3533 - First in human phase 1/2a study of PEN-866, a Heat Shock Protein 90 (HSP90) ligand – SN38 conjugate for patients with advanced solid tumors: Phase 1 results

Background

HSP90 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.

Methods

Pts 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.

Results

21 pts with advanced solid tumors were treated in 7 cohorts (30-360 mg flat dosing or 175 – 200 mg/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 (30-240 mg). In cohort 5 (360 mg), 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 (175 mg/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 175 mg/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 t_1/2 ∼7 h. Of 15 evaluable pts, 1 pt 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.

Conclusions

PEN-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 identification

NCT03221400 July 18, 2017.

Editorial acknowledgement

Legal entity responsible for the study

Tarveda Therapeutics, Inc.

Funding

Tarveda Therapeutics, Inc.

Disclosure

J.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. 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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.