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Ref Type
PMID
Authors J.L. Zhao, E.S. Antonarakis, H. Cheng, D.J. George, R.R. Aggarwal, W. Abida, B. Decker, T. Smart-Curley, J. Schonhoft, A. Anderson, S. Haywood, E. Riedel, B. Carver, A. Wyatt, F. Feng, K. Knudsen, D.E. Rathkopf
Title A phase Ib study of enzalutamide (Enza) plus CC-115 in men with metastatic castration-resistant prostate cancer (mCRPC)
URL https://www.annalsofoncology.org/article/S0923-7534(21)03340-8/fulltext
Abstract Text 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). 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References