Abstract 558P
Background
Rebastinib is a switch control inhibitor of TIE2 kinase. TIE2 is expressed in endothelial cells and in a subset of macrophages with pro-angiogenic, pro-metastatic and immunosuppressive properties associated with chemotherapy resistance. This study aims to investigate the safety and preliminary efficacy of rebastinib and carboplatin in pts with solid tumors.
Methods
This is an open-label, phase Ib/II, study in which rebastinib 50 and 100 mg BID was evaluated with carboplatin AUC5/6 Q3W using 3 + 3 dose escalation rules to determine the RP2D. Dose escalation included pts with metastatic solid tumors for which carboplatin was considered appropriate treatment.
Results
As of March 27, 2020, 22 pts were enrolled in 3 dose-escalating cohorts: rebastinib 50 mg BID + AUC5 (n=3), rebastinib 100 mg BID + AUC5 (n=14), and rebastinib 100 mg BID + AUC6 (n=5). The median age was 61 yrs. Most frequent diagnoses were breast cancer (n=5); neuroendocrine carcinoma (n=3); pancreatic adenocarcinoma, NSCLC, ovarian, and cholangiocarcinoma (n=2 each). The median number of prior anti-cancer therapies was 4 (1, 12). Median duration of treatment was 8.4 weeks (0.9, 22.6). Treatment-emergent adverse events >10% were mostly Grade 1 or 2: thrombocytopenia (36%); constipation (32%); fatigue and nausea (27% each); anemia (18%); ALT/AST increased, dry mouth, neutropenia, peripheral neuropathy, and vision blurred (13% each). One pt had a serious adverse event possibly related to rebastinib (Grade 2 retinal vascular disorder). 2 DLTs out of 12 evaluable pts were reported at 100 mg BID with AUC5. Preliminary clinical activity included 1 PR (4.8%), 10 SD (48%) and a CBR of 52% at 6 weeks. Rebastinib exposure was dose proportional; PK and PD to be presented. Rebastinib 100 mg BID and carboplatin AUC5 was initially selected as the RP2D. An increased frequency of reversible muscular weakness in the dose expansion cohorts was observed and the RP2D was adjusted to rebastinib 50 mg BID.
Conclusions
The preliminary safety of rebastinib in combination with carboplatin AUC5 is acceptable. The dose expansion cohorts in TNBC, platinum-sensitive ovarian cancer, and mesothelioma are currently enrolling at rebastinib 50 mg BID with carboplatin AUC5.
Clinical trial identification
NCT03717415.
Editorial acknowledgement
Legal entity responsible for the study
Deciphera Pharmaceuticals, LLC.
Funding
Deciphera Pharmaceuticals, LLC.
Disclosure
F. Janku: Advisory/Consultancy: Decipehra Pharmaceuticals, LLC; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: IDEAYA Biosciences; Advisory/Consultancy: IFM Therapeutics; Advisory/Consultancy: Immunomet; Advisory/Consultancy: Jazz Pharmaceuticals; Advisory/Consultancy: Novartis; Advisory/Consultancy: PureTech; Advisory/Consultancy: Sequenom; Advisory/Consultancy: Sotio; Advisory/Consultancy: Synlogic; Advisory/Consultancy: Cardiff Oncology; Advisory/Consultancy: Valeant/Dendreon; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Asana Biosciences; Research grant/Funding (institution): Astellas Pharma ; Research grant/Funding (institution): Astex Pharmaceuticals ; Research grant/Funding (institution): BioMed Valley Discoveries ; Research grant/Funding (institution): Bristol-Myers Squibb ; Research grant/Funding (institution): Fujifilm; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Proximagen ; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Symphogen; Shareholder/Stockholder/Stock options: Cardiff Oncology; Non-remunerated activity/ies: Bio-Rad; Research grant/Funding (institution): Deciphera Pharmaceuticals, LLC. A.W. Tolcher: Full/Part-time employment: START; Full/Part-time employment: New Experimental Therapeutics of San Antonio; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (institution): Ascentage Pharma; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy, Research grant/Funding (institution): EMD Serono; Advisory/Consultancy, Research grant/Funding (institution): BioInvent; Advisory/Consultancy, Research grant/Funding (institution): Adagene; Advisory/Consultancy, Research grant/Funding (institution): ADC Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Agenus; Advisory/Consultancy: Aximmune; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Boston Biomedical; Advisory/Consultancy: Forbius (formerly Formation Biologics); Advisory/Consultancy: HBM Partners; Advisory/Consultancy: Mekanistic; Advisory/Consultancy, Research grant/Funding (institution): NBE Therapeutics; Advisory/Consultancy: Nuvalent; Advisory/Consultancy: Pelican; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Scimetex; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Symphogen; Advisory/Consultancy: Syneos; Advisory/Consultancy: Immunome; Advisory/Consultancy: Abgenomics; Advisory/Consultancy: Gilde Healthcare Partners; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Immunomet; Advisory/Consultancy: Menarini; Advisory/Consultancy, Research grant/Funding (institution): Mirati Therapeutics; Advisory/Consultancy: OSI Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): Pieris; Advisory/Consultancy: Aro Biotherapeutics; Advisory/Consultancy: Ridgeway Therapeutics; Advisory/Consultancy: Birdie Biotherapeutics; Advisory/Consultancy, Research grant/Funding (institution): Asana; Advisory/Consultancy: Ellipses; Advisory/Consultancy: Elucida; Advisory/Consultancy: INC Research; Advisory/Consultancy: Karma Oncology; Advisory/Consultancy: Five Prime; Advisory/Consultancy: Partner Therapeutics; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Ryvu Therapeutics; Advisory/Consultancy: Sotio; Advisory/Consultancy: Eleven Bio; Advisory/Consultancy: Jazz Pharmaceuticals; Advisory/Consultancy: PSI Pharma Support America, Inc.; Advisory/Consultancy: TFS Trial Form Support International; Advisory/Consultancy, Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): Aminex; Research grant/Funding (institution): Arrys; Research grant/Funding (institution): CStone Pharmaceuticals; Research grant/Funding (institution): Deciphera Pharmaceuticals LLC,; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Inhibrx; Research grant/Funding (institution): Innate Pharma; Research grant/Funding (institution): Kiromic; Research grant/Funding (institution): Mersana; Research grant/Funding (institution): Naturewise; Research grant/Funding (institution): NextCure; Research grant/Funding (institution): Nitto BioPharma; Research grant/Funding (institution): Tizona Therapeutics, Inc.; Research grant/Funding (institution): Amphivena; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Basilea; Research grant/Funding (institution): eFFECTOR Therapeutics; Research grant/Funding (institution): Gilead Sciences; Research grant/Funding (institution): KeChow; Research grant/Funding (institution): K Group Beta; Research grant/Funding (institution): Janssen Research & Development; Research grant/Funding (institution): Merck Sharp & Dohme; Research grant/Funding (institution): ORIC Pharmaceuticals; Research grant/Funding (institution): Samumed; Research grant/Funding (institution): Spring Bank; Research grant/Funding (institution): Sunshine Guojian; Research grant/Funding (institution): Synthorx; Research grant/Funding (institution): Birdie Biopharmaceuticals; Research grant/Funding (institution): BJ Bioscience Inc; Research grant/Funding (institution): Daiichi Sankyo, Inc.; Research grant/Funding (institution): ImmuneOncia Therapeutics Inc; Research grant/Funding (institution): Odonate Therapeutics Inc; Research grant/Funding (institution): Qilu Puget Sound Biotherapeutics Corp; Research grant/Funding (institution): Shanghai Haihe Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Takeda. L. Rosen: Research grant/Funding (institution): Bayer; Research grant/Funding (institution): CytomX Therapeutics ; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): PsiOxus Therapeutics ; Research grant/Funding (institution): Rgenix; Research grant/Funding (institution), Trial Sponsor: Deciphera Pharmaceuticals, LLC. C. Taglienti: Full/Part-time employment: Decipehra Pharmaceuticals, LLC; Shareholder/Stockholder/Stock options: Deciphera Pharmaceuticals, LLC. K. Kuida: Full/Part-time employment: Deciphera Pharmaceuticals, LLC; Shareholder/Stockholder/Stock options: Deciphera Pharmaceuticals, LLC; Shareholder/Stockholder/Stock options: Vertex Pharmaceuticals. H. Achour: Full/Part-time employment: Decipehra Pharmaceuticals, LLC. R. Ruiz-Soto: Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, I am an inventor in pending patents at Deciphera. I have transferred the rights to Deciphera: Decipehra Pharmaceuticals, LLC; Shareholder/Stockholder/Stock options, Licensing/Royalties, An inventor in 3 patents with Immunogen; transferred the rights to Immunogen.: Immunogen. P. Munster: Honoraria (self): Atlas MedX; Honoraria (self): Celgene; Honoraria (self): CStone; Honoraria (self): Epigene; Honoraria (self): McVeigh; Honoraria (self): Prometheus Laboratories; Honoraria (institution): Xynomics ; Advisory/Consultancy: HUYA Bioscience International; Leadership role, Shareholder/Stockholder/Stock options: Alessa; Research grant/Funding (institution): Andes Biotechnologies ; Research grant/Funding (institution): Biomarin; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Genentech/Roche ; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Immune Design ; Research grant/Funding (institution): Intellikine; Research grant/Funding (institution): Merck ; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): Nekta; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): OncoMed; Research grant/Funding (institution): Onconova Therapeutics; Research grant/Funding (institution): Oncosec; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Piramal Life Science; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Sanofi ; Licensing/Royalties, UCSF patent on using silastic implants to deliver anticancer agents: UCSF.