Study of the Combination of Axitinib Plus Everolimus in Patients With Malignant Advanced Solid Tumors (EVAX)
Malignant Advanced Solid Tumors
Carcinoma, Renal Cell
Drug: Axitinib plus everolimus
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of the Combination of Axitinib (AX) Plus Everolimus (EV) in Patients With Malignant Advanced Solid Tumors|
- Proportion of patients with DLT (dose limiting toxicity) during the first cycle (first 28 days of the combination of both study compounds), per dose level explored [ Time Frame: during cycle 1 ] [ Designated as safety issue: Yes ]
A DLT will be one of the following adverse events, with a possible relationship to the study medications
- Febrile, related bleeding or any grade 4 neutropenia or thrombocytopenia,
- grade 3 non-hematological toxicity, unless adequately treated with usual symptomatic therapy
- grade 4 non-hematological toxicity
- study treatment interruption > 2 weeks, inability to deliver at least 80% of the intended doses of axitinib and/or everolimus between day 8 and 35 due to toxicity.
- Adverse event (AE) will be graded according to NCI-CTC criteria V3 [ Time Frame: After each cycle of treatement ] [ Designated as safety issue: Yes ]Number of AE per patient, per grade, per cycle and per dose level, proportion
- Best response rate will be assessed according to RECIST criteria, during the follow-up [ Time Frame: Every other cycle of treatment ] [ Designated as safety issue: No ]Frequency (total, per dose level), proportion
- Rate of non-tumor progression at 16 weeks [ Time Frame: at 16 weeks ] [ Designated as safety issue: No ]Frequency (total, per dose level), proportion
- Progression-free Survival (PFS) defined as the time between study treatment initiation and either tumor progression or death, regardless of the cause, whichever occurs first and PFS at 1 year [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]Frequency (total, per dose level), probability
- Comparison of PK parameters [ Time Frame: day 1 (axitinib alone) and day 15 (everolimus combined with axitinib) ] [ Designated as safety issue: No ]Plasma PK using peak concentration (Cmax), area under the concentration versus time curve (AUC), volume of distribution at steady state (Vdss), plasma clearance (CL) and plasma half-life (t1/2). PK parameters will be compared to severe (grade 3-4) AEs, tumor responses and non-tumor progression at 16 weeks. PK parameters of axitinib combined to everolimus (day 15) will be compared to PK parameters of axitinib alone in the same patient (day 1). PK of everolimus combined to axitinib (day 15) will be compared to historical data of everolimus alone
|Study Start Date:||March 2011|
|Study Completion Date:||January 2015|
|Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
|Experimental: Axitinib plus everolimus||
Drug: Axitinib plus everolimus
Patients will take both drugs orally, every day, without planned rest period (AX bid and EV once a day). By convention one cycle is 28 days. At the first cycle patients will take one week of AX single agent before starting EV. Patients will be treated at increasing dose levels (DLs) in successive cohorts of 3-6 patients according to the number of patients with dose limiting toxicities (DLT) until the maximum tolerated dose
Phase I study of the combination of axitinib (AX) plus everolimus (EV) in patients with malignant advanced solid tumors.
- To determine the recommended dose for phase II study of the combination of AX + EV
- To determine the safety profile and predictive factors for toxicity, pharmacokinetics (PK), and efficacy in adult solid tumors.
- To assess functional vascular imaging (FVI) as surrogate marker of activity, biomarkers predictive of activity and preliminary efficacy data in metastatic RCC, untreated with antiangiogenics.
Phase I, multicentre, open-label, non-randomized, sequential algorithm based dose-finding (3+3), clinical study in successive cohorts of patients.
Patients will take both drugs orally, every day, without planned rest period (AX bid and EV once a day). By convention one cycle is 28 days. At the first cycle patients will take one week of AX single agent before starting EV. Patients will be treated at increasing dose levels (DLs) in successive cohorts of 3-6 patients according to the number of patients with dose limiting toxicities (DLT) until the maximum tolerated dose (MTD; i.e. the DL at which <= 1/6 patient experiences a DLT during the first cycle). All decision concerning qualification for DLT, dose escalation, study termination, inclusion of additional patients, will be taken by a Trial Monitoring Committee..
The MTD will not be higher than the recommended dose of each single agent. Six additional patients will be entered at the MTD to confirm the feasibility of the dose and preliminarily assess the efficacy of the combination in patients with RCC untreated with antiangiogenics.
Three levels of dose will be explored.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01334073
|Professeur Alain RAVAUD|
|Bordeaux, France, 33000|
|Professeur Jean-Pierre DELORD|
|Toulouse, France, 31000|
|Principal Investigator:||Alain RAVAUD||University Hospital, Bordeaux|
|Study Chair:||Adélaïde Doussau, Dr||Bordeaux University Hospital|