Clinical trial NCT00617981: Phase 3 Study of ThermoDox With Radiofrequency Ablation (RFA) in Treatment of Hepatocellular Carcinoma (HCC)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: hepatocellular carcinoma
liver cancer
Lead sponsor: Imunon
Sponsor class: INDUSTRY
First posted: 2008-02-18
Enrollment: 701
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: 3 years
Secondary outcomes:
measure: Overall Survival as Measured by Time From Randomization to Death or the End of the Study.
timeFrame: 3 years
measure: Number of Participants With Definite Worsening as Per Patient-Reported Outcomes
timeFrame: 3 years
measure: Number of Participants With Local Recurrence
timeFrame: 3 years
measure: Evaluation of Safety
timeFrame: 3 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville, Florida
state: Florida
city: Louisville
country: United States
facility: University Of Louisville
state: Kentucky
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Health System
state: Pennsylvania
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Fuzhou
country: China
facility: The 1st Affiliated Hospital, Fujian Medical University
state: Fujian
city: Wuhan
country: China
facility: Tongji Hospital
state: Hubei
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital, The Affilitated Hospital of Nanjing University Medical School
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Suzhou University
state: Jiangsu
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Tianjin
country: China
facility: Tianjin Cancer Hospital
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital of Zhejiang University
state: Zhejiang
city: Beijing
country: China
facility: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
city: Beijing
country: China
facility: Beijing Cancer Hospital, Peking University School of Oncology
city: Beijing
country: China
facility: Beijing You An Hospital, Capital Medical University
city: Beijing
country: China
facility: Beijing You An Hospital，Capital Medical University
city: Chongqing
country: China
facility: Southwest Hospital, The First Affiliated Hospital of the Third Military Medical University
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center
city: Guangzhou
country: China
facility: Oncology Center of Nanfang Hospital, Southern Medical University
city: Shanghai
country: China
facility: Shanghai Changhai Hospital, Second Military Medical University
city: Tianjin
country: China
facility: Tianjin No. 3 Central Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
state: Veneto
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola Malpighi
city: Milano
country: Italy
facility: Ospedale Classificato San Giuseppe, Milano
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo
city: Napoli
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Pascale" di Napoli
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Univeristaria Pisana
city: Roma
country: Italy
facility: Istituto dei Tumori Regina Elena
city: Torino
country: Italy
facility: Azienda Sanitaria Ospedaliera Ordine Mauriziano di Torino Presidio Ospedaliero "Umberto I"
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Kōfu
country: Japan
facility: Yamanashi Prefectural Central Hospital
city: Mie
country: Japan
facility: Mie University Hospital
city: Niigata City
country: Japan
facility: Saiseikai Niigata Daini Hospital
city: Okayama City
country: Japan
facility: Okayama University Hospital
city: Shiwa
country: Japan
facility: Iwate Medical University Hospital
city: Tokyo
country: Japan
facility: Kyoundo Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Tokyo
country: Japan
facility: Japanese Red Cross Medical Center
city: Tokyo
country: Japan
facility: JR Tokyo General Hospital
city: Tokyo
country: Japan
facility: Kanto Central Hospital
city: Wakayama
country: Japan
facility: Wakayama Medical University
city: Yokohama City
country: Japan
facility: Yokohama City University Medical Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Soonchunhyang University Bucheon Hospital
state: Bucheon-si
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Gangnam-gu
city: Gyeonggi-do
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
state: Goyang-si
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
state: Gyeongsangbuk-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Jongno-gu
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
state: Jung-gu
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Kangnam St.Mary's Hospital
state: Seocho-gu
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Medical Center Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Santa Cruz
country: Philippines
facility: Chinese General Hospital and Medical Center
state: Manila
city: Pasig City
country: Philippines
facility: The Medical City
state: Metro Manila
city: Quezon City
country: Philippines
facility: St. Luke's Medical Center
city: San Juan City
country: Philippines
facility: Cardinal Santos Medical Center
city: Niaosong
country: Taiwan
facility: Chang Gung Memorial Hospital - Kao Shiung
state: Kaohsiung County
city: Linkou
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou
state: Taoyuan
city: Chiayi City
country: Taiwan
facility: Chang-Gung Memorial Hospital - Chiayi Branch
city: Keelung
country: Taiwan
facility: Chang Gung Memorial Hospital - Keelung
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Hat Yai
country: Thailand
facility: Songklanagarind Hospital
state: Songkla
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Pathumthani
country: Thailand
facility: Thammasat University Hospital
Study officials:
affiliation: Queen Mary Hospital, University of Hong Kong
name: Ronnie T Poon, M.D.
role: STUDY_DIRECTOR
affiliation: University of Pisa
name: Riccardo Lencioni, M.D.
role: STUDY_DIRECTOR
References: