Abstract CT048: Phase 1/2 study of olaparib tablets and temozolomide in patients with small cell lung cancer (SCLC) following failure of prior chemotherapy
Authors: Anna F. Farago, Benjamin J. Drapkin, Allison Charles, Beow Yeap, Rebecca S. Heist, Christopher G. Azzoli, David M. Jackman, David A. Barbie, Edwin Choy, Lecia V. Sequist, Shyamala Maheswaran, Daniel A. Haber, Aaron N. Hata, Nicholas Dyson, Alice T. Shaw
Journal: Cancer Research (2017)

Abstract Background: SCLC is an aggressive high-grade neuroendocrine malignancy. While SCLC is often highly sensitive to first line platinum based chemotherapy, response rates to second line cytotoxic chemotherapy range from approximately 10-30%. Inhibition of poly(ADP-ribose) polymerase (PARP) by the PARP inhibitor olaparib (O) has shown activity in SCLC in preclinical studies, though it does not confer PFS or OS benefit in the maintenance setting as monotherapy (Ahmed et al., 2016). Temozolomide (T) is an alkylating agent with modest single agent activity (ORR 22% in the second line setting; Pietanza et al., 2012), and may synergize with PARP inhibitors. Methods: This ongoing phase 1/2 trial of combination O/T in adults with SCLC (NCT02446704) enrolled patients with histologically or cytologically confirmed incurable SCLC which had progressed following at least one prior platinum-based chemotherapy. O (tablet formulation) and T were administered orally on days 1-7 of 21-day cycles at escalating doses using a standard 3+3 design in the phase 1 portion, with a primary objective of determining the recommended phase 2 dose (RP2D). Response assessments were performed every 6 weeks. In parallel, patient derived xenografts (PDXs) were generated from biopsies and circulating tumor cells (CTCs) from a subset of patients both prior to O/T and at the time of acquired resistance. O/T activity was assessed in vivo in PDXs and in short term cultures. Results: In the phase 1 portion, 13 patients were enrolled to four escalating dose levels. No dose limiting toxicities or grade 4-5 toxicities were observed. The most common grade 3 related toxicities were neutropenia (38%), anemia (15%) and thrombocytopenia (15%). O 200 mg BID and T 75 mg/m2 QD was selected as the RP2D. There were 6 confirmed partial responses (ORR 46%) and responses were seen at all dose levels. The median progression free survival was 5.6 months and median duration of response was 3.4 months. In PDXs, the depth and duration of responses of models derived pre-O/T mirrored those of the corresponding patients. Most pre-treatment models were more sensitive to combination O/T than to either O or T alone. Models derived post-progression were highly resistant to O/T. Further testing to identify biomarkers of response and resistance is ongoing. Conclusions: O/T is well tolerated in patients with SCLC and shows promising clinical activity in a phase 1 study. PDXs derived from CTCs provide a powerful platform for performing co-clinical trials and modeling acquired resistance. Additional correlative studies will be presented. Citation Format: Anna F. Farago, Benjamin J. Drapkin, Allison Charles, Beow Yeap, Rebecca S. Heist, Christopher G. Azzoli, David M. Jackman, David A. Barbie, Edwin Choy, Lecia V. Sequist, Shyamala Maheswaran, Daniel A. Haber, Aaron N. Hata, Nicholas Dyson, Alice T. Shaw. Phase 1/2 study of olaparib tablets and temozolomide in patients with small cell lung cancer (SCLC) following failure of prior chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT048. doi:10.1158/1538-7445.AM2017-CT048