Combination of Temsirolimus and Bevacizumab in Patient With Metastatic Renal Cell Carcinoma

Metastatic Renal Cell Carcinoma Clinical Trial

— TORAVA  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00619268
• Other study ID #: TORAVA
• Secondary ID: ET2007-035
• Status: Completed
• Phase: Phase 2
• First received: February 8, 2008
• Last updated: February 14, 2013
• Start date: February 2008
• Est. completion date: February 2012

Study information

• Verified date: February 2013
• Source: Centre Leon Berard
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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®.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: February 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Metastatic Renal Cell Carcinoma

Intervention

Drug:
• Temsirolimus
25 mg once per week administered intravenously
• Bevacizumab
10 mg/kg * 1 time /2 weeks administered intravenously
• Sunitinib
50 mg administered orally once daily in 6 weeks cycles :4 weeks of treatment followed by 2 weeks off
• Interferon alpha-2a
Administered subcutaneously as 9 MU three times per week

Locations

Country	Name	City	State
France	Centre Paul Papin	Angers
France	Centre Hospitalier Universitaire de Besançon	Besançon
France	Centre Hospitalier Universitaire de Bordeaux - Hôpital St André	Bordeaux
France	Institut Bergonié	Bordeaux
France	Centre François Baclesse	Caen
France	Centre Jean Perrin	Clermont Ferrand
France	Centre Georges François Leclerc	Dijon
France	Centre Hospitalier de Versailles	Le Chesnay
France	Centre Hospitalier Universitaire de Lille - Hôpital Claude Huriez	Lille
France	Centre Oscar Lambret	Lille
France	Centre Hospitalier Universitaire DUPUTRYEN	Limoges
France	Centre Hospitalier Universiariare Lyon, Hôpital Lyon Sud	Lyon
France	Centre Léon Bérard	Lyon
France	Institut Paoli Calmette	Marseille
France	Centre Val d'Aurelle	Montpellier
France	Clinique Valdegour-Centre médical Oncogard	Nîmes
France	Fondation Hôpital Saint Joseph	Paris
France	Hopital du Val de Grâce	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Centre Hospilier Universitaire de Poitiers	Poitiers
France	Institut Jean Godinot	Reims
France	Centre Eugène Marquis	Rennes
France	Centre René Gauducheau	Saint Herblain
France	Institut de Cancérologie de la Loire	Saint Priest en Jarez
France	Centre Hospitalier Starsbourg	Strasbourg
France	Hôpital FOCH	Suresnes
France	Institut Claudius Regaud	Toulouse
France	Centre Alexis Vautrin	Vandoeuvre les Nancy
France	Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Centre Leon Berard

Country where clinical trial is conducted

France, 

References & Publications (4)

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. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. — View 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. — View 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. — View Citation

Négrier S, Gravis G, Pérol 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 re — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	progression-free rate		at 48 weeks post-treatment	No
Secondary	Objective response rate:efficacity		Every 12 weeks during 48 weeks	No
Secondary	Duration of response			No
Secondary	Toxicity		at week 2, week 5-6 and after every 5-6 weeks during 48 weeks	No
Secondary	Quality of life		at inclusion, month 6 and at 1 year	No
Secondary	progression-free survival and overall survival			No

External Links

•   Link to abstract presented at 2007 ASCO annual meeting
•   Link to abstract presented at 2007 ASCO annual meeting