Cerulean Pharma Inc. has entered into a collaboration with AstraZeneca AB (AstraZeneca) and the National Cancer Institute (NCI), part of the National Institutes of Health, to study Lynparza (olaparib) and CRLX101. The collaboration will explore the synergistic effects of AstraZeneca's Lynparza, a poly ADP ribose polymerase (PARP) inhibitor, and CRLX101, Cerulean's inhibitor of topoisomerase 1 (Top1).
The NCI will conduct a combination phase I/IIa trial in the branch led by Yves Pommier, M.D., Ph.D., chief of the developmental therapeutics branch.
"The discovery of new, therapeutic combinations that improve patient outcomes is a core part of our strategy. The combination of Lynparza with CRLX101 provides an opportunity to investigate the potential of Lynparza beyond patients with mutations in homologous repair genes such as BRCA," said Susan Galbraith, head of the oncology innovative medicines unit at AstraZeneca.
"This is the first of several studies we will be conducting together to explore the potential of combining CRLX101 with drug candidates in our DNA damage response franchise."
"Cerulean's nanoparticle-drug conjugates, or NDCs, are suited to enable therapeutic combinations because they are designed to concentrate anti-cancer payloads inside tumour cells and spare healthy tissue," said Christopher D. T. Guiffre, Cerulean's president & chief executive officer.
"Preclinical data generated by AstraZeneca with the Lynparza-CRLX101 combination demonstrate the synergistic anti-tumour effect of targeting two validated pathways. While PARP-Top1 combos have traditionally been limited by toxicity, we believe that our NDC and the work AstraZeneca carried out to define a dose and schedule that could be taken into the clinic may allow for the Lynparza-CRLX101 combination to be delivered safely and effectively."
The scientific rationale for combining PARP inhibitors with Top1 inhibitors is well understood. Simply stated, Top1 inhibitors damage DNA, and PARP inhibitors prevent DNA damage repair. CRLX101 is a Top1 inhibitor. Top1 inhibitors trap DNA-topoisomerase complexes, preventing ligation and resulting in persistent single-stranded breaks. Lynparza is a PARP inhibitor that exploits tumour DNA damage repair pathway deficiencies to preferentially kill cancer cells. PARP's main role is to detect and signal single-strand DNA breaks to the enzymatic complex that repairs single-strand DNA breaks.
Under this collaboration, AstraZeneca will supply Lynparza, Cerulean will supply CRLX101, and the NCI will fund and conduct the clinical trial under cooperative research and development agreements with the companies. The clinical trial of Lynparza in combination with CRLX101 in small cell lung cancer will enroll approximately 55 patients with enrollment expected to commence in the first half of 2016.
CRLX101 is a nanoparticle-drug conjugate (NDC) designed to concentrate in tumours and slowly release its anti-cancer payload, camptothecin, inside tumour cells. CRLX101 inhibits topoisomerase I (Top1), which is involved in cellular replication and transcription, and also inhibits hypoxia-inducible factor-1a (HIF-1a), which research suggests is a master regulator of cancer cell survival mechanisms. CRLX101 has shown activity in four different tumour types, both as monotherapy and in combination with other cancer treatments. CRLX101 is in phase 2 clinical development and has been dosed in more than 300 patients. The US FDA has granted CRLX101 Orphan Drug designation for the treatment of ovarian cancer and Fast Track designation in combination with Avastin in metastatic renal cell carcinoma.
Lynparza is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives Lynparza the potential for activity in a range of tumour types with DNA repair deficiencies. Lynparza is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer, and has been launched in the US and Europe. In addition to ovarian cancer, AstraZeneca is investigating the full potential of olaparib in multiple tumour types, with phase III studies in second line gastric cancer, BRCA-mutated pancreatic cancer and adjuvant and metastatic BRCA-mutated breast cancers underway.