Phase 3 Study of ThermoDox With Radiofrequency Ablation (RFA) in Treatment of Hepatocellular Carcinoma (HCC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00617981
Recruitment Status : Completed
First Posted : February 18, 2008
Results First Posted : March 24, 2017
Last Update Posted : April 25, 2017
Information provided by (Responsible Party):

Brief Summary:
The purpose of this study is to determine whether ThermoDox, a thermally sensitive liposomal doxorubicin, is effective in the treatment of non-resectable hepatocellular carcinoma when used in conjunction with radiofrequency ablation (RFA).

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: ThermoDox Drug: 5% Dextrose Solution Phase 3

Detailed Description:

This will be a Phase III, randomized, double-blinded, dummy-controlled, efficacy, and safety study of ThermoDox plus RFA versus RFA plus dummy infusion.

The 50 mg/m2 ThermoDox or dummy infusion will be administered IV over 30 minutes. As part of blinded pre-medication ThermoDox treated subjects will receive 20 mg of dexamethasone orally 48 hours prior to the drug infusion for infusion reaction prophylaxis. Subjects on the control arm will receive a matching dummy pre-medication pill orally at 48 hours prior to infusion of the study treatment. Thirty minutes prior to receiving the ThermoDox infusion, subjects will receive a blinded dose of 20 mg of IV dexamethasone, 50 mg IV diphenhydramine and either 50 mg of IV ranitidine or 20 mg of IV famotidine. Subjects on the control arm will receive a masked dummy pre-medication pill orally at 48 hours prior to infusion of the study medication, and a dummy infusion 30 minutes prior to dummy infusion of D5W (250 cc of 5% Dextrose solution). RFA will be initiated approximately at a minimum of 15 minutes after the initiation of study drug infusion and should be completed no later than 3 hours after study drug infusion initiation. The total length of the RFA procedure is proportional to the size of the tumor(s) involved and is anticipated to range from 12 to 60 minutes for each lesion with an estimated overall procedure time of less than 3 hours.

Subjects with incomplete ablations will be re-treated to complete the ablation according to the treatment assigned at randomization. The completion of an ablation in this manner will restart the timeline of the study-related visits/procedures. This repeated ablation procedure cannot occur earlier than 21 days post-ablation but no later than 14 days after the first post-ablation CT scan assessment. These subjects will start over at screening (see Table 1). If a complete ablation is not achieved after these two study treatments, the subject will be considered a treatment failure and the patient will be discontinued and followed for survival only.

Subjects who recur with local and/or distant intrahepatic HCC after a complete initial ablation will have met the primary endpoint of progression-free survival. However, if these subjects have lesions that are amenable to RFA the standard of care is to consider them for repeat RFA. Therefore, these subjects may receive treatment to which they were randomized if they continue to meet the inclusion and exclusion criteria of the protocol. Subjects who develop any extrahepatic lesion will have met the primary endpoint and will be discontinued from study treatment but will still be followed for overall survival.

Dynamic Contrast CT imaging will be used to assess the effectiveness of the ablation therapy. The blind will be maintained at the level of CT scan reads. All protocol-specified CT images will be centrally read and assessed by the endpoint committee in a blinded fashion. Posttreatment CT scans will be obtained at months 1, 3, 5, 7, 9 and 12 and every three months thereafter until withdrawal. Adverse event assessments and laboratory examinations will occur at each visit. All subjects will be monitored throughout the investigational period.

Patients that meet inclusion/exclusion criteria may be at risk for contrast-induced nephropathy (CIN) when undergoing the required CT with contrast procedures. The investigators must be mindful of the risk factors (e.g. diabetes, borderline renal function) associated with CIN and employ strategies to reduce the risk of CIN. In subjects with diabetes or borderline renal function (creatinine greater than 1.5 mg/dL) special precautions (e.g. hydration, contrast dose reduction, follow up creatinine determination) should be employed. An accepted procedure is adequate intravenous volume expansion with isotonic saline (1.0 - 1.5 mL/kg per hour) for 3-12 hours before the procedure and continued for 6-24 hours.

