Safety and Efficacy of RO4929097 in Combination With Temsirolimus: A Pharmacokinetic and Pharmacodynamic Phase I Study in Patients With Advanced Solid Tumours With an Expansion of Cohort With Patients With Recurrent/Metastatic Endometrial and Renal Cell Cancers
Overview
- Phase
- Phase 1
- Intervention
- temsirolimus
- Conditions
- Endometrial Papillary Serous Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 18
- Locations
- 2
- Primary Endpoint
- Recommended phase II dose defined as the dose level at which less than or equal to 1 of 6 patients experienced DLT assessed using NCI CTCAE version 4.0
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus together in treating patients with advanced solid tumors. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the recommended phase II dose (RP2D) and safety profile of temsirolimus in combination with RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) in patients with advanced solid tumors. SECONDARY OBJECTIVES: I. To obtain pharmacokinetic (PK) profiles for both drugs when administered in combination in order to quantify the expected interactive effects in PK between these two agents. II. To evaluate pharmacodynamic (PD) effects of both drugs when administered in combination, with the goal of identifying potential predictive and PD markers that need further exploration and validation in future trials. OUTLINE: This is a multicenter, dose-escalation study. Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or orally (PO) on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples may be collected periodically for pharmacokinetic and correlative analyses. After completion of study treatment, patients are followed up for 4 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Meets one of the following sets of criteria:
- •Dose-escalation group:
- •Histologically and/or cytologically confirmed solid malignancy
- •Metastatic or unresectable disease
- •Disease for which standard curative or palliative measures do not exist or are no longer effective
- •Expansion group:
- •Histologically and/or cytologically confirmed endometrial (endometrioid, uterine papillary serious carcinoma, or carcinosarcoma) or renal cell cancer
- •Metastatic or unresectable disease
- •Disease for which standard curative or palliative measures do not exist or are no longer effective
- •Measurable or non-measurable disease
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: temsirolimus
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: laboratory biomarker analysis
Treatment (temsirolimus and RO4929097)
Patients receive temsirolimus IV over 30 minutes on day -6 (course 1 only). Patients then receive temsirolimus IV or PO on days 1, 8, and 15 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: pharmacological study
Outcomes
Primary Outcomes
Recommended phase II dose defined as the dose level at which less than or equal to 1 of 6 patients experienced DLT assessed using NCI CTCAE version 4.0
Time Frame: 21 days
Safety profile assessed using NCI CTCAE version 4.0
Time Frame: Up to 4 weeks post-treatment
Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Attempts to model associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics, however, logistic regression may be used if warranted.
Secondary Outcomes
- Objective response to treatment assessed using the RECIST criteria 1.1(Up to 4 weeks post-treatment)
- Pharmacokinetic profiles(Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours)
- Pharmacodynamic effects(Up to 4 weeks post-treatment)