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|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)|
|Journal||Annals of Oncology|
|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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|PIK3CA act mut||castration-resistant prostate carcinoma||predicted - sensitive||CC-115 + Enzalutamide||Phase I||Actionable||In a Phase Ib trial, combination of Xtandi (enzalutamide) and CC-115 was safe and resulted in a PSA reduction >= 50% (PSA50) in 80% and >=90% (PSA90) in 58% of patients with metastatic castration-resistant prostate cancer at 12 weeks, patients harboring PIK3CA activating mutations or TSC1/2 loss (n=16) achieved superior PSA50, PSA90, and median time on treatment (94%, 63%, 57 wks) compared to PI3K pathway wild-type (n=24) patients (71%, 54%, 44 wks) (Ann Oncol (2021) 32 (suppl_5): S626-S677; NCT02833883).||detail...|
|PTEN inact mut||castration-resistant prostate carcinoma||predicted - sensitive||CC-115 + Enzalutamide||Phase I||Actionable||In a Phase Ib trial, Xtandi (enzalutamide) and CC-115 combination therapy was safe and resulted in a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% of patients with metastatic castration-resistant prostate cancer at 12 weeks, patients harboring PTEN mutation or deletion (n=11) achieved superior PSA50, PSA90, and median time on treatment (91%, 55%, 59 wks) compared to PTEN wild-type (n=29) patients (76%, 59%, 44 wks) (Ann Oncol (2021) 32 (suppl_5): S626-S677; NCT02833883).||detail...|