Global Study Looking at the Combination of RAD001 Plus Best Supportive Care (BSC) and Placebo Plus BSC to Treat Patients With Advanced Hepatocellular Carcinoma.

NCT01035229 | Completed Phase 3 Results DMC

• 2 other identifiers: CRAD001O23012009-010196-25
• Study Type: interventional
• Target: 546
• Locations: 17 countries
• Sites: 128

Brief Summary

The purpose of this study is to compare treatment with RAD001 plus best supportive care (BSC) to placebo plus BSC in patients with advanced HCC whose disease progressed while on or after sorafenib treatment or who are intolerant to sorafenib.

Conditions

Carcinoma

Keywords

Hepatocellular carcinoma; randomized trial; medical treatment; RAD001; placebo; Advanced Hepatocellular Carcinoma (HCC)

Outcome Measures

Primary Outcomes (1)

• Overall Survival (OS)

  OS was defined as the time from the date of randomization to the date of death from any cause. The comparison of OS between the 2 arms was done using a stratified log-rank test at one-sided 2.5% level of significance.

  When 454 OS events were observed

Secondary Outcomes (6)

• Time to Tumor Progression (TTP)

  Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient

• Percentage of Participants With Disease Control Rate (DCR)

  Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient

• Time to Definitive Deterioration of ECOG Performance Score (PS) Score

  Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.

• Time to Definitive Deterioration of EORTC QLQ-C30 Scores

  Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.

• Pharmacokinetics Assessments - Cmin

  Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.

Study Arms (2)

Everolimus + Best Supportice Care (BSC)

EXPERIMENTAL

Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the investigational drug. In addition to taking Everolimus, all patients also received BSC as per normal local practice.

Drug: Everolimus; Other: Best Supportive Care (BSC)

Placebo + Best Supportive Care

PLACEBO COMPARATOR

Placebo Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placeb Everolimus, all patients also received BSC as per normal local practice.

Drug: Everolimus Placebo; Other: Best Supportive Care (BSC)

Interventions

Everolimus DRUG

Everolimus (labeled as RAD001) was formulated as tablets of 2.5 mg strength and blisterpacked in units of 10 tablets.

Also known as: RAD001

Everolimus + Best Supportice Care (BSC)

Everolimus Placebo DRUG

Everolimus Placebo matched to the everolimus 2.5 mg tablet strength was blister-packed in units of 10 tablets. Matching placebo tablets were formulated to be indistinguishable from the everolimus tablets. Everolimus placebo was taken as a daily oral dose of 7.5 mg and was defined as the control drug.

Placebo + Best Supportive Care

Best Supportive Care (BSC) OTHER

BSC was defined as drug or non-drug therapies, nutritional support, physical therapy or anything that the Investigator believed to be in the patient's best interest, but excluding other antineoplastic treatments. BSC administered to the patient throughout the study was to be reported on the Concomitant Medication/Significant Non-Drug Therapy electronic case report from (eCRF). Permitted BSC treatments during the study included, but were not limited to, the following: Pain medication to allow the patient to be as comfortable as possible, Bisphosphonates for bone metastases, Localized radiotherapy, for the treatment of pre-existing, painful bone metastases, Nutritional support or appetite stimulants (i.e. megestrol) as recommended by the Investigator, Oxygen therapy and blood products or transfusions

Everolimus + Best Supportice Care (BSC); Placebo + Best Supportive Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced liver cancer
• Prior systemic treatment with sorafenib for advanced HCC and for whom their disease progressed during or after sorafenib treatment, or were intolerant to sorafenib treatment. Specifically, this can be defined as:
• Documented radiological confirmation (radiology scans or report) of disease progression during or after sorafenib treatment
• Intolerance to sorafenib (at any dose and/or duration) is defined as documented sorafenib-related grade 3 or 4 adverse events that led to sorafenib discontinuation.
• NOTE:
• Sorafenib must be the last antineoplastic treatment before randomization
• Prior local and/or hormonal therapy (e.g., tamoxifen) before sorafenib is allowed
• One systemic chemotherapy regimen for advanced HCC is allowed before sorafenib treatment
• ECOG performance status of ≤ 2
• Child-Pugh A

You may not qualify if:

• Active bleeding during the last 28 days
• Prior therapy with mTOR inhibitors
• Prior liver or other organ transplantation which mandates systemic immunosuppression

