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 Cytotoxic agents
Ovarian Cancer
Therapy
Biological therapy
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.