Faculty Collaboration Database

Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy. Invest New Drugs 2015 Jun;33(3):700-9

Date

04/24/2015

Pubmed ID

25902899

DOI

10.1007/s10637-015-0238-2

Scopus ID

2-s2.0-84937758561 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

PURPOSE: Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway.

RESULTS: Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive.

CONCLUSION: Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted.

Author List

Rodrigues HV, Ke D, Lim J, Stephen B, Bellido J, Janku F, Zinner R, Tsimberidou A, Hong D, Piha-Paul S, Fu S, Naing A, Subbiah V, Karp D, Falchook G, Kurzrock R, Wheler J

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Everolimus
Female
Humans
Indazoles
Male
Middle Aged
Mutation
Neoplasm Staging
Neoplasms
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Pyrimidines
Sulfonamides
Treatment Outcome
Young Adult