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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
University Hospital, Bordeaux
ClinicalTrials.gov Identifier:
NCT01334073
First received: April 5, 2011
Last updated: March 31, 2014
Last verified: March 2014
  Purpose

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


Condition Intervention Phase
Malignant Advanced Solid Tumors
Carcinoma, Renal Cell
Drug: Axitinib plus everolimus
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University Hospital, Bordeaux:

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 [ 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 25
Study Start Date: March 2011
Estimated Study Completion Date: February 2015
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01334073

Locations
France
Professeur Alain RAVAUD
Bordeaux, France, 33000
Professeur Jean-Pierre DELORD
Toulouse, France, 31000
Sponsors and Collaborators
University Hospital, Bordeaux
Investigators
Principal Investigator: Alain RAVAUD University Hospital, Bordeaux
Study Chair: Adélaïde Doussau, Dr Bordeaux University Hospital
  More Information

Publications:
Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT01334073     History of Changes
Other Study ID Numbers: CHUBX 2010/09
Study First Received: April 5, 2011
Last Updated: March 31, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by University Hospital, Bordeaux:
Phase I
Axitinib
Everolimus
Maximum tolerated dose (MTD)
solid tumor
Renal cell cancer (RCC)
Pharmacokinetics (PK/PD)

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Everolimus
Sirolimus
Axitinib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 27, 2014