Safety and Efficacy of Bevacizumab Plus RAD001 Versus Interferon Alfa-2a and Bevacizumab for the First-line Treatment in Adult Patients With Kidney Cancer

Carcinoma, Renal Cell Clinical Trial

Official title:

A Randomized, Open-label, Multi-center Phase II Study to Compare Bevacizumab Plus RAD001 Versus Interferon Alfa-2a Plus Bevacizumab for the First-line Treatment of Patients With Metastatic Clear Cell Carcinoma of the Kidney

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00719264
• Other study ID #: CRAD001L2201
• Secondary ID: 2008-000077-38
• Status: Completed
• Phase: Phase 2
• First received: July 15, 2008
• Last updated: May 27, 2015
• Start date: November 2008
• Est. completion date: April 2013

Study information

• Verified date: May 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBelgium: Federal Agency for Medicines and Health Products, FAMHPBrazil: Ministry of HealthCzech Republic: State Institute for Drug ControlEgypt: Ministry of Health and PopulationFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Ministry of HealthHong Kong: Department of HealthHungary: National Institute of PharmacyItaly: Ministry of HealthKorea: Food and Drug AdministrationNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Russia: Ministry of Health of the Russian FederationSingapore: Health Sciences AuthoritySlovakia: State Institute for Drug ControlSouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesSwitzerland: SwissmedicTaiwan: Department of HealthThailand: Ministry of Public HealthTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

To estimate the difference in efficacy and safety of bevacizumab and RAD001 compared to bevacizumab and interferon alfa-2a for first-line treatment of patients with metastatic carcinoma of the kidney.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 365
• Est. completion date: April 2013
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients with metastatic renal cell carcinoma

2. Patients with at least one measurable lesion

3. Patients with progressive metastatic renal cell carcinoma

4. Patients who had a prior partial or complete nephrectomy

5. Patients with a Karnofsky Performance Status =70%.

6. Adequate bone marrow function

7. Adequate liver function

8. Adequate renal function

9. Adequate coagulation profile

Exclusion Criteria:

1. 4 weeks post-major surgery

2. Patients who had radiation therapy within 28 days prior to start of study

3. Patients in need for major surgical procedure during the course of the study.

4. Patients with a serious non-healing wound, ulcer, or bone fracture.

5. Patients with a history of seizure(s) not controlled with standard medical therapy.

6. Patients who have received prior systemic treatment for their metastatic RCC.

7. Patients who received prior therapy with VEGF pathway inhibitor

8. Patients who have previously received systemic mTOR inhibitors

9. Patients with a known hypersensitivity RAD001 (everolimus) or other rapamycins or to its excipients.

10. Patients with history or current central nervous system (CNS) metastases or spinal cord compression.

11. Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment.

12. Patients with proteinuria at screening.

13. Patients with inadequately controlled hypertension

14. Patients receiving ongoing or with recent need for full therapeutic dose of oral or parenteral anticoagulants or chronic daily treatment with aspirin

15. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent.

16. Patients with a known history of HIV

17. Patients with hypersensitivity to interferon alfa-2a or any component of the product.

18. Patients with an active, bleeding diathesis or coagulopathy or recurrent thromboembolism

19. Patients who have any severe and/or uncontrolled medical conditions or other conditions

20. Left Ventricular Ejection Fraction < lower limit of institutional normal assessed by ECHO or MUGA

21. Patients who have a history of another primary malignancy = 3 years

22. Female patients who are pregnant or breast feeding

23. Patients who are using other investigational agents or who had received investigational drugs = 4 weeks prior to study treatment start.

24. Patients unwilling to or unable to comply with the protocol

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma, Renal Cell
• Carcinoma
• Carcinoma, Renal Cell
• Hypernephroid
• Nephroid Carcinoma,

Intervention

Drug:
• RAD001(everolimus)
10 mg qd
• interferon alfa-2a
dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3
• bevacizumab
10 mg/kg every 2 weeks