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (131)

Highlands Oncology Group Dept of Highlands Oncology Grp

Fayetteville, Arkansas, 72703, United States

Location

Compassionate Cancer Care Medical Group CCCMG

Fountain Valley, California, 92708, United States

Location

University of California San Diego - Moores Cancer Center SC - 3

La Jolla, California, 92093-0658, United States

Location

California Pacific Medical Center California Pacific Med

San Francisco, California, 94120-7999, United States

Location

Rocky Mountain Cancer Centers RMCC - Denver-Midtown (4)

Greenwood Village, Colorado, United States

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Queen's Medical Center Queens Cancer Center

Honolulu, Hawaii, 96817, United States

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The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Dept. of SKCC @ JHU

Baltimore, Maryland, 21287-0013, United States

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Massachusetts General Hospital Dept. of Mass General Hospital

Boston, Massachusetts, 02114, United States

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Midwest Cancer Care Physicians Research Medical Center

Kansas City, Missouri, 64131, United States

Location

VA Sierra Nevada Health Care System Dept. of VA Sierra Nevada HCS

Reno, Nevada, 89502, United States

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University of Rochester Medical Center Rochester

Rochester, New York, 14642, United States

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Northwest Cancer Specialists Rose Quarter Cancer Center

Portland, Oregon, 97210, United States

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St. Luke's Hospital and Health Network St. Luke's Cancer Network (2)

Bethlehem, Pennsylvania, United States

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Texas Cancer Center - Abilene

Abilene, Texas, 79606, United States

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Methodist Charlton Cancer Center Methodist

Dallas, Texas, 75237, United States

Location

University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(3)

Dallas, Texas, 75390-8527, United States

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Cancer Care Centers of South Texas / HOAST CCC of So. TX- San Antonio

San Antonio, Texas, 78229, United States

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Blue Ridge Research Center at Roanoke Neurological Center Blue Ridge Cancer Care

Roanoke, Virginia, 24018, United States

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University of Washington Cancer Care SC

Seattle, Washington, 98109-1023, United States

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Novartis Investigative Site

Camperdown, New South Wales, 2050, Australia

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Novartis Investigative Site

Kogarah, New South Wales, 2217, Australia

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Novartis Investigative Site

Westmead, New South Wales, 2145, Australia

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Heidelberg, Victoria, 3084, Australia

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Parkville, Victoria, 3050, Australia

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Graz, 8036, Austria

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Innsbruck, A-6020, Austria

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Vienna, 1090, Austria

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Brussels, 1070, Belgium

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Brussels, 1200, Belgium

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Edegem, 2650, Belgium

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Leuven, 3000, Belgium

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London, Ontario, N6A 4L6, Canada

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Toronto, Ontario, M4N 3M5, Canada

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Montreal, Quebec, H2X 1P1, Canada

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Montreal, Quebec, H3A 1A1, Canada

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Nanjing, Jiangsu, 210002, China

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Xi’an, Shanxi, 710032, China

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Chengdu, Sichuan, 610041, China

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Hangzhou, Zhejiang, 310016, China

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Beijing, 100039, China

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Guangzhou, 510060, China

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Amiens, 80054, France

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Avignon, 84082, France

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Bordeaux, 33075, France

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Caen Cedex9, 14033, France

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Chambray-lès-Tours, 37170, France

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Clermont-Ferrand, 63003, France

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Clichy, 92110, France

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Dijon, 21079, France

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Lille, 59037, France

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Lyon, 69317, France

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Marseille Cédex 5, 13385, France

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Montpellier, 34298, France

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Nantes, 44093, France

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Nice, 06202, France

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Reims, 51092, France

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Rouen, 76031, France

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Saint-Priest-en-Jarez, 42277, France

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Strasbourg, 67091, France

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Mannheim, Baden-Wurttemberg, 68305, Germany

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Berlin, 13353, Germany

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Essen, 45147, Germany

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Esslingen am Neckar, 73730, Germany

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Frankfurt, 60590, Germany

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Göttingen, D-37075, Germany

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Hamburg, 20246, Germany

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Hanover, 30625, Germany

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Leipzig, 04103, Germany

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München, 81377, Germany

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Würzburg, 97080, Germany

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Thessaloniki, Greece, 57001, Greece