All randomized subjects will be followed for safety and overall survival.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 701 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-Blinded, Dummy-Controlled Study of the Efficacy and Safety of ThermoDox® (Thermally Sensitive Liposomal Doxorubicin) in Combination With Radiofrequency Ablation (RFA) Compared to RFA-Alone in the Treatment of Non-Resectable Hepatocellular Carcinoma
Actual Study Start Date : May 2008
Actual Primary Completion Date : January 2013
Actual Study Completion Date : August 2016

Arm Intervention/treatment
Experimental: 1
ThermoDox 50 mg/m2 start infusion over 30 minutes about 15 minutes before radiofrequency ablation begins.
Drug: ThermoDox
Thermally Sensitive Liposomal Doxorubicin 50 mg/m2 Single 30 minute intravenous infusion

Sham Comparator: 2
Sham infusion over 30 minutes about 15 minutes before radiofrequency ablation begins.
Drug: 5% Dextrose Solution
Single 30 minute intravenous infusion

Primary Outcome Measures :
  1. Progression Free Survival Will be Measured From the Date of Randomization to the First Date on Which One of the Following Occurs. o Local Recurrence o Any New Distant Intrahepatic HCC Tumor o Any New Extrahepatic HCC Tumor o Death From Any Cause [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Overall Survival as Measured by Time From Randomization to Death or the End of the Study. [ Time Frame: 3 years ]
  2. Time to Definite Worsening as Per Patient-Reported Outcomes [ Time Frame: 3 years ]
  3. Time to Local Recurrence. [ Time Frame: 3 years ]
  4. Safety [ Time Frame: 3 years ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Diagnosed hepatocellular carcinoma (HCC)
  • No more than 4 HCC lesions with at least one ≥ 3.0 cm and none > 7.0 cm in maximum diameter, based on diagnosis at screening.
  • If a subject has a large lesion (5.0 - 7.0 cm), any other lesions must be less than 5.0 cm.
  • Anticipated ablation volume will be no larger than either removal of 3 hepatic segments or removal of more than 30% of total liver volume (as per maximum surgical limit).
  • If additional lesions are discovered during the laparoscopic or open treatment procedure, that were undetectable by CT at screening, the size and location of the lesion(s) will be recorded in the CRF and the lesions will be treated at the discretion of the physician and guided by the local standard of care. The subject will remain on study if all lesions are treated. If any lesions cannot be completely ablated within two treatment attempts the subject will be considered a treatment failure.
  • Study subjects being considered for re-treatment after disease progression may have more than 4 lesions.
  • Male or female 18 years of age or older.
  • Are willing to sign an informed consent form, indicating that they are aware of the investigational nature of this study that is in keeping with the policies of the institution.
  • Be an appropriate candidate for receiving RFA as a medically indicated treatment as evaluated by the following factors:

    • Number of lesions
    • Size of lesions
    • Overall health of liver
    • Not a candidate for surgical resection
  • Have an echocardiogram revealing a Left Ventricular Ejection Fraction (LVEF) ≥ 50%. Measurements with a multiple gated acquisition (MUGA) scan are allowed if an echocardiogram cannot be performed. The same method of measurement should be used to evaluate ejection fraction (EF) of the subject for the duration of the study.
  • Willing to return to the study site for their study visits.
  • Have life expectancy of ≥ 4 months.
  • Have Child-Pugh Class A or B liver disease without encephalopathy or/and ascites.

Exclusion Criteria:

