Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer.

Abstract

BACKGROUND:

Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor).

METHODS:

The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer.

RESULTS:

Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months).

CONCLUSIONS:

The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.

• Authors: Brian M Wolpin, Kimmie Ng, Andrew X Zhu, Thomas Abrams, Peter C Enzinger, Nadine J McCleary, Deborah Schrag, Eunice L Kwak, Jill N Allen, Pankaj Bhargava, Jennifer A Chan, Wolfram Goessling, Lawrence S Blaszkowsky, Jeffrey G Supko, Meaghan Elliot, Kaori Sato, Eileen Regan, Jeffrey A Meyerhardt, Charles S Fuchs
• Journal: The oncologist (Oncologist) Vol. 18 Issue 4 Pg. 377-8 ( 2013) ISSN: 1549-490X [Electronic] England
• PMID: 23580238 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• Phenylurea Compounds
• Quinolines
• tivozanib
• Everolimus
• Sirolimus

Topics

• Antineoplastic Combined Chemotherapy Protocols
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Disease-Free Survival
• Drug-Related Side Effects and Adverse Reactions
• Everolimus
• Humans
• Neoplasm Staging
• Phenylurea Compounds (administration & dosage, adverse effects)
• Quinolines (administration & dosage, adverse effects)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives)
• Treatment Outcome