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Athens, GR, 124 62, Greece

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Larissa, GR, 411 10, Greece

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Hong Kong, Hong Kong

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Budapest, H-1122, Hungary

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Debrecen, 4032, Hungary

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Szeged, H-6720, Hungary

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Szombathely, 9700, Hungary

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Petah Tikva, 49100, Israel

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Ramat Gan, 5266202, Israel

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Benevento, BN, 82100, Italy

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Bologna, BO, 40138, Italy

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Foggia, FG, 71100, Italy

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Milan, MI, 20122, Italy

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Rozzano, MI, 20089, Italy

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Modena, MO, 41100, Italy

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Palermo, PA, 90127, Italy

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Padua, PD, 35128, Italy

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Aviano, PN, 33081, Italy

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Pavia, PV, 27100, Italy

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Roma, RM, 00128, Italy

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Roma, RM, 00168, Italy

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Frattamaggiore, 80020, Italy

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Napoli, 80131, Italy

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Nagoya, Aichi-ken, 464-8681, Japan

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Chiba, Chiba, 260-8677, Japan

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Kashiwa, Chiba, 277-8577, Japan

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Matsuyama, Ehime, 791-0280, Japan

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Fukuoka, Fukuoka, 810-8563, Japan

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Fukuoka, Fukuoka, 811-1395, Japan

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Iizuka, Fukuoka, 820-8505, Japan

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Gifu, Gifu, 500-8513, Japan

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Ōgaki, Gifu, 503-8502, Japan

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Kanazawa, Ishikawa-ken, 920-8641, Japan

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Yokohama, Kanagawa, 232-0024, Japan

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Kumamoto, Kumamoto, 860-8556, Japan

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Sendai, Miyagi, 980-8574, Japan

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Osaka, Osaka, 537-8511, Japan

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Sayama, Osaka, 589-8511, Japan

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Chuo-ku, Tokyo, 104-0045, Japan

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Mitaka, Tokyo, 181-8611, Japan

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Shinagawa-ku, Tokyo, 141-8625, Japan

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Seoul, Korea, 03080, South Korea

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Seoul, Korea, 03722, South Korea

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Seoul, Korea, 05505, South Korea

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Seoul, Korea, 06351, South Korea

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Córdoba, Andalusia, 14004, Spain

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Sabadell, Barcelona, 08208, Spain

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Barcelona, Catalonia, 08035, Spain

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Barcelona, Catalonia, 08036, Spain

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Madrid, Madrid, 28034, Spain

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Pamplona, Navarre, 31008, Spain

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Niaosong Township, Taiwan, 83301, Taiwan

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Taichung, Taiwan, 40447, Taiwan

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Tainan, Taiwan, 70403, Taiwan

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Taipei, Taiwan, 10048, Taiwan

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Taipei, Taiwan, ROC, 112, Taiwan

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Linkou District, 33305, Taiwan

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Liouying Township, Taiwan

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Bangkok, 10400, Thailand

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Novartis Investigative Site

Bangkok, 10700, Thailand

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Related Publications (2)

• Zhu AX, Chen D, He W, Kanai M, Voi M, Chen LT, Daniele B, Furuse J, Kang YK, Poon RT, Vogel A, Chiang DY. Integrative biomarker analyses indicate etiological variations in hepatocellular carcinoma. J Hepatol. 2016 Aug;65(2):296-304. doi: 10.1016/j.jhep.2016.04.015. Epub 2016 Apr 27.

  PMID: 27130844 DERIVED

• Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL, Dorval E, Peck-Radosavljevic M, Santoro A, Daniele B, Furuse J, Jappe A, Perraud K, Anak O, Sellami DB, Chen LT. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014 Jul 2;312(1):57-67. doi: 10.1001/jama.2014.7189.

  PMID: 25058218 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Carcinoma; Carcinoma, Hepatocellular

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Three patients (1 in the everolimus arm and 2 in the placebo arm were excluded from the Safety Set. These three patients were randomized but never received any study treatment.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

trialandresults.registries@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2009
• First Posted: December 18, 2009
• Study Start: April 1, 2010
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: September 22, 2016
• Results First Posted: October 27, 2014

Record last verified: 2016-08

Locations

JP (18); US (19); AU (5); KR (4); DE (11); FR (18); TW (7); HU (4); ES (6); BE (4); IT (14); CA (4); CN (6); IL (2); HK (1); TH (2); GR (3)