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Investigational New Drugs

, Volume 31, Issue 5, pp 1182–1191 | Cite as

A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors

  • Ivan Diaz-Padilla
  • Hal Hirte
  • Amit M. Oza
  • Blaise A. Clarke
  • Brenda Cohen
  • Michael Reedjik
  • Tong Zhang
  • Suzanne Kamel-Reid
  • S. Percy Ivy
  • Sebastien J. Hotte
  • Albiruni A. R. Razak
  • Eric X. Chen
  • Irene Brana
  • Monika Wizemann
  • Lisa Wang
  • Lillian L. Siu
  • Philippe L. BedardEmail author
PHASE I STUDIES

Summary

Background To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus. Methods Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations. Results Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted. Conclusions RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.

Keywords

RO4929097 Temsirolimus Clinical trial Notch Gamma-secretase inhibitor 

Notes

Disclosures

The authors declare no conflict of interest for this manuscript.

Funding

This study (PJC-005/NCI-8500) is conducted by the Princess Margaret Hospital Phase I Consortium with support from the US National Cancer Institute U01 Cooperative Agreement Award (U01-CA132123).

Supplementary material

10637_2013_1_MOESM1_ESM.doc (86 kb)
ESM 1 (DOC 85.5 kb)

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Copyright information

© The Author(s) 2013

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Ivan Diaz-Padilla
    • 1
  • Hal Hirte
    • 2
  • Amit M. Oza
    • 1
  • Blaise A. Clarke
    • 3
  • Brenda Cohen
    • 4
  • Michael Reedjik
    • 4
  • Tong Zhang
    • 5
  • Suzanne Kamel-Reid
    • 5
  • S. Percy Ivy
    • 6
  • Sebastien J. Hotte
    • 2
  • Albiruni A. R. Razak
    • 1
  • Eric X. Chen
    • 1
  • Irene Brana
    • 1
  • Monika Wizemann
    • 1
  • Lisa Wang
    • 1
  • Lillian L. Siu
    • 1
  • Philippe L. Bedard
    • 1
    Email author
  1. 1.Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of MedicineUniversity of TorontoTorontoCanada
  2. 2.JuravinskiCancer CentreHamiltonCanada
  3. 3.Department of Laboratory MedicineUniversity of TorontoOntarioCanada
  4. 4.Department of Surgical Oncology, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
  5. 5.Department of Cellular and Molecular Biology, The Ontario Cancer InstituteUniversity Health NetworkTorontoCanada
  6. 6.Cancer Therapy Evaluation ProgramNational Cancer InstituteBethesdaUSA

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