391P - Phase I Expansion of olaparib (PARP inhibitor) and AZD5363 (AKT inhibitor) in recurrent ovarian, endometrial and triple negative breast cancer

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Anti-Cancer Agents & Biologic Therapy
Drug Development
Ovarian Cancer
Endometrial Cancer
Breast Cancer
Presenter Shannon Westin
Citation Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367
Authors S. Westin1, J. Litton2, R. Williams1, P. Soliman1, M. Frumovitz1, K. Schmeler1, A. Jazaeri1, A. Sood1, K. Lu1, S. Moulder3, R. Murthy2, A. Rodriguez1, C. Samuel2, L. Engerman1, A. Cyriac1, P. Rugman4, J. Lindemann5, E. McMurtry6, G. Mills7, R. Coleman1
  • 1Gynecologic Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 2Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 3Breast Medical Oncology, MD Anderson Cancer Center, 77030 - Houston/US
  • 4Astrazeneca, AstraZeneca, NR1 - Cambridge/GB
  • 5Astrazeneca, AstraZeneca UK, SG8 6HB - Melbourn/GB
  • 6Astrazeneca, Astrazeneca, SK10 4TG - Macclesfield/GB
  • 7Systems Biology, MD Anderson Cancer Center, 77030-4095 - Houston/US

Abstract

Background

We sought to confirm the recommended phase II dose (RP2D) of the combination of olaparib and AZD5363 in women’s cancers and evaluate molecular markers of response and resistance.

Methods

Olaparib tablet formulation (O) was given orally BID, AZD5363 (A) was given orally on a 4 day on/3 day off schedule. Two dose levels were planned per the ComPAKT study (Yap AACR 2015). Responses were defined using RECIST 1.1. Patients had biopsies at baseline and after 28 days of treatment for planned correlative testing.

Results

To date, 38 patients (pts) have been enrolled. Median number of prior therapies was 4 (1-8). Only 7 (18%, 5 ovarian, 2 breast) pts had known germline BRCA mutation. The first two pts on DL1 (O 300mg; A 400mg) experienced DLTs of diarrhea and vomiting. Therefore, 6 pts were treated on DL-1 (O 300mg; A 320mg). There were no DLTs on DL-1, therefore, 6 additional pts were treated on DL1. There were no DLTs on re-explored DL1. DL1 was confirmed as the RP2D. Expansion phase was performed with an additional 24 pts. Most common adverse events (≥15%) were anemia (89%, G3/4 16%), nausea (76%, G3/4 5%), diarrhea (74%, G3/4 5%), leukopenia (61%, G3/4 11%), elevated creatinine (58%, G3/4 3%), hyperglycemia (42%, G3/4 0%), fatigue (42%, G3/4 0%),vomiting (39%, G3/4 5%), anorexia (32%, G3/4 0%), mucositis (26%, G3/4 0%), hypertriglyceridemia (18%, G3/4 0%), thrombocytopenia (18%, G3/4 0%), neutropenia (18%, G3/4 10%), hypercholesterolemia (18%, G3/4 0%), hyponatremia (16%, G3/4 5%) and constipation (16%, G3/4 0%). Of 30 pts evaluable for response, overall response rate (RR) was 24%. Seven had confirmed partial response including 1 ovarian, 4 endometrial and 2 triple negative breast cancer pts. RR among endometrial cancer pts was 50% (4/8). Six additional pts had stable disease for greater than 4 months including 4 ovarian and 1 endometrial cancer pts. Assessment of molecular correlatives of response and resistance are ongoing.

Conclusions

The combination of olaparib tablet formulation and AZD5363 is well tolerated at the confirmed RP2D and demonstrates preliminary evidence of durable tumor activity in ovarian, endometrial and triple negative breast cancer. Promising response was seen in the endometrial cancer cohort.

Clinical trial identification

NCT02208375 August 4, 2014

Legal entity responsible for the study

University of Texas MD Anderson Cancer Center

Funding

AstraZeneca, NIH SPORE for Uterine Cancer, NIH SPORE for Ovarian Cancer, Sabin Family Foundation

Disclosure

S. Westin: Advisory Board/Consulting: AstraZeneca, Clovis, Roche/Genenetech, Medivation, Ovation, Casdin Capital, Vermillion. Research Support: AstraZeneca, Critical Outcomes Technologies, Inc, Novartis. J. Litton: Research Support: GSK, Medivation/Pfizer, Novartis, EMD-Serono. Advisory Board/Consulting: Novartis, Medivation/Pfizer. P. Soliman: Research: Novartis. M. Frumovitz: Research support: Novadaq, Navidea. Consulting: Novadaq. A. Jazaeri: Research Support: AstraZeneca, Lion Biotech, Pfizer. Advisory Board/Consulting: EMD-Serono, Genentech. S. Moulder: Research support: Oncothyreon, Novartis, Pfizer, EMD-Serono. P. Rugman, J. Lindemann, E. McMurtry: Employee of AstraZeneca. G. Mills: Research Support: Abbvie, Adelson Medical, Research Foundation, AstraZeneca, Nanostring, Pfizer, Tesaro. Consultant: AstraZeneca, Medimmune, Pfizer Licensed Technology HRD Assay to Myriad Genetics. R. Coleman: Research Support: AstraZeneca, Clovis, Janssen, Merck, Roche-Genentech, Millennium. Advisory Board/Consulting: AstraZeneca, Clovis, Abbvie, Janssen, Merck, Roche-Genentech, Tesaro, Novartis, Pfizer, Bayer, Array, Millennium. All other authors have declared no conflicts of interest.