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

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

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).

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: ThermoDox; Drug: 5% Dextrose Solution

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
• Enrollment (Actual): 701
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 2L4
      • Toronto General Hospital
• China
  • Beijing, China, 100021
    • Cancer Institute and Hospital, Chinese Academy of Medical Sciences
  • Beijing, China, 100036
    • Beijing Cancer Hospital, Peking University School of Oncology
  • Beijing, China, 100069
    • Beijing You An Hospital, Capital Medical University
  • Beijing, China, 100069
    • Beijing You An Hospital，Capital Medical University
  • Chongqing, China, 400038
    • Southwest Hospital, The First Affiliated Hospital of the Third Military Medical University
  • Guangzhou, China, 510060
    • Sun Yat-sen University Cancer Center
  • Guangzhou, China, 510515
    • Oncology Center of Nanfang Hospital, Southern Medical University
  • Shanghai, China, 200433
    • Shanghai Changhai Hospital, Second Military Medical University
  • Tianjin, China, 300170
    • Tianjin No. 3 Central Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350005
      • The 1st Affiliated Hospital, Fujian Medical University
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Nanjing Drum Tower Hospital, The Affilitated Hospital of Nanjing University Medical School
    • Suzhou, Jiangsu, China, 215006
      • The first affiliated hospital of suzhou University
  • Jilin
    • Changchun, Jilin, China, 130021
      • The First Hospital of Jilin University
  • Tianjin
    • Tianjin, Tianjin, China, 300060
      • Tianjin cancer hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310013
      • The First Affiliated Hospital of Zhejiang University
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola Malpighi
  • Milano, Italy, 20123
    • Ospedale Classificato San Giuseppe, Milano
  • Monza, Italy, 20052
    • Azienda Ospedaliera San Gerardo
  • Napoli, Italy, 80131
    • Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Pascale" di Napoli
  • Pisa, Italy, 56124
    • Azienda Ospedaliero-Univeristaria Pisana
  • Roma, Italy, 00144
    • Istituto dei Tumori Regina Elena
  • Torino, Italy, 10128
    • Azienda Sanitaria Ospedaliera Ordine Mauriziano di Torino Presidio Ospedaliero "Umberto I"
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Azienda Ospedaliera di Padova
• Japan
  • Chiba, Japan, 260-8677
    • Chiba University Hospital
  • Kōfu, Japan, 400-8506
    • Yamanashi Prefectural Central Hospital
  • Mie, Japan, 514-8507
    • Mie University Hospital
  • Niigata City, Japan, 950-1104
    • Saiseikai Niigata Daini Hospital
  • Okayama City, Japan, 700-8558
    • Okayama University Hospital
  • Shiwa, Japan, 020-8505
    • Iwate Medical University Hospital
  • Tokyo, Japan, 113-8655
    • The University of Tokyo Hospital
  • Tokyo, Japan, 150-8935
    • Japanese Red Cross Medical Center
  • Tokyo, Japan, 101-0062
    • Kyoundo Hospital
  • Tokyo, Japan, 151-8528
    • JR Tokyo General Hospital
  • Tokyo, Japan, 158-8531
    • Kanto Central Hospital
  • Wakayama, Japan, 641-8510
    • Wakayama Medical University
  • Yokohama City, Japan, 232-0024
    • Yokohama City University Medical Center
• Korea, Republic of
  • Busan, Korea, Republic of, 602-739
    • Pusan National University Hospital
  • Seongnam-si, Korea, Republic of, 464-707
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 120-752
    • Yonsei University Severance Hospital
  • Seoul, Korea, Republic of, 136-705
    • Korea University Medical Center Anam Hospital
  • Bucheon-si
    • Gyeonggi-do, Bucheon-si, Korea, Republic of
      • Soonchunhyang University Bucheon Hospital
  • Gangnam-gu
    • Seoul, Gangnam-gu, Korea, Republic of, 135-710
      • Samsung Medical Center
  • Goyang-si
    • Gyeonggi-do, Goyang-si, Korea, Republic of, 411-706
      • Inje University Ilsan Paik Hospital
  • Gyeongsangbuk-do
    • Daegu, Gyeongsangbuk-do, Korea, Republic of, 700-721
      • Kyungpook National University Hospital
  • Jongno-gu
    • Seoul, Jongno-gu, Korea, Republic of, 110-744
      • Seoul National University Hospital
  • Jung-gu
    • Daegu, Jung-gu, Korea, Republic of, 700-721
      • Kyungpook National University Hospital
  • Seocho-gu
    • Seoul, Seocho-gu, Korea, Republic of, 137-701
      • The Catholic University of Korea, Kangnam St.Mary's Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
• Philippines
  • Quezon City, Philippines, 1112
    • St. Luke's Medical Center
  • San Juan City, Philippines, 1053
    • Cardinal Santos Medical Center
  • Manila
    • Santa Cruz, Manila, Philippines, 1003
      • Chinese General Hospital and Medical Center
  • Metro Manila
    • Pasig City, Metro Manila, Philippines, 1605
      • The Medical City
• Taiwan
  • Chiayi City, Taiwan, 613
    • Chang-Gung Memorial Hospital - Chiayi Branch
  • Keelung, Taiwan, 204
    • Chang Gung Memorial Hospital - Keelung
  • Taichung, Taiwan, 404
    • China Medical University Hospital
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan, 114
    • Tri-Service General Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Kaohsiung County
    • Niaosong, Kaohsiung County, Taiwan, 833
      • Chang Gung Memorial Hospital - Kao Shiung
  • Taoyuan
    • Linkou, Taoyuan, Taiwan, 333
      • Chang Gung Memorial Hospital - Linkou
• Thailand
  • Bangkok, Thailand, 10330
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand, 10700
    • Siriraj Hospital
  • Pathumthani, Thailand, 12120
    • Thammasat University Hospital
  • Songkla
    • Hat Yai, Songkla, Thailand, 90110
      • Songklanagarind Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville, Florida
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Geisinger Health System
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ThermoDox + RFA; 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: Sham + RFA; Sham infusion over 30 minutes about 15 minutes before radiofrequency ablation begins.	Drug: 5% Dextrose Solution; Single 30 minute intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival as Measured by Time From Randomization to Death or the End of the Study.		3 years
Number of Participants With Definite Worsening as Per Patient-Reported Outcomes	Number of participants with significant symptom deterioration, defined as greater than or equal to 4-point increase from baseline in the eight-item Functional Assessment of Cancer Therapy-Hepatobiliary Symptom Index.	3 years
Number of Participants With Local Recurrence	Number of participants with local progression in the intent-to-treat (ITT) population.	3 years
Evaluation of Safety		3 years

Collaborators and Investigators

• Sponsor: Imunon
• Investigators: Study Director: Ronnie T Poon, M.D., Queen Mary Hospital, University of Hong Kong; Study Director: Riccardo Lencioni, M.D., University of Pisa

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2008
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: February 6, 2008
• First Submitted That Met QC Criteria: February 15, 2008
• First Posted (Estimated): February 18, 2008

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: May 2, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: hepatocellular carcinoma; liver cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 104-06-301