  • Have serious medical illnesses including, but not limited to, congestive heart failure, myocardial infarction or cerebral vascular accident within the last six months, or life threatening cardiac arrhythmias.
  • Is scheduled for liver transplantation.
  • Have previously received any treatment for HCC (except for study subjects being considered for completion of treatment or re-treatment).
  • Have previously received any doxorubicin (study subjects being considered for completion of treatment or re-treatment may have received ThermoDox previously).
  • Have extrahepatic metastasis.
  • Are pregnant or breast-feeding. In women of childbearing potential, a negative pregnancy test (serum) is required prior to study treatment.
  • Women of childbearing potential who are not practicing an acceptable form of birth control (i.e. diaphragm, cervical cap, condom, surgical sterility or birth control pills. Women whose partner has undergone a vasectomy must use a second form of birth control).
  • Have any known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents to be used in this study.
  • Have portal or hepatic vein tumor invasion/thrombosis.
  • Have INR > 1.5 times the institution's upper normal limit (UNL), except in subjects who are therapeutically anticoagulated for medical conditions unrelated to HCC such as atrial fibrillation. Subjects may be re-screened after condition is treated or anticoagulant is withheld.
  • Have platelet count < 75,000/mm3, absolute neutrophil count < 1500/mm3, or Hgb < 10.0 g/dL (unless the hemoglobin value has been stable, the subject is cardiovascularly stable, asymptomatic and judged able to withstand the RFA procedure).
  • Have serum creatinine ≥ 2.5 mg/dL or calculated creatinine clearance (CrCl) ≤ 25.0 mL/min.
  • Have serum bilirubin > 3.0 mg/dL.
  • Have serum albumin < 2.8 g/dL.
  • Have body temperature >1010F (38.30C) immediately prior to study treatment.
  • Have contraindications to receiving doxorubicin HCl.
  • Are being treated with other investigational agents.
  • Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication (study subjects being considered for completion of treatment or re-treatment may have received ThermoDox previously).
  • Have other concurrent malignancy (subjects with treated squamous cell carcinoma of the skin or basal cell carcinoma of the skin may be included), evidence of extrahepatic cancer from their primary malignancy, or ongoing, medically significant active infection.
  • Documented HIV positive.
  • NYHA class III or IV functional classification for heart failure.
  • Evidence of hemachromatosis.
  • Have history of contrast-induced nephropathy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00617981

