ombrabulin (AVE8062) / Sanofi - LARVOL DELTA

Phase I study of ombrabulin in combination with paclitaxel and carboplatin in Japanese patients with advanced solid tumors. (PubMed, Int J Gynecol Cancer) - P1 | "Although the maximum tolerated dose/maximum administered dose of ombrabulin (35 mg/m2) with taxane-platinum combination may be tolerable in Japanese patients in the first cycle, the dosages in the repeated treatment should be carefully selected for further study."

Journal • P1 data • Alopecia • Cardiovascular • Cervical Cancer • Fatigue • Hematological Disorders • Immunology • Infectious Disease • Musculoskeletal Pain • Nephrology • Neutropenia • Oncology • Ovarian Cancer • Pain • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • Uterine Cancer

An in vitro pharmacogenomic approach reveals subtype-specific therapeutic vulnerabilities in atypical teratoid/rhabdoid tumors (AT/RT). (PubMed, Pharmacol Res) - "Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our in vitro pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future in vivo and clinical evaluations of novel pharmacological strategies."

IO biomarker • Journal • Preclinical • B Cell Lymphoma • Brain Cancer • CNS Tumor • Embryonal Tumor • Glioma • Lymphoma • Malignant Glioma • Medulloblastoma • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • BCL2 • CDC37 • EIF4E • HSP90AA1 • SMARCA4 • SMARCB1

Discovery, synthesis, activities, structure-activity relationships, and clinical development of combretastatins and analogs as anticancer drugs. A comprehensive review. (PubMed, Nat Prod Rep) - "These antimitotic agents inhibited tubulin polymerization by reversibly binding to the colchicine binding sites...Medicinal chemistry efforts led to the identification of three new leads (AVE8062, BNC105P, SCB01A) with improved in vitro and in vivo potency and an often-improved cellular spectrum...Clinical trials with tumor genetic mapping, particularly from previous responders, may help boost the success of these compounds in future studies. A comprehensive review of combretastatin series A-D, including bioassay guided discovery, total syntheses, and structure-activity relationship (SAR) studies, biological and mechanistic studies, and preclinical and clinical evaluations of the isolated combretastatins and analogs, along with the personal perspective of the author who originated this project, is presented."

Journal • Review • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

Phase I study of ombrabulin in combination with paclitaxel and carboplatin in Japanese patients with advanced solid tumors. (PubMed, Int J Gynecol Cancer) - P1 | "Although the maximum tolerated dose/maximum administered dose of ombrabulin (35 mg/m) with taxane-platinum combination may be tolerable in Japanese patients in the first cycle, the dosages in the repeated treatment should be carefully selected for further study."

Combination therapy • Journal • Metastases • P1 data • Alopecia • Cardiovascular • Cervical Cancer • Fatigue • Hematological Disorders • Immunology • Infectious Disease • Musculoskeletal Pain • Nephrology • Neutropenia • Oncology • Ovarian Cancer • Pain • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • Uterine Cancer

Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials. (PubMed, Front Oncol) - "Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results...On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials...Many trials are ongoing. Nevertheless, predictive factors are still missing."

Clinical • Journal • Review • Fibrosis • Oncology • Osteosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

The vascular disrupting agent ombrabulin (AVE8062) enhances the efficacy of standard therapies in head and neck squamous cell carcinoma xenograft models (Invest New Drugs) - Ombrabulin attenuated tumor growth of HEP2 & FaDu xenografts compared to control tumors; A more pronounced tumor growth delay & tumor regression were induced when ombrabulin was added to local irradiation, cisplatin or cetuximab in FaDu tumors compared to single agent treatments; Triple agent therapies combining ombrabulin, irradiation, & either cisplatin or cetuximab were more effective than double combination treatment regimens & increased tumor growth delay in both HEP2 & FaDu tumor models

Preclinical-animal • Oncology

A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors (NCT01193595) (ASCO 2012) - Presentation time: Monday June 4, 8:00 AM to 12:00 PM; P1, N=25; 2009-017797-20; Two pts with ovarian cancer (11.5/5; 20/10) had confirmed PRs (4.4 months & 7+ months). 13/23 pts with ≥ 1 tumor assessment had SD (N=8; median 4.3 months; 5 ongoing); MTD has not been reached

P1 data • Oncology

DISRUPT: A randomized phase 2 trial of ombrabulin (AVE8062) combined with a taxane-platinum regimen in the first-line treatment of metastatic non-small cell lung cancer (NSCLC) (ESMO 2012) - Presentation time: September 29, 2012; 1:00 PM - 2:00 PM; P2, N=176; DISRUPT; PFS was not significantly improved in the ombrabulin group vs Pbo (median 5.7 vs 5.5 months, respectively; p=0.39); Overall RR were similar (ombrabulin 32%; Pbo 31%); Median OS was 11.0 months in both arms; Safety profiles were comparable; Rates of Gr 3-4 AEs were 57% for ombrabulin & 52% for Pbo

P2 data • Non Small Cell Lung Cancer