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Kortrijk
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Santo Andre	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Czech Republic	Novartis Investigative Site	Olomouc
Czech Republic	Novartis Investigative Site	Prague
Egypt	Novartis Investigative Site	Cairo
France	Novartis Investigative Site	Avignon
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Caen Cedex
France	Novartis Investigative Site	La Roche sur Yon Cedex
France	Novartis Investigative Site	Montellier cedex 5
France	Novartis Investigative Site	Nantes cedex 2
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Rouen Cedex
France	Novartis Investigative Site	Strasbourg	Cedex
France	Novartis Investigative Site	Strasbourg Cedex
France	Novartis Investigative Site	Suresnes
France	Novartis Investigative Site	Toulouse Cedex 9
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dessau
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Göttingen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Tübingen
Hong Kong	Novartis Investigative Site	HongKong
Hong Kong	Novartis Investigative Site	Shatin, New Territories
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Italy	Novartis Investigative Site	Aviano	PN
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Catanzaro	CZ
Italy	Novartis Investigative Site	Cremona	CR
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Negrar	VR
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Perugia	PG
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Trento	TN
Korea, Republic of	Novartis Investigative Site	Daegu
Korea, Republic of	Novartis Investigative Site	Goyang	Gyeonggi-do
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Taegu
Netherlands	Novartis Investigative Site	Leiden 2333 ZA
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Obninsk	Russia
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Bratislava
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Pretoria
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Jaen	Andalucía
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Santander
Spain	Novartis Investigative Site	Santander	Cantabria
Spain	Novartis Investigative Site	Zaragoza
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Chur
Taiwan	Novartis Investigative Site	Lin-Kou
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei	Taiwan, ROC
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Songkla
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Altunizade
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Balcova / Izmir
Turkey	Novartis Investigative Site	Bursa
Turkey	Novartis Investigative Site	Mecidiyekoy/Istanbul
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Southampton
United States	St. Luke's Hospital and Health Network St. Luke's Cancer Network	Bethlehem	Pennsylvania
United States	Karmanos Cancer Institute Dept.of KarmanosCancerInst (5)	Detroit	Michigan
United States	City of Hope National Medical Center Dept.ofCityofHopeMedicalCtr(3)	Duarte	California
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	Las Colinas Hematology Oncology Grapevine	Irving	Texas
United States	Nevada Cancer Institute Dept. of Nevada Cancer (3)	Las Vegas	Nevada
United States	University of California at Los Angeles Dept. of Hem/Oncology	Los Angeles	California
United States	USC/Kenneth Norris Comprehensive Cancer Center Regulatory Contact 3	Los Angeles	California
United States	Seattle Cancer Care Alliance Dept. of SCCA	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Roche Pharma AG

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Czech Republic,  Egypt,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Korea, Republic of,  Netherlands,  Russian Federation,  Singapore,  Slovakia,  South Africa,  Spain,  Switzerland,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) of Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab	Tumor response and disease progression were assessed using response evaluation criteria in solid tumors (RECIST), version 1.0. All target and non-target lesions identified at baseline were assessed using the same method, CT scan with contrast or MRI with contrast, throughout the trial. All scans were reviewed by independent, central radiology. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.	Time from randomization to the date of radiological progressive disease as per independent central review, death from any cause, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cutoff date.	No
Secondary	Overall Survival (OS) Treatment Effect in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab	Overall survival (OS) was defined as the time of randomization to the date of death due to any cause.	Time from randomization to the date of death from any cause, reported between date of first participant randomized and up to 2 years after the last participant randomized (data cutoff: 30Aug2012)	No
Secondary	Best Overall Response in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab	Overall response is defined as the number of participants having achieved confirmed Complete Response (CR) + Partial Response (PR). Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.	Time from first participant randomized until 31Dec2011, cutoff date.	No
Secondary	Response Duration Differences in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab	The duration of response, applied only to participants with best overall response at CR or PR, is defined as the number of days between the date of first documented response (CR or PR) and the date of the event: radiological progression as per central review or death due to underlying cancer, whichever occurs first. If no event, participant is censored at the last adequate assessment.	Time from first documented response date of radiological progressive disease as per independent central review, death due to underlying cancer, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cut-off date.	No
Secondary	Number of Participants Who Experienced Adverse Events (AEs), Serious Adverse Events and Deaths	Participants were monitored for adverse events, serious adverse events and deaths throughout the study. Participants were assessed continuously at each 28-day cycle.	From the first participant randomized until the last patient discontinued the study treatment + 28 days	Yes
Secondary	Time to Definitive Deterioration of the Functional Assessment of Cancer Therapy Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) Risk Score by at Least 2 Score Units	The analysis of this outcome measure was based on the FKSI-DRS scale which is a validated disease-related symptom index containing 9 items that measure symptoms predominantly related to kidney cancer. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). If at least 5 of the 9 questions have been answered, the FKSI-DRS total score is calculated by subtracting nine times the mean of the scores of the answered items from 36. Participants with less than 5 out of the 9 questions answered will have a missing FKSI-DRS total score. The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration is defined as a decrease by at least 2 units compared to baseline, with no later increase above this threshold observed during the study. A single measure reporting a decrease of at least 2 units was considered definitive only if it is the last one available for the participant.	Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first patient randomized until 31Dec2011	No
Secondary	Time to Definitive Deterioration of the Global Health Status and the Physical Functioning (PF) Subscale Scores of the European Organization for the Research and Treatment of Cancer (EORTC)-Core Quality of Life Questionnaire (QLQ-C30) by at Least 10%	The EORTC QLQ-C30 contains 30 items. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). The PF subscale consists of 5 questions each scored from 1 (not at all) to 4 (very much). The score for the PF subscale and global health status range from 0 to 100, with a higher score representing a high level of functioning/high quality of life. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the participant.	Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first participant randomized until 31Dec2011	No
Secondary	Duration of Exposure of RAD001 in Participants Randomized to the Treatment Combination of RAD001 and Bevacizumab	This outcome measure was assessed continuously.	From the date of the first participant treated until the last patient discontinued the study treatment + 28 days	Yes