  Hide Study Locations
United States, California
Los Angeles, California, United States, 90095
United States, Florida
Mayo Clinic - Jacksonville, Florida
Jacksonville, Florida, United States, 32224
United States, Kentucky
University Of Louisville
Louisville, Kentucky, United States, 40202
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Mount Sinai School of Medicine
New York, New York, United States, 10029
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140
Geisinger Health System
Wilkes Barre, Pennsylvania, United States, 18711
United States, Texas
University of Texas Health Science Center
San Antonio, Texas, United States, 78229
Canada, British Columbia
Vancouver General Hospital
Vancouver, British Columbia, Canada
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada, M5G 2L4
China, Fujian
The 1st Affiliated Hospital, Fujian Medical University
Fuzhou, Fujian, China, 350005
China, Hubei
Tongji Hospital
Wuhan, Hubei, China, 430030
China, Jiangsu
Nanjing Drum Tower Hospital, The Affilitated Hospital of Nanjing University Medical School
Nanjing, Jiangsu, China, 210008
The First Affiliated Hospital of Suzhou University
Suzhou, Jiangsu, China, 215006
China, Jilin
The First Hospital of Jilin University
Changchun, Jilin, China, 130021
China, Tianjin
Tianjin Cancer Hospital
Tianjin, Tianjin, China, 300060
China, Zhejiang
The First Affiliated Hospital of Zhejiang University
Hangzhou, Zhejiang, China, 310013
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Beijing, China, 100021
Beijing Cancer Hospital, Peking University School of Oncology
Beijing, China, 100036
Beijing You An Hospital, Capital Medical University
Beijing, China, 100069
Beijing You An Hospital,Capital Medical University
Beijing, China, 100069
Southwest Hospital, The First Affiliated Hospital of the Third Military Medical University
Chongqing, China, 400038
Sun Yat-Sen University Cancer Center
Guangzhou, China, 510060
Oncology Center of Nanfang Hospital, Southern Medical University
Guangzhou, China, 510515
Shanghai Changhai Hospital, Second Military Medical University
Shanghai, China, 200433
Tianjin No. 3 Central Hospital
Tianjin, China, 300170
Hong Kong
Queen Mary Hospital
Hong Kong, Hong Kong
Azienda Ospedaliera di Padova
Padova, Veneto, Italy, 35128
Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola Malpighi
Bologna, Italy, 40138
Ospedale Classificato San Giuseppe, Milano
Milano, Italy, 20123
Azienda Ospedaliera San Gerardo
Monza, Italy, 20052
Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Pascale" di Napoli
Napoli, Italy, 80131
Azienda Ospedaliero-Univeristaria Pisana
Pisa, Italy, 56124
Istituto dei Tumori Regina Elena
Roma, Italy, 00144
Azienda Sanitaria Ospedaliera Ordine Mauriziano di Torino Presidio Ospedaliero "Umberto I"
Torino, Italy, 10128
Chiba University Hospital
Chiba, Japan, 260-8677
Iwate Medical University Hospital
Iwate, Japan, 020-8505
Yamanashi Prefectural Central Hospital
Koufu City, Japan, 400-8506
Mie University Hospital
Mie, Japan, 514-8507
Saiseikai Niigata Daini Hospital
Niigata City, Japan, 950-1104
Okayama University Hospital
Okayama City, Japan, 700-8558
Kyoundo Hospital
Tokyo, Japan, 101-0062
The University of Tokyo Hospital
Tokyo, Japan, 113-8655
Japanese Red Cross Medical Center
Tokyo, Japan, 150-8935
JR Tokyo General Hospital
Tokyo, Japan, 151-8528
Kanto Central Hospital
Tokyo, Japan, 158-8531
Wakayama Medical University
Wakayama, Japan, 641-8510
Yokohama City University Medical Center
Yokohama City, Japan, 232-0024
Korea, Republic of
Soonchunhyang University Bucheon Hospital
Gyeonggi-do, Bucheon-si, Korea, Republic of
Samsung Medical Center
Seoul, Gangnam-gu, Korea, Republic of, 135-710
Inje University Ilsan Paik Hospital
Gyeonggi-do, Goyang-si, Korea, Republic of, 411-706
Kyungpook National University Hospital
Daegu, Gyeongsangbuk-do, Korea, Republic of, 700-721
Seoul National University Hospital
Seoul, Jongno-gu, Korea, Republic of, 110-744
Kyungpook National University Hospital
Daegu, Jung-gu, Korea, Republic of, 700-721
The Catholic University of Korea, Kangnam St.Mary's Hospital
Seoul, Seocho-gu, Korea, Republic of, 137-701
Pusan National University Hospital
Busan, Korea, Republic of, 602-739
Seoul National University Bundang Hospital
Gyunggido, Korea, Republic of, 464-707
Yonsei University Severance Hospital
Seoul, Korea, Republic of, 120-752
Korea University Medical Center Anam Hospital
Seoul, Korea, Republic of, 136-705
Asan Medical Center
Seoul, Korea, Republic of, 138-736
University Malaya Medical Centre
Kuala Lumpur, Malaysia, 59100
The Medical City
Pasig City, Metro Manila, Philippines, 1605
St. Luke's Medical Center
Quezon City, Philippines, 1112
Cardinal Santos Medical Center
San Juan City, Philippines, 1053
Chinese General Hospital and Medical Center
Sta Cruz, Manila, Philippines, 1003
Chang-Gung Memorial Hospital - Chiayi Branch
Putzu City, Chiayi, Taiwan, 613
Chang Gung Memorial Hospital - Kao Shiung
KaoShiung, Kaohsiung County, Taiwan, 833
Chang Gung Memorial Hospital - Linkou
Linkou, Taoyuan, Taiwan, 333
Chang Gung Memorial Hospital - Keelung
Keelung, Taiwan, 204
China Medical University Hospital
Taichung, Taiwan, 404
Taichung Veterans General Hospital
Taichung, Taiwan, 407
National Taiwan University Hospital
Taipei, Taiwan, 100
Taipei Veterans General Hospital
Taipei, Taiwan, 112
Tri-Service General Hospital
Taipei, Taiwan, 114
Songklanagarind Hospital
Hat Yai, Songkla, Thailand, 90110
King Chulalongkorn Memorial Hospital
Bangkok, Thailand, 10330
Siriraj Hospital
Bangkok, Thailand, 10700
Thammasat University Hospital
Pathumthani, Thailand, 12120
Sponsors and Collaborators
Study Director: Ronnie T Poon, M.D. Queen Mary Hospital, University of Hong Kong
Study Director: Riccardo Lencioni, M.D. University of Pisa

Responsible Party: Celsion Identifier: NCT00617981     History of Changes
Other Study ID Numbers: 104-06-301
First Posted: February 18, 2008    Key Record Dates
Results First Posted: March 24, 2017
Last Update Posted: April 25, 2017
Last Verified: March 2017

Keywords provided by Celsion:
hepatocellular carcinoma
liver cancer

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action