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Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy.
- Source :
-
Investigational new drugs [Invest New Drugs] 2015 Jun; Vol. 33 (3), pp. 700-9. Date of Electronic Publication: 2015 Apr 24. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols adverse effects
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Dose-Response Relationship, Drug
Everolimus adverse effects
Female
Humans
Indazoles
Male
Middle Aged
Neoplasm Staging
Neoplasms pathology
Pyrimidines adverse effects
Sulfonamides adverse effects
Treatment Outcome
Young Adult
Drug Resistance, Neoplasm
Everolimus therapeutic use
Mutation genetics
Neoplasms drug therapy
PTEN Phosphohydrolase metabolism
Phosphatidylinositol 3-Kinases genetics
Pyrimidines therapeutic use
Sulfonamides therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 33
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 25902899
- Full Text :
- https://doi.org/10.1007/s10637-015-0238-2