On November 20, 2014 Nektar Therapeutics reported results of a study investigating the preclinical anti-tumor activity and tolerability of etirinotecan pegol (NKTR-102) in combination with the PARP inhibitor rucaparib in a BRCA1-deficient MX-1 breast tumor model (Press release Nektar Therapeutics, NOV 20, 2014, View Source [SID:1234500995]). The preclinical study results demonstrated that all dose combinations of NKTR-102 and rucaparib were well-tolerated, synergistic, and led to 100% prolonged survival in this tumor model. These data were presented during the Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, sponsored by the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"We are encouraged by these results which demonstrate that NKTR-102 in combination with the PARP inhibitor rucaparib has a synergistic effect resulting in 100% prolonged survival in a BRCA 1-deficient tumor model," said Stephen K. Doberstein, Ph.D., senior vice president and chief scientific officer of Nektar Therapeutics. "As a next-generation topo-I inhibitor with broad anti-tumor activity, NKTR-102 has the potential to be combined with a number of targeted agents in multiple tumor settings."

NKTR-102 is the first long-acting topoisomerase I inhibitor with an extended half-life and a unique structure that is also designed to concentrate the drug in tumors. In patients, NKTR-102 leads to greatly prolonged plasma SN38 exposure compared to irinotecan (elimination half-life of 50 days compared to 2 days) yet peak SN38 concentrations are at least 5- to 10-times less, which may also result in a favorable tolerability profile.

Preclinical Study Design and Results
Study investigators initiated tumor xenografts with MX-1 human breast carcinomas maintained by serial subcutaneous transplantation in female athymic nude (Crl:NU(Ncr)-Foxn1nu), 8-week-old mice. On the day of tumor implant, each test mouse received a 1-mm3 MX-1 fragment implanted subcutaneously in the right flank. Animals were randomized into treatment groups (n=10/grp) when their tumors reached 63-196 mm3 and subsequently received either vehicle, NKTR-102, rucaparab, or combinations of NKTR-102 + rucaparib. Doses selected were known to provide clinically relevant exposure levels. Twice weekly, animals were weighed, and tumor volumes were measured until the endpoint (2000 mm3 or Day 88) was met. Efficacy was measured by tumor growth delay and regression response rate.

NKTR-102 and rucaparib in combination exhibited marked synergy, demonstrated by durable complete responses, even at the lowest doses of both agents dosed in combination. The combination of NKTR-102 and rucaparib was tolerated at all dose levels. Doses used in this study provide exposures of NKTR-102 (SN38 trough) and rucaparib that are achievable clinically, underscoring the translational relevance of these results.

Combination studies of NKTR-102 and rucaparib are ongoing in patient-derived xenograft models in collaboration with Professor Paul Haluska at Mayo Clinic and Clovis Oncology.