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

Primary Purpose

Malignant Advanced Solid Tumors, Carcinoma, Renal Cell

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Axitinib plus everolimus
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Advanced Solid Tumors focused on measuring Phase I, Axitinib, Everolimus, Maximum tolerated dose (MTD), solid tumor, Renal cell cancer (RCC), Pharmacokinetics (PK/PD)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Professeur Alain RAVAUD
  • Professeur Jean-Pierre DELORD

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Axitinib plus everolimus

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
Best response rate will be assessed according to RECIST criteria, during the follow-up
Frequency (total, per dose level), proportion
Rate of non-tumor progression at 16 weeks
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
Frequency (total, per dose level), probability
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

Full Information

First Posted
April 5, 2011
Last Updated
July 22, 2015
Sponsor
University Hospital, Bordeaux
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1. Study Identification

Unique Protocol Identification Number
NCT01334073
Brief Title
Study of the Combination of Axitinib Plus Everolimus in Patients With Malignant Advanced Solid Tumors
Acronym
EVAX
Official Title
Phase I Study of the Combination of Axitinib (AX) Plus Everolimus (EV) in Patients With Malignant Advanced Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
July 2015
Overall Recruitment Status
Completed
Study Start Date
March 2011 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Advanced Solid Tumors, Carcinoma, Renal Cell
Keywords
Phase I, Axitinib, Everolimus, Maximum tolerated dose (MTD), solid tumor, Renal cell cancer (RCC), Pharmacokinetics (PK/PD)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alain RAVAUD
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Adélaïde Doussau, Dr
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Study Chair
Facility Information:
Facility Name
Professeur Alain RAVAUD
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Facility Name
Professeur Jean-Pierre DELORD
City
Toulouse
ZIP/Postal Code
31000
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
20028756
Citation
Su Y, Amiri KI, Horton LW, Yu Y, Ayers GD, Koehler E, Kelley MC, Puzanov I, Richmond A, Sosman JA. A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin Cancer Res. 2010 Jan 1;16(1):348-57. doi: 10.1158/1078-0432.CCR-09-2087. Epub 2009 Dec 22.
Results Reference
background
PubMed Identifier
20512579
Citation
O'Reilly T, Lane HA, Wood JM, Schnell C, Littlewood-Evans A, Brueggen J, McSheehy PM. Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. Cancer Chemother Pharmacol. 2011 Jan;67(1):193-200. doi: 10.1007/s00280-010-1307-z. Epub 2010 May 30.
Results Reference
background
PubMed Identifier
18516765
Citation
Choueiri TK. Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr Opin Investig Drugs. 2008 Jun;9(6):658-71.
Results Reference
background

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

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