Clinical Trial: Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase 1B/II Study of GDC-0449 (NSC 747691) in Combination With RO4929097, a Gamma-Secretase Inhibitor (GSI) in Advanced/Metastatic Sarcomas

Brief Summary: This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of gamma-secretase inhibitor RO4929097 (RO4929097) when given in combination with fixed-dose Hedgehog antagonist GDC-0449 (GDC-0449) which will become the recommended dose for the phase II portion of this study. (Phase Ib) II. To assess the progression-free survival (PFS) of the combination of RO4929097 with and without GDC-0449 in two arms of patients with advanced sarcoma. (Phase II)

SECONDARY OBJECTIVES:

I. To describe the tolerability and adverse event profile of daily GDC-0449 administered orally in combination with daily RO4929097 administered orally for 21 consecutive days. (Phase Ib) II. To describe the pharmacokinetics of the combination of the combination of GDC-0449 and RO4929097. (Phase Ib) III. To assess Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 overall response rates (complete and partial response [CR+PR]) for combination therapy. (Phase Ib and II) IV. To conduct pharmacodynamic studies in tissue biopsies (pre- and post-study) for explorative and hypothesis-generating studies. (Phase Ib and II) V. To assess overall survival. (Phase II) VI. To further describe the pharmacokinetics and pharmacodynamics of the combination of GDC-0449 and RO4929097 at the phase II dose at the continuous schedule. (Phase II) V. To conduct pharmacodynamic studies in tissue biopsies (pre- and post- study drug[s]) for explorative and hypothesis generating studies. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of gamma-secretase/notch signalling pathway inhibitor RO4929097 followed by a phase II study.

PHASE IB:

PART A: Patients receive vis
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Maximum-tolerated Dose of Gamma-secretase Inhibitor RO4929097, Defined as the Dose Level Where no More Than 1 Out of 6 Patients Experience DLT at the Highest Dose Level Below the MAD, Graded According to NCI-CTCAE Version 4.0 (Phase Ib) [ Time Frame: Up to 28 days ]
  • Progression-free Survival (PFS) of the Combination of RO4929097 With and Without GDC-0449 in Patients With Advanced Sarcoma. (Phase II) [ Time Frame: 1 year ]
    Progression-free survival (PFS) of the combination of RO4929097 with and without GDC-0449 in patients with advanced sarcoma. (Phase II)


Original Primary Outcome:

  • Maximum-tolerated dose of gamma-secretase inhibitor RO4929097 (Phase Ib)
  • Progression-free survival (Phase II)


Current Secondary Outcome: Response Rate (CR + PR) as Assessed by RECIST 1.1 (Phase Ib and II) [ Time Frame: Up to 4 months ]

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions


Original Secondary Outcome:

  • Pre- and post-treatment protein levels from pre- and post-treatment biopsies (Phase Ib and II)
  • Response rate as assessed by RECIST 1.1 (Phase Ib and II)
  • Overall survival (Phase II)


Information By: National Cancer Institute (NCI)

Dates:
Date Received: June 29, 2010
Date Started: June 2010
Date Completion:
Last Updated: June 9, 2016
Last Verified: April 2016