Clinical trial NCT00619268: Combination of Temsirolimus and Bevacizumab in Patient With Metastatic Renal Cell Carcinoma
Official title: Open Label, Randomized, Multicenter Phase II Study of a Combination of Torisel® (Temsirolimus) and Avastin® (Bevacizumab) Versus Sutent® (Sunitinib) and Versus a Combination of Avastin® (Bevacizumab) and Roféron® (Interferon Alpha-2a) in First-line Treatment of Patients With Metastatic Renal Cell Carcinoma.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Keywords: Temsirolimus
Bevacizumab
Metastatic renal cell carcinoma
Non-progression
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2008-02-20
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The TORAVA trial is designed to evaluate the progression-free rate at 48 weeks of a combination of Torisel® and Avastin® given at first-line treatment in patients with metastatic renal cancer.

Eligible patients will be randomly assigned, in a 2:1:1 ratio, to either Avastin® + Torisel®, or Sutent® or IFN+Avastin®.

Detailed description: This is a phase II, open label, randomized, parallel group, multicenter study evaluating first-line treatment of patients with metastatic renal cancer using a combination of Torisel® administered intravenously as 25 mg every week and Avastin® administered intravenously as 10 mg/kg every 2 weeks.

Two standard arms with either Sutent® (given orally as 50 mg once daily during 4 weeks, followed by 2 weeks off) or a combination of Avastin® (administered intravenously as 10 mg/kg every 2 weeks) and Interferon (IFN, administered subcutaneously as 9 MU three times a week) will be used to validate the results obtained in the experimental arm (randomization eliminates selection biases), and to assess Sutent® efficacy rate on a more representative population than in Motzer's trial (Motzer NEJM 2007).

The study is not designed to provide head-to-head comparisons between the experimental arm (Avastin® + Torisel®) and the two standard arms (Sutent® and IFN + Avastin®). Randomization will be used as a tool for allocating patients evenly into the 3 treatment arms to ensure proper balance of prognostic factors. If the progression-free rates observed in randomly assigned control patients are inconsistent with historical data, it may be a warning that the results observed for the experimental arm should be viewed with caution. Patients will be randomly assigned to either option in a 2:1:1 ratio (half less patients in the standard arms used only as historical comparators), and stratified according to inclusion center and performance status (ECOG PS 0 vs. 1 vs. 2).

In the absence of severe toxicity, treatment will be continued until documented progression of the disease (RECIST criteria). Toxicity will be evaluated throughout the treatment period and until disappearance or stabilization of the side effect(s). In case of progression, each investigator makes his/her own treatment decisions, provided that all anti-cancer treatments given to the patients within the frame of the study are reported, as well as their results.

Response rates will be assessed between weeks 11-12, 23-24, 35-36, 47-48 in the first year (corresponding to 2 cycles of Sutent®) and every 3 months afterwards until treatment stop, or until patient death or end of clinical data collection.

Eligibility criteria: Inclusion Criteria:

* Male or female patients\>= 18 years of age;
* Patients with histological or cytological evidence of metastatic renal cell carcinoma mostly of all type,except for papillary;
* No prior systemic treatment (chemotherapy, immunotherapy, anti-angiogenic drugs, or treatment under evaluation) for metastatic renal cancer;
* No brain metastases revealed by MRI or CT-scan within 28 days prior to randomization. Patients with a history of brain metastases treated by surgery +/- radiation therapy can be included if they have normal brain MRI;
* E.C.O.G performance status =\<2;
* At least one measurable lesion using the RECIST criteria;
* Blood tests and renal and liver functions in the normal range with, in the 7 days prior to study entry, blood or serum values as follows:

Hemoglobin \> 8g/dl; Neutrophil count \> 1500\*10exp9/L; Platelets \> 100\*10exp9/L; Serum creatinine \< 200µmol/L; Total Bilirubin \< 1.5 times upper limit of normal; ALT and AST \< 2.5 times upper limit of normal or \< 5 ULN for patients with liver metastases, PT or INR \< 1.5 times upper limit of normal in the absence of anticoagulant therapy;

* Absence of proteinuria confirmed by urinary dipstick test
* Fertile women must use effective means of contraception
* Mandatory affiliation with a healthy security insurance
* Signed written informed consent.

