598P - A phase Ib study of enzalutamide (Enza) plus CC-115 in men with metastatic castration-resistant prostate cancer (mCRPC)

Background

CC-115 is a potent and selective dual mTORC1/2 and DNA-PK inhibitor with promising antitumor activity when combined with androgen receptor (AR) inhibition in pre-clinical models.

Methods

This was a phase Ib multicenter trial testing Enza (160mg QD) with escalating doses of oral CC-115 in first-line mCRPC patients (pts). The primary objectives were to determine the safety, pharmacokinetics (PK) and recommended phase II dose (RP2D). The secondary objectives were to assess PSA response, preliminary antitumor activity, and exploratory biomarkers.

Results

41 pts were treated in dose-escalation (n=9) and expansion cohorts (n=32). Pts received CC-115 at 10mg BID (n=13), 7.5mg BID (n=10), and 5mg BID (n=18). There was no PK interaction between drugs. The most common adverse effects were rash (63%, Grade (Gr) 1-3), diarrhea (37%, Gr 1-2), and hypertension (27%, Gr 1-3). The most common Gr 3 toxicity was rash, which resolved with a brief course of topical or oral steroids. A high incidence of Gr 3 rash prompted CC-115 dose reduction from 10mg to 7.5mg and ultimately 5mg BID. In 40 evaluable pts, 80% achieved a ≥50% reduction in PSA (PSA50) and 58% achieved a ≥90% reduction in PSA (PSA90) by 12 weeks. Importantly, the pts with PTEN mutation/deletion or any PI3K pathway alterations (PTEN mut/del, PI3CA activating mut, TSC1/2 loss) by genomic profiling showed an improved PSA response and longer time on treatment, compared to the pts without these mutations (Table). Table: 598P

Conclusions

The combination of Enza and CC-115 was safe and without PK interactions. Pts with PTEN deletion/mutation or any PI3K pathway alterations had an improved PSA response and longer median time on treatment, suggesting that dual AR and PI3K inhibition in pts with PI3K pathway alterations may lead to improved outcomes. Prostate Cancer Clinical Trials Consortium-managed trial.

Clinical trial identification

NCT02833883.

Editorial acknowledgement

Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center.

Funding

Celgene Corporation, Gateway for Cancer Research.

Disclosure

E.S. Antonarakis: Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Institutional, Research Grant: Bristol Myers-Squibb; Financial Interests, Institutional, Research Grant: Celgene; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Dendreon; Financial Interests, Personal, Advisory Role: Eli Lilly and Co.; Financial Interests, Personal, Advisory Role: ESSA; Financial Interests, Personal, Research Grant: Genentech; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Johnson & Johnson; Financial Interests, Personal, Advisory Role: Medivation; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Licensing Fees: Qiagen; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Tokai. H. Cheng: Financial Interests, Institutional, Funding: Color Genomics Foundation; Financial Interests, Institutional, Funding: Clovis Oncology; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Funding: Fred Hutchinson Cancer Research Center; Financial Interests, Personal, Advisory Role: AstraZeneca. D.J. George: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: Innocrin Pharma; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Myovant Sciences; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Michael J. Hennessy Associates; Financial Interests, Personal, Advisory Role: Vizuri; Financial Interests, Personal, Advisory Role: Constellation Pharmaceuticals; Financial Interests, Personal, Advisory Role: Physicans' Education Resource; Financial Interests, Personal, Advisory Role: Propella Therapeutics; Financial Interests, Personal, Leadership Role: Capio BioSciences; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Exelixis; Financial Interests, Personal, Other, Travel: Bayer; Financial Interests, Personal, Other, Travel: Exelixis; Financial Interests, Personal, Other, Travel: Merck; Financial Interests, Personal, Other, Travel: Pfizer; Financial Interests, Personal, Other, Travel: Sanofi; Financial Interests, Personal, Other, Travel: Janssen Oncology; Financial Interests, Personal, Other, Travel: UroToday; Financial Interests, Personal, Other, Honoraria: Sanofi; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Other, Honoraria: Exelixis; Financial Interests, Personal, Other, Honoraria: EMD Serono; Financial Interests, Personal, Other, Honoraria: OncLive; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: UroToday; Financial Interests, Personal, Other, Honoraria: Acceleron Pharma; Financial Interests, Personal, Other, Honoraria: American Association for Cancer Research; Financial Interests, Personal, Other, Honoraria: Axess Oncology; Financial Interests, Personal, Other, Honoraria: Janssen Oncology; Financial Interests, Personal, Other, Honoraria: Millennium Medical Publishing; Financial Interests, Institutional, Funding: Exelixis; Financial Interests, Institutional, Funding: Janssen Oncology; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Astellas Pharma; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Financial Interests, Institutional, Funding: Acerta Pharma; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Dendreon; Financial Interests, Institutional, Funding: Innocrin Pharma; Financial Interests, Institutional, Funding: Calithera Biosciences; Financial Interests, Institutional, Funding: Sanofi/Aventis. R.R. Aggarwal: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Dendreon; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications; Financial Interests, Personal, Advisory Role: Clovis Oncology; Financial Interests, Personal, Advisory Role: Axiom Biotechnologies; Financial Interests, Personal, Other, Honoraria: Clovis Oncology; Financial Interests, Institutional, Funding: Zenith Epigenetics; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Xynomic Pharma; Financial Interests, Institutional, Funding: Cancer Targeted Technology; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Abbvie; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: BioXCel therapeutics. W. Abida: Financial Interests, Personal, Advisory Role: Clovis Oncology; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: MORE Health; Financial Interests, Personal, Advisory Role: ORIC Pharmaceuticals; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: Zenith Epigenetics; Financial Interests, Institutional, Sponsor/Funding: Clovis Oncology; Financial Interests, Institutional, Sponsor/Funding: GlaxoSmithKline; Financial Interests, Institutional, Sponsor/Funding: ORIC Pharmaceuticals; Financial Interests, Institutional, Sponsor/Funding: Epizyme; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: GlaxoSmithKline; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Clovis Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: ORIC Pharmaceuticals. J. Schonhoft: Financial Interests, Institutional, Stocks/Shares: Epic Sciences. A. Anderson: Financial Interests, Institutional, Stocks/Shares: Epic Sciences. A. Wyatt: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: ESSA Pharma. F. Feng: Financial Interests, Personal, Advisory Role: Blue Earth Diagnostics; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Janssen Biotech; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: Myovant Sciences; Financial Interests, Personal, Advisory Role: Roivant; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: SerImmune; Financial Interests, Personal, Leadership Role: PFS Genomics; Financial Interests, Institutional, Royalties: University of Michigan; Financial Interests, Personal, Stocks/Shares: PFS Genomics; Financial Interests, Personal, Other, Honoraria: Genentech; Financial Interests, Personal, Funding: Zenith Epigenetics. K. Knudsen: Financial Interests, Personal, Advisory Role: CellCentric; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Atrin Pharmaceuticals; Financial Interests, Personal, Advisory Role: Context Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Genentech; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Stocks/Shares: Genomic Health; Financial Interests, Personal, Other, Honoraria: CellCentric; Financial Interests, Personal, Other, Honoraria: Sanofi; Financial Interests, Personal, Funding: Celgene. D.E. Rathkopf: Financial Interests, Personal, Advisory Role: Jansen; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Myovant Sciences; Financial Interests, Institutional, Funding: Janssen Oncology; Financial Interests, Institutional, Funding: Medivation; Financial Interests, Institutional, Funding: Celgene; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Institutional, Funding: Millennium; Financial Interests, Institutional, Funding: Ferring; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Taiho Pharmaceutical; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Genentech/Roche; Financial Interests, Institutional, Funding: TRACON Pharma; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Phosplatin Therapeutics. All other authors have declared no conflicts of interest.