461P - First in human phase I/IIa study of PEN-866, a heat shock protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumours: Phase I results

Abstract

BackgroundHSP90 is a molecular chaperone that plays a key role in regulating the maturation and functional stability of a wide repertoire of cellular proteins, many of which play essential roles in tumorigenesis and is highly expressed in tumors. PEN-866, a miniature drug conjugate with an SN-38 payload that targets and binds to the activated tumor HSP90, yielded complete tumor regressions in multiple xenograft models. This study assessed the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. MethodsPts with progressive, advanced solid tumors were enrolled in escalating cohorts of 2-6 pts. The primary objective was to determine the maximum tolerated dose (MTD) of PEN-866 administered weekly for 3 of 4 weeks in a 28-day course. Preliminary efficacy was assessed using RECIST 1.1. Results21 pts with advanced solid tumors were treated in 7 cohorts (30-360mg flat dosing or 175 – 200mg/m2 BSA-based dosing). As of 30 Apr 2019, the median/mean number of cycles is 2/3.1 (range 1-15), with 5 pts ongoing. PEN-866 was well tolerated with no dose limiting toxicities (DLTs) in the first 4 cohorts (30-240mg). In cohort 5 (360mg), 1 of 3 pts had grade(G)3 diarrhea, a DLT that resolved with dose reduction. Two other pts experienced G3, uncomplicated neutropenia. In cohort 6 (175mg/m2) 2 additional pts experienced G3 uncomplicated neutropenia. In cohort 7, 2 DLTs were observed (G5 dehydration and G3 fatigue). The MTD was determined to be 175mg/m2. The most frequent (≥20% pts) PEN-866 related adverse events at data cut-off were nausea, diarrhea, fatigue, vomiting, alopecia, and neutropenia. PK was nonlinear, plasma exposures increased greater than dose proportionally and median t1/2 ∼7h. Of 15 evaluable pts, 1pt with squamous cell cancer of the anus had a partial response (-47%), 7 pts had stable disease (SD) at 8 wks, 4 were sustained for 12-57 wks, including 1 ongoing SD for 57 wks. Updated safety and efficacy data will be presented. ConclusionsPEN-866 appears well tolerated with an expected adverse event profile and preliminary evidence of antitumor activity. PEN-866 will be evaluated in phase 2a expansion cohorts (NCT03221400). Clinical trial identificationNCT03221400 July 18, 2017. Legal entity responsible for the studyTarveda Therapeutics, Inc. FundingTarveda Therapeutics, Inc. DisclosureJ.C. Bendell: Research grant / Funding (institution): Tarveda Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Gilead; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Merck; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: MedImmune; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Celgene; 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G. Falchook: Research grant / Funding (institution): Tarveda Therapeutics, Inc; Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to institution: Fujifilm; Speaker Bureau / Expert testimony: Total Health Conferencing; Research grant / Funding (institution), Travel / Accommodation / Expenses: Millennium; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Ciclomed; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): American Society of Clinical Oncology; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Curis; Research grant / Funding (institution): DelMar; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hutchison MediPharma; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Jounce; Research grant / Funding (institution): Kolltan; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): miRNA Therapeutics; Research grant / Funding (institution): National Institutes of Health; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Oncothyreon; Research grant / Funding (institution): Precision Oncology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Rgenix; Research grant / Funding (institution): Strategia; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): U.T. MD Anderson Cancer Center; Research grant / Funding (institution): Vegenics.S. Sen: Advisory / Consultancy, Advisory/Consultancy to Institution: Daiichi Sankyo; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Fujifilm; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): SynthorX. M.L. Johnson: Research grant / Funding (institution): Tarveda Therapeutics, Inc; Research grant / Funding (institution), Travel / Accommodation / Expenses: Abbvie; Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Mirati Therapeutics; Research grant / Funding (institution): Genmab; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Genentech/Roche; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): Syndax; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Merck; Research grant / Funding (institution): Neovia; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Sanofi; Research grant / Funding (institution): Hengrui Therapeutics, Inc; Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi Sankyo; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Dynavax; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: LOXO; Research grant / Funding (institution): Cytomx; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: BeiGene; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): Corvus; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Incyte; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Gritstone; Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol Myers Squibb; Research grant / Funding (institution): Kadmon; Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Oncomed; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Guardant Health; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Shattuck Labs; Research grant / Funding (institution): GlaxoSmithKline; Travel / Accommodation / Expenses, Spouse / Financial dependant: Astellas; Spouse / Financial dependant: Otsuka Pharmaceuticals; Advisory / Consultancy, Advisory/Consultancy to Institution: Celgene; Advisory / Consultancy, Advisory/Consultancy to Institution: Calithera; Advisory / Consultancy, Advisory/Consultancy to Institution: Araxes Pharma; Advisory / Consultancy, Advisory/Consultancy to Institution: Mersana Therapeutics; Advisory / Consultancy, Advisory/Consultancy to Institution: Ribon Therapeutics; Travel / Accommodation / Expenses: Exelixis; Travel / Accommodation / Expenses: Sysmex Inostics; Travel / Accommodation / Expenses: Vapotherm. K. Kriksciukaite: Full / Part-time employment: Tarveda Therapeutics, Inc. L. Mei: Full / Part-time employment: Tarveda Therapeutics, Inc. R. Wooster: Shareholder / Stockholder / Stock options: Tarveda Therapeutics, Inc. J. Bloss: Full / Part-time employment: Tarveda Therapeutics, Inc. All other authors have declared no conflicts of interest.