Abstract 3533
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 t1/2 ∼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; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Taiho; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: OncoMed; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: BI; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: ARMO; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Ipsen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: Oncogenex; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Advisory/Consultancy to Institution: FORMA; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Five Prime; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Macrogenics; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: GSK; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: LEAP; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: AstraZeneca; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: TG Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Incyte; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Apexigen; Research grant / Funding (institution): Koltan; Research grant / Funding (institution): SynDevRex; Research grant / Funding (institution): Forty Seven; Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Array; Research grant / Funding (institution): Onyx; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Celldex; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Agios; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Merrimack; Research grant / Funding (institution): Tyrogenex; Research grant / Funding (institution): Marshall Edwards; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Evelo; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Effector; Research grant / Funding (institution): Novocare; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Sierra; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Innate; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Arch Oncology; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Prelude Oncology; Research grant / Funding (institution): Unum Therapeutics; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Harpoon; Research grant / Funding (institution): ADC; Advisory / Consultancy, Research grant / Funding (institution), Advisory/Consultancy to Institution: Amgen; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Imclone; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Rgenix; Research grant / Funding (institution): Bellicum; Advisory / Consultancy, Advisory/Consultancy to Institution: Phoenix Bio; Advisory / Consultancy, Advisory/Consultancy to Institution: Cyteir; Advisory / Consultancy, Advisory/Consultancy to Institution: Molecular Partners; Advisory / Consultancy, Advisory/Consultancy to Institution: Torque; Advisory / Consultancy, Advisory/Consultancy to Institution: Tizona; Advisory / Consultancy, Advisory/Consultancy to Institution: Janssen; Advisory / Consultancy, Advisory/Consultancy to Institution: Tolero; Advisory / Consultancy, Advisory/Consultancy to Institution: Translational Drug Development; Advisory / Consultancy, Advisory/Consultancy to Institution: Seattle Genetics; Advisory / Consultancy, Advisory/Consultancy to Institution: Moderna Therapeutics; Advisory / Consultancy, Advisory/Consultancy to Institution: Tanabe Research Laboratories; Advisory / Consultancy, Advisory/Consultancy to Institution: BeiGene; Advisory / Consultancy, Advisory/Consultancy to Institution: Continuum Clinical; Advisory / Consultancy, Advisory/Consultancy to Institution: Kyn. 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.
Resources from the same session
592 - Effects of novel targeted anticancer drugs on cytotoxicity, apoptosis, angiogenesis, EMT, drug resistance and autophagic mechanism
Presenter: Seyma Aydinlik
Session: Poster Display session 1
Resources:
Abstract
3235 - Delineating the mechanisms of alpha 1-3 fucosyltransferase FUT11 in ovarian cancer
Presenter: Qi Chen
Session: Poster Display session 1
Resources:
Abstract
3577 - The tyrosine kinase inhibitor Dasatinib blocks tumor growth, invasion and recurrence potential by interrupting the communication between cancer cells and their surrounding microenvironment in triple negative breast cancer
Presenter: Miriam Nuncia-Cantarero
Session: Poster Display session 1
Resources:
Abstract
4808 - NORE1A induces a feedback termination of TNF signaling by antagonizing TNFR1 through ITCH-mediated destruction complex
Presenter: Jieun Ahn
Session: Poster Display session 1
Resources:
Abstract
1294 - Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small-cell cell lung cancer cell models
Presenter: Jordi Codony-Servat
Session: Poster Display session 1
Resources:
Abstract
1559 - Expression of IL-17RA promotes cancer stem-like properties of colorectal cancer cells by Stat3 activation
Presenter: Chih-Yung Yang
Session: Poster Display session 1
Resources:
Abstract
1615 - Adaption of Pancreatic Cancer Cells to AKT1 Inhibition Induces the Acquisition of Cancer Stem-Cell Like Phenotype Through Upregulation of Mitochondrial Functions
Presenter: Hugo Arasanz
Session: Poster Display session 1
Resources:
Abstract
4793 - Bub3 is phosphorylated by the Ataxia-Telangiectasia Mutated Kinase in mitosis and required for activation of the mitotic spindle checkpoint in Breast Cancer
Presenter: Mingming Xiao
Session: Poster Display session 1
Resources:
Abstract
1448 - The regulation of INK4 locus by long non-coding RNAs
Presenter: Yojiro Kotake
Session: Poster Display session 1
Resources:
Abstract
1858 - Vascular Endothelial Growth Factor in Colorectal Cancer Pathology, Survival and Treatment
Presenter: Liz Baker
Session: Poster Display session 1
Resources:
Abstract