Exclusion Criteria:

* Patient with pure papillary renal cell carcinoma
* Prior systemic treatment for metastatic renal cancer
* History of other malignancies, other than curatively treated in-situ carcinoma of the cervix or basal cell carcinoma of the skin, or any other curatively treated cancer with no sign of recurrence within 5 years prior to randomization
* Evidence of brain metastasis by computerized tomographic scan or MRI in the 28 days prior to randomization. Patients with history of brain metastases treated by exclusive brain therapy are not allowed to participate, even if brain MRI is normal
* Significant cardiovascular disease or uncontrolled hypertension while receiving appropriate medication (\>= 160 mm Hg systolic and/or \>= 90 mm Hg diastolic)
* Hepatic affection like chronic advanced hepatitis, liver cirrhosis or chronic hepatitis recently treated or in process of treatment by immunosuppressive agents, hepatitis auto-immune or history of auto-immune disease
* Major surgical procedure, open biopsy, or serious non healing wound within 28 days prior to randomization
* Uncontrolled hypercalcemia while receiving appropriate treatment
* Uncontrolled hypercholesterolemia or hypertriglyceridemia
* Patient under anti-vitamin K therapy
* Patient under strong CYP3A4 inhibitors
* Patient with severe neuropsychiatric disorder (or comitial crises)
* Patient included in another clinical trial, except for supportive care trials
* Pregnant or lactating women (mandatory negative serum or urinary pregnancy test at study entry for all women of childbearing potential)

Primary outcomes:
measure: progression-free rate
timeFrame: at 48 weeks post-treatment
Secondary outcomes:
measure: Objective response rate:efficacity
timeFrame: Every 12 weeks during 48 weeks
measure: Duration of response
measure: Toxicity
timeFrame: at week 2, week 5-6 and after every 5-6 weeks during 48 weeks
measure: Quality of life
timeFrame: at inclusion, month 6 and at 1 year
measure: progression-free survival and overall survival
Other outcomes:
Locations:
city: Angers
country: France
facility: Centre Paul Papin
city: Besançon
country: France
facility: Centre Hospitalier Universitaire de Besançon
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux - Hôpital St André
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles
city: Lille
country: France
facility: Centre Hospitalier Universitaire de Lille - Hôpital Claude Huriez
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Centre Hospitalier Universitaire DUPUTRYEN
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: Centre Hospitalier Universiariare Lyon, Hôpital Lyon Sud
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Montpellier
country: France
facility: Centre Val d'Aurelle
city: Nîmes
country: France
facility: Clinique Valdegour-Centre médical Oncogard
city: Paris
country: France
facility: Fondation Hôpital Saint Joseph
city: Paris
country: France
facility: Hopital du Val de Grâce
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Poitiers
country: France
facility: Centre Hospilier Universitaire de Poitiers
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Saint Herblain
country: France
facility: Centre René Gauducheau
city: Saint Priest en Jarez
country: France
facility: Institut de Cancérologie de la Loire
city: Strasbourg
country: France
facility: Centre Hospitalier Starsbourg
city: Suresnes
country: France
facility: Hôpital FOCH
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandoeuvre les Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Leon Berard
name: Sylvie NEGRIER, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Bernard ESCUDIER, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. doi: 10.1056/NEJMoa060655.
citation: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. doi: 10.1056/NEJMoa065044.
citation: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. doi: 10.1056/NEJMoa066838.
citation: Negrier S, Gravis G, Perol D, Chevreau C, Delva R, Bay JO, Blanc E, Ferlay C, Geoffrois L, Rolland F, Legouffe E, Sevin E, Laguerre B, Escudier B. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011 Jul;12(7):673-80. doi: 10.1016/S1470-2045(11)70124-3. Epub 2011 Jun 12.
citation: Polena H, Creuzet J, Dufies M, Sidibe A, Khalil-Mgharbel A, Salomon A, Deroux A, Quesada JL, Roelants C, Filhol O, Cochet C, Blanc E, Ferlay-Segura C, Borchiellini D, Ferrero JM, Escudier B, Negrier S, Pages G, Vilgrain I. The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma. Br J Cancer. 2018 May;118(9):1179-1188. doi: 10.1038/s41416-018-0054-5. Epub 2018 Mar 22.