Abstract B32: CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, combined with DDR agents provides a novel approach to increasing therapeutic index

Topoisomerase I inhibitors are used as standard-of-care chemotherapy in many types of cancer but are associated with significant toxicities. There is potential to improve their efficacy further by combining with inhibitors of the DNA damage response, such as the poly ADP ribose polymerase (PARP) inhibitor olaparib. However, while preclinical data highlight the improved efficacy of this combination, subsequent clinical trials have struggled due to dose limiting myelotoxicity. CRLX101 is an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a potent topoisomerase I inhibitor. This agent is preferentially targeted to tumours and demonstrated a generally favorable toxicity profile in the clinic. Here, we explored the molecular mechanism and therapeutic potential of combining CRLX101 with either olaparib or the WEE1 G2 checkpoint kinase inhibitor AZD1775, by testing both efficacy and safety in preclinical models. In vitro studies using NCI-H417a small cell lung cancer (SCLC) cells demonstrated that combination with both olaparib and AZD1775 potentiated the efficacy of CRLX101 although by different mechanisms. Cellular analyses revealed that CRLX101 treatment alone predominantly activated ATM-mediated DNA damage response and resulted in late S/G2 cell cycle arrest. Combination with a PARP inhibitor further enhanced the CRLX101-induced DNA damage response and prolonged cell cycle arrest in late S/G2 phase. In contrast, WEE1 inhibition abrogated late S/G2 cell cycle arrest induced by CRLX101, resulting in aberrant mitotic entry and enhanced cell death. Our in vivo studies using wild type Wistar rat model showed that CRLX101, olaparib and AZD1775, are well tolerated as single agents. However, concurrent combination of CRLX101 with either olaparib or AZD1775 resulted in a dose-dependent decrease in hematological parameters. We investigated sequenced schedules and demonstrated that at a 24h delay between the CRLX101 and olaparib mitigates much of the combined bone marrow toxicity, while improving the efficacy above CRLX101 alone in xenograft tumors from NCI-H417a cells. Collectively, these preclinical data demonstrate increased anti-tumor efficacy of CRLX101 when combined with DDR inhibitors. The combination schedule for CRLX101 and olaparib identified in our preclinical models as providing an increased therapeutic index has been used to develop protocols to test this combination in a relapsed (2nd line) SCLC human clinical trial (