Clinical trial NCT01334073: Study of the Combination of Axitinib Plus Everolimus in Patients With Malignant Advanced Solid Tumors
Official title: Phase I Study of the Combination of Axitinib (AX) Plus Everolimus (EV) in Patients With Malignant Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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)
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
First posted: 2011-04-12
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 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
timeFrame: during cycle 1
Secondary outcomes:
measure: Adverse event (AE) will be graded according to NCI-CTC criteria V3
timeFrame: After each cycle of treatement
measure: Best response rate will be assessed according to RECIST criteria, during the follow-up
timeFrame: Every other cycle of treatment
measure: Rate of non-tumor progression at 16 weeks
timeFrame: at 16 weeks
measure: 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
timeFrame: 1 year
measure: Comparison of PK parameters
timeFrame: day 1 (axitinib alone) and day 15 (everolimus combined with axitinib)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Professeur Alain RAVAUD
city: Toulouse
country: France
facility: Professeur Jean-Pierre DELORD
Study officials:
affiliation: University Hospital, Bordeaux
name: Alain RAVAUD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Adélaïde Doussau, Dr
role: STUDY_CHAIR
References:
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.
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.
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.