A phase I/II study of cabazitaxel (Cbz) combined with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed after docetaxel (D) chemotherapy: Preliminary results.

Abstract

5049^ Background: Both Cbz and AA have demonstrated significantly improved survival in randomized Ph 3 studies in pts with mCRPC and progressive disease after D treatment. Cbz and AA have established non-overlapping adverse event (AE) profiles. A Ph 1/2 study was initiated to investigate the combination of Cbz + AA for the treatment of mCRPC (NCT01511536). Methods: Pts with progressive mCRPC after D were enrolled. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + AA (Ph 1), and the PSA response rate (RR) with this combination (Ph 2). Secondary endpoints included AEs, pharmacokinetics (PK) and efficacy. All pts received oral AA 1000 mg QD and P 5 mg BID. In Ph 1, pts received 1 of 2 dose levels (DL) of Cbz (20 and 25 mg/m2 IV Q3W) according to a 3+3 design. A 2-cycle DLT observation period was used. Here, we report results of Ph 1. Results: Ten pts were enrolled in Ph 1; 9 were evaluable: 3 at DL1 and 6 at DL2 completed 2 cycles without DLTs (total number of cycles = 46). In general, AEs were Grade (Gr) 1/2; the most frequent all-Gr AEs by pt cycle were asthenia (39%), diarrhea (37%; Gr 3 in 1 pt), back pain (26%), nausea (20%), constipation (20%), anemia (17%), decreased appetite (17%) and fatigue (15%; Gr 3 in 2 pts). In the safety population, 0/3 pts at DL1 and 2/7 pts at DL2 experienced Gr 3–4 neutropenia. The MTD was established at the full approved doses of both drugs (Cbz 25 mg/m2/AA 1000 mg). In 6 pts evaluable for PK (DL1 and DL2), median Cbz clearance (coefficient of variation %) was similar at cycle 1 (Cbz alone: 28.9 L/h/m2 [11%]) and cycle 2 (Cbz + AA coadministration: 28.6 L/h/m2 [42%]). In 9 evaluable pts, 55% PSA RR was observed. Conclusions: In this Ph 1 study, Cbz in combination with AA appeared to have a manageable safety profile. Gr 3–4 neutropenia was observed in 2 of 10 patients. Daily AA treatment did not affect Cbz clearance; Cbz exposure was comparable to previous studies of Cbz + P treatment. The Ph 2 portion is ongoing at the established MTD. Detailed safety, PK and preliminary efficacy data (Ph 1) will be presented. Clinical trial information: NCT01511536.