876O - Randomized phase 2 study of investigational, selective aurora A kinase inhibitor alisertib (MLN8237) with weekly paclitaxel vs paclitaxel alone in...

Date 28 September 2014
Event ESMO 2014
Session Gynaecological cancers
Topics Anti-Cancer Agents & Biologic Therapy
Ovarian Cancer
Presenter Robert Coleman
Citation Annals of Oncology (2014) 25 (suppl_4): iv305-iv326. 10.1093/annonc/mdu338
Authors R.L. Coleman1, A. Roszak2, K. Behbakht3, I.L. Ray-Coquard4, U. Matulonis5, H. Liu6, C. Schusterbauer7, C. Dansky Ullmann7
  • 1Department Of Gynecologic Oncology And Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 2Department Of Gynaecological Radiotherapy And Oncology, Greater Poland Cancer Centre, Poznan/PL
  • 3Division Of Gynecologic Oncology, Department Of Obstetrics And Gynecology, University of Colorado School of Medicine, Aurora/US
  • 4Department Of Adult Medical Oncology, Centre Léon Bérard, Lyon/FR
  • 5Medical Gynecologic Oncology Program, Department Of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston/US
  • 6Statistics, Takeda Pharmaceuticals International Co., Cambridge/US
  • 7Clinical Research, Takeda Pharmaceuticals International Co., Cambridge/US

Abstract

Aim

Alisertib has shown modest single-agent activity in platinum-resistant OC and enhanced cytotoxicity with paclitaxel (P) preclinically. A phase 1 study in 49 pts with OC or breast cancer determined the MTD of alisertib + weekly P (A + P). We conducted this phase 2 study to compare A + P vs P in pts with recurrent OC.

Methods

Adult pts with epithelial ovarian, fallopian tube, or primary peritoneal cancer and ≤4 prior cytotoxic chemotherapies who relapsed within 1 yr of last platinum therapy were randomized 1:1 to alisertib 40 mg PO BID (3 d on, 4 d off for 3 wks) + P 60 mg/m2 IV (d 1, 8, 15) in 28-d cycles, or P 80 mg/m2 IV (d 1, 8, 15). Response was per RECIST v1.1 and/or CA-125 criteria. Primary endpoint was PFS. Secondary endpoints included ORR, duration of response (DOR), OS, and AEs (NCI-CTCAE v4.02).

Results

142 pts were randomized (73 A + P, 69 P); median age was 62 (30–81) yrs, 89% had primary OC, 63% were refractory/relapsed 0–6 mos after last platinum therapy. Pts received a median of 5 (1–19) (A + P) vs 4 (1–14) (P) cycles; 44% vs 33% received ≥6 cycles; 32% vs 20% remained on therapy. Table shows efficacy data at cut-off for this interim analysis of Nov 1, 2013.

A + P, N = 73 P, N = 69 HR (80% CI), p-value
By RECIST + CA-125 criteria
PFS events, n (%) 35 (48) 44 (64)
Median PFS, mos 7.0 4.4 0.674 (0.503, 0.902), p = 0.079
ORR*, n/N (%) 39/68 (57) 31/63 (49) p = 0.384
Median DOR, mos 6.9 5.8
By RECIST alone
PFS events, n (%) 25 (34) 37 (54)
Median PFS, mos 7.6 4.6 0.554 (0.397, 0.773), p = 0.021
ORR*, n/N (%) 27/62 (44) 19/54 (35) p = 0.447
Median DOR, mos Not estimable 7.6

*Investigator-assessed.

With A + P vs P, 100% vs 84% of pts had drug-related AEs, including neutropenia 71% vs 14% (febrile neutropenia 14% vs 0%), stomatitis 62% vs 9%, diarrhea 53% vs 13%, fatigue 51% vs 36%, nausea 41% vs 35%, anemia 41% vs 23%, alopecia 36% vs 29%, vomiting 19% vs 12%, constipation 18% vs 12%, decreased appetite 18% vs 4%, and peripheral neuropathy 8% vs 19%. With A + P vs P, 85% vs 20% of pts had Gr ≥3 drug-related AEs, including neutropenia 64% vs 9%, and stomatitis 22% vs 0, 36% vs 28% had serious AEs, 14% vs 1% discontinued due to AEs, and 1 pt in each arm died on study.

Conclusions

This interim analysis shows an improved PFS with A + P vs P in pts with recurrent OC, with increased AEs that were generally expected and manageable. Final analysis is planned after 110 PFS events.

Disclosure

R. Coleman: Research funding: Takeda; H. Liu, C. Schusterbauer and C. Dansky Ullmann: Employment: Takeda Pharmaceuticals International Co. All other authors have declared no conflicts of interest.