Tivantinib and Temsirolimus in Treating Patients With Solid Tumors That is Metastatic or Cannot be Removed by Surgery
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|ClinicalTrials.gov Identifier: NCT01625156|
Recruitment Status : Completed
First Posted : June 21, 2012
Last Update Posted : October 20, 2015
|Condition or disease||Intervention/treatment||Phase|
|Adult Solid Neoplasm||Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Temsirolimus Drug: Tivantinib||Phase 1|
I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARQ197 (tivantinib) in combination with temsirolimus in adult subjects with advanced solid tumors who are extensive cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) metabolizers.
I. To characterize the tolerability and/or MTD of ARQ 197 and in combination with temsirolimus in adult subjects who are poor CYP2C19 metabolizers (CYP2C19*2/*2, *2/*3 or *3/*3 polymorphisms).
II. To identify the pharmacokinetic parameters of ARQ 197 after a single dose and at steady state in extensive and poor CYP2C19 metabolizers.
III. To assess the steady state pharmacokinetics of ARQ 197 alone and in combination with temsirolimus.
IV. To determine impact of cytochrome P450, family 3, subfamily A, polypeptide 4/cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A4/5) polymorphisms on ARQ 197 pharmacokinetic parameters.
V. To determine the pharmacokinetics of temsirolimus and its active metabolite sirolimus in combination with ARQ 197 and compare to historical pharmacokinetic data.
VI. To determine impact of CYP3A4/5 polymorphisms on temsirolimus pharmacokinetic parameters.
VII. To describe the dose-limiting toxicities and determine the safety profile of the combination of ARQ 197 and temsirolimus.
VIII. To evaluate the preliminary anti-tumor activity of ARQ197 and temsirolimus in patients with advanced solid tumors.
IX. To correlate archived tumor tissue expression of c-Met with objective response to ARQ 197 and temsirolimus therapy.
OUTLINE: This is a dose-escalation study of tivantinib.
Patients receive tivantinib orally (PO) twice daily (BID) and temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22 (days 8, 15, 22, and 29 of course 1). Courses repeat every 28 days (35 days in course 1) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for at least 4 weeks.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||11 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Study of ARQ 197 in Combination With Temsirolimus in Advanced Solid Tumors|
|Study Start Date :||May 2012|
|Actual Primary Completion Date :||September 2015|
|Actual Study Completion Date :||October 2015|
Experimental: Treatment (tivantinib, temsirolimus)
Patients receive tivantinib PO BID and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 (days 8, 15, 22, and 29 of course 1). Courses repeat every 28 days (35 days in course 1) in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- MTD and RP2D of tivantinib in combination with temsirolimus defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) and two or more patients have experienced a DLT at the next higher dose level [ Time Frame: First 35 days ]Categorized according to NCI Common Toxicity Criteria version 4.0.
- Incidence of adverse events and toxicities of tivantinib in combination with temsirolimus [ Time Frame: Up to 4 weeks after completion of study treatment ]Categorized according to NCI Common Toxicity Criteria version 4.0. Summarized in terms of type, severity (grade 1-5), and dose level in tabular format. Wilson score method will be used to construct confidence intervals.
- Pharmacokinetic analysis [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours (days 1 and 7), pre-dose and 0.5 hours (day 8), pre-dose (days 15 and 22 of course 1 and day 1 of course 2) ]Plots of individual, mean, and median plasma concentration versus time will be presented where appropriate. The comparison of PK parameters between dose levels will be performed using a two-sample t-test.
- Response rate validated by the RECIST criteria [ Time Frame: Up to 4 weeks after completion of study treatment ]Summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. Ninety-five percent confidence intervals will be constructed using the Wilson Score method.
- Tumor tissue expression levels of c-Met [ Time Frame: Up to course 2, day 1 ]Tumor tissue expression levels of c-Met will be summarized using standard descriptive statistics (for patients in the dose expansion cohort). A two-sample t-test will be used to compare mean tumor expression levels of c-Met between responders (complete response [CR] or partial response [PR]) versus non-responders (stable disease [SD], progressive disease), and between patients with clinical benefit (CR, PR or SD) versus patients with progressive disease.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01625156
|United States, Wisconsin|
|University of Wisconsin Hospital and Clinics|
|Madison, Wisconsin, United States, 53792|
|Wisconsin Clinical Cancer Center|
|Milwaukee, Wisconsin, United States, 53226|
|Principal Investigator:||Kari Wisinski||University of Wisconsin, Madison|