I hypothesize the optimal targeting of the DNA damage repair and related pathways will yield improved clinical outcome in homologous recombination deficient (HRD)-women's cancers, which are rare subsets of women's cancers with critical unmet need. I have initiated a new clinical trials direction, targeted to treat this population. During FY2015, we have completed patients accrual for the phase 1 olaparib/carboplatin study non-mutation carrier cohorts (08-C-0092) and for the PK/PD study of olaparib/carboplatin (11-C-0022). Analyses of prospectively planned exploratory translational endpoints of both studies are nearly complete (SAs 1-2). Findings from high-grade serous ovarian cancer (HGSOC) non-mutation carrier cohort (08-C-0092) were presented at 2015 ASCO and a manuscript is under preparation. My medical oncology fellow, Dr. Chiou, won 2015 Conquer Cancer Foundation of ASCO Merit Award based on clinical data from a HGSOC non-mutation carrier cohort of 08-C-0092 study. Dr. Chiou also presented the PK/PD study of olaparib/carboplatin (11-C-0022) clinical and correlative endpoints data at 2015 AACR Clinical Trial Plenary session. Further, I recently published our work on development and application of HRD-biomarker, using a high-throughput flow cytometry method. Our findings indicate a ratio of gH2AX/MRE11 measured in peripheral blood mononuclear cells (PBMCs) by flow cytometry may be a surrogate marker of both DNA DSB damage and repair, and this assay may be used as a predictive biomarker for response to olaparib/carboplatin treatment. We also published the exploratory biomarker endpoints, prospectively planned in the phase 2 study of olaparib and cediranib combination in platinum-sensitive recurrent ovarian cancer (12-C-0081). Our findings suggest circulating endothelial cells (CECs) and IL-8 may be predictive and prognostic biomarkers to olaparib and cediranib treatment. The promising data from a phase 2 study of olaparib/cedirarnib led us to develop an international phase 2/3 study of olaparib/cediranib compared to standard chemotherapy in platinum-resistant recurrent ovarian cancer through NRG (NSABP-RTOG-GOG) Oncology (PI: Jung-min Lee). A phase 3 study will examine biomarkers including CECs and other translational studies. The concept was approved by NCI/CTEP and the protocol is now under review by CTEP, with an anticipated opening in 3Q 2015. I have expanded my HRD-women's cancers clinical program, and have developed and opened two new phase 2 studies and one new phase 1/2 study during FY2015. First, a phase 2 study of BMN 673 (PARPi after PARPi study, 15-C-0050) examines a hypothesis that BMN673, which has a greater PARP-DNA trapping activity compared to other PARPi, may yield clinical benefit in BRCAm associated-ovarian cancer patients who have had progression on prior PARPi monotherapy. Blood and tissue acquisition is a key element of this trial; by requiring pretreatment biopsies, I will be able to sample BRCAm women who have recently progressed on PARPi yielding a strong prospective collection for secondary mutation analysis. I will further evaluate the other mechanisms of PARPi clinical resistance. This study will provide initial findings with which to lead to randomized trials in the role of repeat PARPi therapy. Secondly, I hypothesize targeting other elements of DNA damage repair and cell cycle checkpoint pathways will yield clinical benefit in HRD-women's cancers. CHK1/2 are major regulators of the cell cycle and are intimately associated with the cellular response to DNA damage and repair. CHK1 functions as the primary mediator of cell-cycle arrest in tumors with dysfunctional p53. When CHK1 protein is depleted, more replication origins are activated in early S phase than the replication apparatus can tolerate, resulting in slowed and arrested DNA replication forks and DNA DSB. Thus, I hypothesized inhibition of CHK1/2 (CHKi) will yield clinical activity in HRD-women's cancers. My phase 2 study is the Eli Lilly's first investigator-initiated trial of an early phase development agent of LY2606368, the second generation CHKi with single agent activity (14-C-0156). Several translational endpoints have been built into this study for potential therapeutic targets and predictive biomarkers. We have enrolled 17 patients since Jan 2015, and have observed early clinical activity in HGSOC at low genetic risk group, which led to development of a preclinical project to examine the preclinical synergy of CHKi and PARPi in HGSOC. This preclinical project was approved by Eli Lilly Nonclinical Research Request team, and is currently ongoing. Lastly, emerging data indicate that DNA damage repair inhibition and the VEGF/VEGFR pathway inhibition modulate immune response by increasing tumor mutational loads. Mutational load yields neoantigens that are associated with response to immune checkpoint inhibition. I hypothesized that increased DNA damage and reduced angiogenesis, subsequently creating higher mutational loads and a more antigenic environment, would complement the anti-tumor activity of an immune checkpoint inhibitor in recurrent ovarian cancer. I have successfully negotiated with AstraZeneca/MedImmune and opened an investigator-initiated phase 1/2 study of a PD-L1 inhibitor, MEDI4736 in combination with olaparib or cediranib in June 2015 (15-C-0145). This is the first phase 1/2 clinical trial testing immune checkpoint inhibition and a PARP inhibitor or VEGFR inhibition combination therapies in recurrent ovarian cancer. The correlative endpoints built into this study will further our understanding of the immune modulation by targeted agents and therapeutic susceptibility to the two different combinations. Six patients have been enrolled on the dose level 1 of the two separate cohorts (MEDI4736+olaparib and MEDI4736+cediranib). I anticipate identifying a recommended phase 2 dose and opening a phase 2 component of the study in 4Q2015. This project will provide initial findings to justify combination therapies using the PD-1/PD-L1 pathway inhibition and other small molecule targeted agents in recurrent ovarian cancer. Further, this study has the potential to benefit participating recurrent ovarian cancer patients and provide data to advance testing of the three agents (MEDI4736 + olaparib + cediranib) in recurrent ovarian cancer and in other cancers that develop in part due to genomic instability. My clinical fellow, Dr. Chiou was awarded 2015 AACR/ASCO Vail Workshop on Methods in Clinical Cancer Research, based on the proposal of MEDI4736 in combination with olaparib and cediranb in recurrent ovarian cancer. Collectively, this focused clinical and translational approach will make our branch/CCR a recognized center focusing on the treatment of women with genetically high-risk breast and/or ovarian cancer, or those with tumor HRD phenotypes with a strong translational research program.
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