Date: 2016-05-10
Type of information: Treatment of the first patient
phase: 1-2
Announcement: treatment of the first patient
Company: Cerulean Pharma (USA - MA) AstraZeneca (UK) National Cancer Institute (NCI) (USA)
Product: Lynparza™ (olaparib) and CRLX101 - poly-CD-PEG-camptothecin
Action
mechanism: poly ADP-ribose polymerase (PARP) inhibitor/enzyme inhibitor/topoisomerase inhibitor. CRLX101 is a dynamically tumor-targeted nanoparticle-drug conjugate (NDC) designed to concentrate in tumors and slowly release its anti-cancer payload, camptothecin, inside tumor cells. CRLX101 inhibits topoisomerase 1 (topo 1), which is involved in cellular replication, and hypoxia-inducible factor-1? (HIF-1?), which research suggests is a master regulator of cancer cell survival mechanisms thought to promote drug and radiation resistance. CRLX101 has shown activity in four tumor types in late stage disease and in a front line setting, and it has shown activity as monotherapy and in combination with other cancer treatments. CRLX101 is currently in Phase 2 clinical development and has been dosed in more than 250 patients. Lynparza™ (olaparib) is an oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. Lynparza™ is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer, and has been launched in the U.S. 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. 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. In preclinical studies, CRLX101 causes transient DNA damage in bone marrow and sustained DNA damage in tumors, consistent with the prolonged circulation and tumor targeting of CRLX101. By having a proper dosing schedule of CRLX101 and Lynparza™, it may be possible to mitigate much of the combined bone marrow toxicity in the clinic, while achieving a combination benefit.
Disease: advanced solid tumors
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On May 10, 2016, Cerulean Pharma announced that the first patient has been dosed in an open-label, single center Phase 1/2 clinical trial of its lead NDC candidate, CRLX101, in combination with Lynparza™ (olaparib) in patients with advanced solid tumors. This trial is being conducted by the National Cancer Institute (NCI), in collaboration with AstraZeneca and Cerulean. It is under the direction of NCI investigators, Anish Thomas, MBBS, M.D., Staff Clinician at the Thoracic and Gastrointestinal Oncology Branch of the Center for Cancer Research at the NCI, and Yves Pommier, M.D., Ph.D., an expert in DNA repair, and Chief of the Developmental Therapeutics Branch at the NCI. The Phase 1 portion of this study will enroll up to 30 patients with advanced solid tumors that are resistant or refractory to standard therapy. The trial is designed to identify the maximum tolerated dose, or recommended Phase 2 dose of CRLX101 when combined with Lynparza™, and to provide additional data on pharmacokinetics, pharmacodynamics and safety.
