ac-7700 and Carcinoma--Non-Small-Cell-Lung

The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models.. In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated.. Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2).. A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level.. ClinicalTrials.gov number, NCT01095302.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma, Non-Small-Cell Lung; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Serine; Taxoids; Treatment Outcome

DISRUPT evaluated whether adding the vascular-disrupting agent ombrabulin to a taxane-platinum doublet in the first-line setting improved progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC).. Patients were randomised to ombrabulin 35 mg/m(2) or placebo followed by a taxane-platinum regimen every 3 weeks.. Overall, 176 patients were randomised. After 124 events, median PFS was not significantly improved with ombrabulin vs placebo (5.65 vs 5.45 months; HR 0.948; 60% CI 0.813-1.106; one-sided P=0.39). The two groups showed similar overall survival (median 11.0 months in both groups), objective response rate (32% ombrabulin; 31% placebo) and safety profiles.. This study did not meet its primary endpoint of improving PFS by adding ombrabulin to a taxane-platinum regimen for first-line treatment of metastatic NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platinum; Serine; Taxoids; Treatment Outcome