- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01198184
Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 and Temsirolimus in Treating Patients With Advanced Solid Tumors
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
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Ontario
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Hamilton, Ontario, Canada, L8V 5C2
- Juravinski Cancer Centre at Hamilton Health Sciences
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Toronto, Ontario, Canada, M5G 2M9
- University Health Network-Princess Margaret Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
- Measurable disease is defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
- No known brain metastases
- ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%)
- Life expectancy > 12 weeks
- Leukocytes ≥ 3,000/mm^3
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 90 g/L (or ≥ 9 g/dL)
- Total bilirubin normal
- AST/ALT ≤ 2.5 times upper limit of normal
- Serum creatinine normal OR creatine clearance ≥ 60 mL/min
- Fasting cholesterol ≤ 350 mg/dL (9.0 mmol/L)
- Fasting triglycerides ≤ 400 mg/dL (4.56 mmol/L)
No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation
- Note: it is acceptable to use corrected calcium when interpreting calcium levels
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use two effective forms of contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study therapy
- Able to swallow medication
- No malabsorption syndrome or other condition that would interfere with intestinal absorption
- No diarrhea ≥ grade 2 that is not under control with standard anti-diarrhea medications
No uncontrolled concurrent illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable anginal pectoris
- Cardiac arrhythmia other than chronic, stable atrial fibrillation
- Psychiatric illness or social situations that would limit compliance with study medications
- QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females, as measured by ECG using Bazett formula
No history of risk factors for QT interval prolongation including, but not limited to, a family or personal history of any of the following:
- Long QT syndrome
- Torsades de pointes
- Recurrent syncope without known etiology
- Sudden unexpected death
- No pre-existing significant pulmonary infiltrates of unknown origin
- No serologic positivity for hepatitis A, B, or C or history of liver disease or other forms of hepatitis or cirrhosis
- No HIV-positive patients on combination antiretroviral therapy
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or temsirolimus
- Female patients may not donate ova during or after study treatment
- Male patients may not donate sperm during and for ≥ 12 months after completion of study treatment
- Patients may not donate blood during and for ≥ 12 months after completion of study treatment
- Any number of prior therapies allowed
- Recovered from side effects of previous systemic anticancer therapy to < CTCAE grade 2 toxicity (except alopecia)
- Concurrent leuteinizing hormone-releasing hormone agonist allowed in patients with castration-resistant prostate cancer
- No prior gamma-secretase inhibitor or any inhibitor of the PI3K/Akt/mTOR pathway
At least 4 weeks since prior radiotherapy or systemic therapy (6 weeks for carmustine, nitrosoureas, or mitomycin C)
- Exceptions may be made for low-dose, non-myelosuppressive radiotherapy for symptomatic palliation
- No other concurrent investigational agents
- No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
- No concurrent medications that are strong inducers, inhibitors, or substrates of CYP3A4
- No antiarrhythmics or other concurrent medications with known potential to prolong QT interval
- No concurrent food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including grapefruit or grapefruit juice
- No other concurrent anticancer agents or therapies
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: 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.
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Correlative studies
Correlative studies
Other Names:
Given PO
Other Names:
Given IV or PO
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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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.
|
Up to 4 weeks post-treatment
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Objective response to treatment assessed using the RECIST criteria 1.1
Time Frame: Up to 4 weeks post-treatment
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All analyses will be considered exploratory and inference will be performed with appropriate caution.
For all statistical tests, two-sided tests will be performed and no p-value adjustment performed due to the exploratory nature of these tests.
A p-value of 0.05 or less will be considered statistically significant.
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Up to 4 weeks post-treatment
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Pharmacokinetic profiles
Time Frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours
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All analyses will be considered exploratory and inference will be performed with appropriate caution.
For all statistical tests, two-sided tests will be performed and no p-value adjustment performed due to the exploratory nature of these tests.
A p-value of 0.05 or less will be considered statistically significant.
|
Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours
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Pharmacodynamic effects
Time Frame: Up to 4 weeks post-treatment
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All analyses will be considered exploratory and inference will be performed with appropriate caution.
For all statistical tests, two-sided tests will be performed and no p-value adjustment performed due to the exploratory nature of these tests.
A p-value of 0.05 or less will be considered statistically significant.
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Up to 4 weeks post-treatment
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Urologic Neoplasms
- Urogenital Neoplasms
- Neoplasms by Site
- Kidney Diseases
- Urologic Diseases
- Adenocarcinoma
- Neoplasms, Glandular and Epithelial
- Uterine Neoplasms
- Genital Neoplasms, Female
- Uterine Diseases
- Disease Attributes
- Kidney Neoplasms
- Cystadenocarcinoma
- Neoplasms, Cystic, Mucinous, and Serous
- Carcinoma, Renal Cell
- Carcinoma
- Recurrence
- Endometrial Neoplasms
- Cystadenocarcinoma, Serous
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Sirolimus
- R04929097
Other Study ID Numbers
- NCI-2011-02529 (REGISTRY: CTRP (Clinical Trial Reporting Program))
- U01CA132123 (U.S. NIH Grant/Contract)
- 8500 (CTEP)
- CDR0000684714
- PJC-005 (OTHER: University Health Network-Princess Margaret Hospital)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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