH - Proto-Oncogene Proteins B-raf MH - Pyridones/adverse effects MH - Pyrimidinones/adverse effects MH - *Tumor Suppressor Protein p53 PMC - PMC9395504 OTO - NOTNLM OT - BRAFV600E OT - Dabrafenib OT - MDM2 inhibitors OT - Metastatic melanoma OT - Trametinib COIS- HAH, HW, VVU are employees of Amgen Inc, and may own stock/stock options in the company. DBJ has served on advisory boards or as a consultant for Bristol-Myers Squibb (BMS), Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck Sharp & Dohme (MSD), Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, and Targovax, and has received research funding from BMS and Incyte. RJS has served as consultant and/or advisory boards for Asana Biosciences, AstraZeneca, BMS, Eisai, Iovance, MSD, Novartis, Oncosec, Pfizer, Replimune and has received research funding from Amgen and Merck. SS has served on advisory boards for BMS, Jansen, MSD, Novartis, and Astra Zeneca and has received research funding from Genentech, MSD, Merck Serono, Novartis and Amgen. GVL has served as consultant advisor or on advisory boards for Aduro Biotech, Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexel AG, Highlight Therapeutics, MSD, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, Specialised Therapeutics. KTF has served on the board of directors of Loxo Oncology, Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals, Kinnate Pharmaceuticals and Scorpion Therapeutics; Corporate Advisory Board of X4 Pharmaceuticals; has served on the advisory boards of PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, and ALX Oncology; has served as a consultant to Elli Lilly and Company, Novartis, Genentech, BMS, MSD, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Debiopharm; and has received research funding from Novartis and Sanofi. see Competing interests in the Author Declarations Section. EDAT- 2022/06/01 06:00 MHDA- 2022/08/25 06:00 PMCR- 2022/05/30 CRDT- 2022/05/31 12:43 PHST- 2022/02/12 00:00 [received] PHST- 2022/04/26 00:00 [accepted] PHST- 2022/06/01 06:00 [pubmed] PHST- 2022/08/25 06:00 [medline] PHST- 2022/05/31 12:43 [entrez] PHST- 2022/05/30 00:00 [pmc-release] AID - 10.1007/s10637-022-01253-3 [pii] AID - 1253 [pii] AID - 10.1007/s10637-022-01253-3 [doi] PST - ppublish SO - Invest New Drugs. 2022 Oct;40(5):1051-1065. doi: 10.1007/s10637-022-01253-3. Epub 2022 May 30.