Abstract CT010: Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations
Authors: Michalarea Vasiliki , Roda Desam , Drew Yvette , Carreira Suzanne , O’Carrigan Brent S. , Shaw Heather , Roux Rene , Kumar Sanjeev , Ward Sarah , Parmar Mona , Turner Alison , Hall Emma , Serrano Fandos Sonia , Perez Raquel , Tunariu Nina , Raynaud Florence , Cullberg Marie , Foxley Andrew , Lindemann Justin PO , Pass Martin , Rugman Paul , Lopez Juanita S. , Banerji Udai , Basu Bristi , Plummer Ruth , Kristeleit Rebecca , de Bono Johann S. , Yap Timothy A. 
Published: July 2016

Abstract
Background: Preclinical synergy between PARP and PI3K pathway inhibition in BRCA m and sporadic cancers provided rationale for this trial.
Methods: Ola 300mg BID was combined with 2 schedules of AZD BID: 4 days on 3 days off (4/7) and 2 days on 5 days off (2/7) using a novel intrapatient dose escalation design (Michalarea et al, AACR 2015). Cohort expansion of pts with gBRCA m tumors and sporadic tumors with relevant somatic mutations or BRCAness phenotype, assessed 2 regimens: (1) 300mg BID Ola + 400mg BID 4/7 AZD and (2) 300mg BID Ola + 640mg BID 2/7 AZD. Targeted next generation sequencing (NGS) of tumor and cell-free (cf)DNA from 3-weekly plasma samples with a 113 gene panel was undertaken in all pts.
Results: 53 pts with advanced cancers (21 gBRCA m) were enrolled (20 in dose escalation; 33 in dose expansion), including ovarian (9/19 with BRCA m), breast (8/16 with BRCA m), prostate (3/4 with BRCA m) and bile duct (1/2 with BRCA m) cancers. Common G1-2 toxicities were nausea, fatigue, anemia, diarrhea, anorexia, mucositis and vomiting on both schedules. 1 dose limiting toxicity (DLT) of G3 rash was seen at 300mg BID Ola + 480mg BID 4/7 AZD. In 4/7 schedule (n = 23), non-DLT G3 toxicities were anemia (n = 3), diarrhea, vomiting and proteinuria (all n = 1). In 2/7 schedule (n = 30), non-DLT G3 toxicities were transaminitis, nausea, fatigue, anemia (all n = 2), rash, hyperglycemia and diarrhea (all n = 1). There were 10 RECIST complete or partial responses (CR/PR) out of 37 (15 BRCA m) evaluable pts, including gBRCA m breast (n = 4), platinum-resistant gBRCA m ovarian (n = 2), BRCA wildtype (WT) triple negative breast (n = 1), BRCA WT ovarian (n = 2) and BRCA unknown prostate (n = 1) cancer pts. A BRCA1 m prostate cancer pt has MRI and PSA responses for 21mths+. A PI3K/mTOR inhibitor resistant peritoneal mesothelioma pt had CA125 response and RECIST stable disease (SD) for 21m. Of 5 ovarian cancer pts who had prior PARP inhibitors, 1 pt had RECIST PR at 13wks+ and 2 pts had SD with tumor shrinkage (18 and 24 wks). 160 cfDNA samples from 38 pts underwent NGS (minimum coverage 500X). Driver mutations were detected and tracked from baseline in 28 (76%) pts. Concordance in mutation status between tumor and cfDNA was 100% in 24/28 (86%) pts. 70% of pts had DNA repair gene mutations, most frequently BRCA. TP53 (40%) and KRAS (25%) were the most commonly detected somatic mutations. Changes in cfDNA concentrations appeared to correlate with treatment response in 72% of pts, while tracking of mutation allele frequency in serial cfDNA samples during treatment showed potential clonal responses.
Conclusion: The combination of Ola and AZD is well tolerated with multiple responses in both gBRCA and non-BRCA m tumors, and prior PARP inhibitor treated cancers. The recommended phase 2 doses are 300mg BID Ola + 400mg BID 4/7 AZD and 300mg BID Ola + 640mg BID 2/7 AZD.
Citation Format: Vasiliki Michalarea, Desam Roda, Yvette Drew, Suzanne Carreira, Brent S. O’Carrigan, Heather Shaw, Rene Roux, Sanjeev Kumar, Sarah Ward, Mona Parmar, Alison Turner, Emma Hall, Sonia Serrano Fandos, Raquel Perez, Nina Tunariu, Florence Raynaud, Marie Cullberg, Andrew Foxley, Justin PO Lindemann, Martin Pass, Paul Rugman, Juanita S. Lopez, Udai Banerji, Bristi Basu, Ruth Plummer, Rebecca Kristeleit, Johann S. de Bono, Timothy A. Yap. Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT010.