Study of the Combination of Axitinib Plus Everolimus in Patients With Malignant Advanced Solid Tumors

Study Overview
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Brief Summary
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The aim of the study is to determine the MTD of the combination of everolimus plus axitinib in solid tumors, especially RCC.

Detailed Description
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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.

Official Title
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Phase I Study of the Combination of Axitinib (AX) Plus Everolimus (EV) in Patients With Malignant Advanced Solid Tumors

Conditions
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Malignant Advanced Solid Tumors, Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Axitinib plus everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Histologically proven advanced adult solid tumors, with the exception of Hodgkin and non Hodgkin lymphoma. Patients with hepatocellular carcinomas (HCC) may be enrolled without histological documentation if they meet the consensus non-invasive diagnostic criteria. Failure or contra-indication of all standard therapies, except for the patients with advanced renal cell carcinoma, enrolled at the recommended dose who will be naïve of previous lines of therapy while metastatic. Age > 18 years ECOG Performance status (PS) 0-1 Life expectancy > 3 months Measurable/evaluable disease according to RECIST CRITERIA version 1.0 Acceptable biological values: Hemoglobin > 10g /dL; neutrophils > 1.5 x 109/L; platelets > 100 x 109/L, AST and ALT < 2.5 x the upper normal limits (UNL), or < 5 x UNL in case of liver metastases, GGT < 3 x the upper normal limits (UNL), PAL < 2.5 x the upper normal limits (UNL), or < 5 x UNL in case of liver metastases, serum bilirubin < 1.5 x ULN, creatinine clearance (Cockroft & Gault formula) > 60 mL/min. 24 hours proteinuria ≤ 1 g/24 h Albumin > 30 g/l Amylase and lipase ≤ 1.5 UNL Electrolytes (calcium, sodium, potassium, chlore, magnesium, phosphate) in the normal range. Supplementation could be possible before study entry. Total cholesterol ≤ 2.5 UNL Triglycerides ≤ 2.5 UNL BP < 140/90 Washout period from last anticancer therapy, including radiation and surgery > 3 weeks and recovery of toxicities to NCI-CTC grade < 1. Written informed Consent. Use of effective contraceptive method (Intrauterine device, oral combined contraceptive) for women of child-bearing age or whose partner is included in the trial. Patient with french social security. Additional inclusion criteria before the association axitinib plus everolimus period No toxicity with NCI-CTC grade > 2 at the end of axitinib alone period just before starting axitinib and everolimus (cycle 1) BP < 140/ 90 Exclusion criteria Brain metastasis Severe underlying cardiovascular disease, even medically controlled, such as angina pectoris, myocardial infarction, cardiac insufficiency, cardiac failure, cerebral strokes, lower limb ischemic disease, thromboembolic disease, and any patient, who, in the investigator's opinion is at high risk for arterial or venous thromboembolism. Hepatitis B or C carrier or at a chronic state Uncontrolled hypertension, or diabetes mellitus despite medical treatment. Inability to swallow pills Unresolved pneumopathy, no need for antibiotherapy Any medical or social condition, which; in the investigator's opinion, would jeopardize patient's safety, patient's compliance to the protocol, or the interpretation of study results. These conditions include (but are not limited to): severe infection, cardiac failure, chronic gastrointestinal disease compromising oral drug absorption, psychiatric illnesses, foreseeable poor treatment compliance with oral medications, patients living far away from the investigational centers, etc… Hypersensitivity to Axitinib or Everolimus Participation to another clinical trial, or use of an unapproved medication within 4 weeks prior to study treatment initiation. Pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axitinib plus everolimus<br> | Drug: Axitinib plus everolimus<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | during cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event (AE) will be graded according to NCI-CTC criteria V3 | Number of AE per patient, per grade, per cycle and per dose level, proportion | After each cycle of treatement | 
| Best response rate will be assessed according to RECIST criteria, during the follow-up | Frequency (total, per dose level), proportion | Every other cycle of treatment | 
| Rate of non-tumor progression at 16 weeks | Frequency (total, per dose level), proportion | at 16 weeks | 
| 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 | Frequency (total, per dose level), probability | 1 year | 
| Comparison of PK parameters | 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 | day 1 (axitinib alone) and day 15 (everolimus combined with axitinib) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, Axitinib, Everolimus, Maximum tolerated dose (MTD), solid tumor, Renal cell cancer (RCC), Pharmacokinetics (PK/PD)