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Investigational New Drugs

, Volume 33, Issue 3, pp 700–709 | Cite as

Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy

  • Heloisa Veasey Rodrigues
  • Danxia Ke
  • JoAnn Lim
  • Bettzy Stephen
  • Jorge Bellido
  • Filip Janku
  • Ralph Zinner
  • Apostolia Tsimberidou
  • David Hong
  • Sarina Piha-Paul
  • Siqing Fu
  • Aung Naing
  • Vivek Subbiah
  • Daniel Karp
  • Gerald Falchook
  • Razelle Kurzrock
  • Jennifer Wheler
PHASE I STUDIES

Summary

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.

Keywords

Everolimus Pazopanib PIK3CA mutation PTEN loss 

Notes

Acknowledgments

Financial support

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline and The University of Texas MD Anderson Cancer Center Support Grant P30 CA016672 (F. Meric-Bernstam, J. Wheler).

Compliance with ethical standards

Disclosure of potential conflict of interest

Filip Janku received research funding from Novartis. Dr. Falchook received major commercial research grant from GlaxoSmithKline and Novartis and travel reimbursement from GlaxoSmithKline. All remaining authors declare no conflicts of interest.

Research involving human participants

The study was reviewed and approved by the MD Anderson Institutional Review Board. All procedures were performed in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all patients before study-related procedures were started.

Supplementary material

10637_2015_238_MOESM1_ESM.doc (68 kb)
Supplementary Table 1 (DOC 68 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Heloisa Veasey Rodrigues
    • 1
  • Danxia Ke
    • 2
  • JoAnn Lim
    • 2
  • Bettzy Stephen
    • 2
  • Jorge Bellido
    • 2
  • Filip Janku
    • 2
  • Ralph Zinner
    • 2
  • Apostolia Tsimberidou
    • 2
  • David Hong
    • 2
  • Sarina Piha-Paul
    • 2
  • Siqing Fu
    • 2
  • Aung Naing
    • 2
  • Vivek Subbiah
    • 2
  • Daniel Karp
    • 2
  • Gerald Falchook
    • 3
  • Razelle Kurzrock
    • 4
  • Jennifer Wheler
    • 2
  1. 1.Centro de Oncologia e Hematologia do Hospital Israelita Albert EinsteinSão PauloBrazil
  2. 2.Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program)The University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Sarah Cannon Research Institute at HealthONEDenverUSA
  4. 4.Department of MedicineUniversity of CaliforniaSan Diego, La JollaUSA

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