PLX038 (PEGylated SN38) and Rucaparib in Solid Tumors and Small Cell Cancers

Summary

Participation Requirements

Description

Background: We hypothesize that a dose-escalation strategy that incorporates tumor targeted DNA- damaging chemotherapy and DNA-damage response (DDR) inhibitors could allow safe and effective administration of DDR inhibitor-chemotherapy combination. PLX038 is a PEGylated conjugate of SN38 with improv...

Background: We hypothesize that a dose-escalation strategy that incorporates tumor targeted DNA- damaging chemotherapy and DNA-damage response (DDR) inhibitors could allow safe and effective administration of DDR inhibitor-chemotherapy combination. PLX038 is a PEGylated conjugate of SN38 with improved properties including increased solubility, higher exposure and longer half-life. SN-38 is the active metabolite of CPT-11 (irinotecan) that inhibits topoisomerase 1 (Top1) and causes DNA strand breakage. As a specific DNA damaging agent, SN-38 enhances cell kill in tumors deficient in the DNA- damage response and when combined with inhibitors of the DDR. Rucaparib is a potent oral poly ADP ribose polymerase (PARP) inhibitor that is approved for the maintenance treatment of participants with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy and for the treatment of adult participants with deleterious BRCA mutation- associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. We hypothesize that the combination of PLX038 plus rucaparib is more efficacious than either agent alone. Objectives: Phase I: To identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib. Phase II: To assess the efficacy with respect to clinical benefit rate (CBR) (CR+PR+SD) for 4 months according to Response Evaluation Criteria (RECIST 1.1) of a combination of PLX038 and rucaparib in participants with small cell lung cancer and extra-pulmonary small cell carcinomas. Eligibility: Subjects with histologically confirmed solid tumors (Phase I) OR histologically or cytologically confirmed small cell lung cancer (SCLC) (Phase II) OR histologically or cytologically confirmed extra-pulmonary small cell carcinomas (Phase II). Age greater than or equal to 18 years Subjects must have evaluable or measurable disease. ECOG performance status less than or equal to 2 Adequate organ function Design: This is an open label Phase I/II trial accruing initially one cohort to determine maximum tolerated dose (MTD) of combined treatment of PLX038 and rucaparib (Phase I); and to examine the safety and efficacy of PLX038 in combination with rucaparib in the following cohort (Phase II). PLX038 will be administered by IV infusion on day 1 of every 21-days cycle, rucaparib will be administered PO twice daily on days 5 to 19 of every cycle. Treatment will continue until progression or unacceptable toxicity. Biomarkers of participants response to treatment will be investigated in an exploratory manner pre and post-treatment.

Tracking Information