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

Hepatocellular Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00617981
• Other study ID #: 104-06-301
• Status: Completed
• Phase: Phase 3
• Start date: May 2008
• Est. completion date: August 2016

Study information

• Verified date: May 2024
• Source: Imunon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 701
• Est. completion date: August 2016
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• ThermoDox
Thermally Sensitive Liposomal Doxorubicin 50 mg/m2 Single 30 minute intravenous infusion
• 5% Dextrose Solution
Single 30 minute intravenous infusion

Locations

Country	Name	City	State
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
China	Beijing Cancer Hospital, Peking University School of Oncology	Beijing
China	Beijing You An Hospital, Capital Medical University	Beijing
China	Beijing You An Hospital,Capital Medical University	Beijing
China	Cancer Institute and Hospital, Chinese Academy of Medical Sciences	Beijing
China	The First Hospital of Jilin University	Changchun	Jilin
China	Southwest Hospital, The First Affiliated Hospital of the Third Military Medical University	Chongqing
China	The 1st Affiliated Hospital, Fujian Medical University	Fuzhou	Fujian
China	Oncology Center of Nanfang Hospital, Southern Medical University	Guangzhou
China	Sun Yat-Sen University Cancer Center	Guangzhou
China	The First Affiliated Hospital of Zhejiang University	Hangzhou	Zhejiang
China	Nanjing Drum Tower Hospital, The Affilitated Hospital of Nanjing University Medical School	Nanjing	Jiangsu
China	Shanghai Changhai Hospital, Second Military Medical University	Shanghai
China	The First Affiliated Hospital of Suzhou University	Suzhou	Jiangsu
China	Tianjin Cancer Hospital	Tianjin	Tianjin
China	Tianjin No. 3 Central Hospital	Tianjin
China	Tongji Hospital	Wuhan	Hubei
Hong Kong	Queen Mary Hospital	Hong Kong
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola Malpighi	Bologna
Italy	Ospedale Classificato San Giuseppe, Milano	Milano
Italy	Azienda Ospedaliera San Gerardo	Monza
Italy	Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Pascale" di Napoli	Napoli
Italy	Azienda Ospedaliera di Padova	Padova	Veneto
Italy	Azienda Ospedaliero-Univeristaria Pisana	Pisa
Italy	Istituto dei Tumori Regina Elena	Roma
Italy	Azienda Sanitaria Ospedaliera Ordine Mauriziano di Torino Presidio Ospedaliero "Umberto I"	Torino
Japan	Chiba University Hospital	Chiba
Japan	Yamanashi Prefectural Central Hospital	Kofu
Japan	Mie University Hospital	Mie
Japan	Saiseikai Niigata Daini Hospital	Niigata City
Japan	Okayama University Hospital	Okayama City
Japan	Iwate Medical University Hospital	Shiwa
Japan	Japanese Red Cross Medical Center	Tokyo
Japan	JR Tokyo General Hospital	Tokyo
Japan	Kanto Central Hospital	Tokyo
Japan	Kyoundo Hospital	Tokyo
Japan	The University of Tokyo Hospital	Tokyo
Japan	Wakayama Medical University	Wakayama
Japan	Yokohama City University Medical Center	Yokohama City
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Kyungpook National University Hospital	Daegu	Gyeongsangbuk-do
Korea, Republic of	Kyungpook National University Hospital	Daegu	Jung-gu
Korea, Republic of	Inje University Ilsan Paik Hospital	Gyeonggi-do	Goyang-si
Korea, Republic of	Soonchunhyang University Bucheon Hospital	Gyeonggi-do	Bucheon-si
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Medical Center Anam Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul	Gangnam-gu
Korea, Republic of	Seoul National University Hospital	Seoul	Jongno-gu
Korea, Republic of	The Catholic University of Korea, Kangnam St.Mary's Hospital	Seoul	Seocho-gu
Korea, Republic of	Yonsei University Severance Hospital	Seoul
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Philippines	The Medical City	Pasig City	Metro Manila
Philippines	St. Luke's Medical Center	Quezon City
Philippines	Cardinal Santos Medical Center	San Juan City
Philippines	Chinese General Hospital and Medical Center	Santa Cruz	Manila
Taiwan	Chang-Gung Memorial Hospital - Chiayi Branch	Chiayi City
Taiwan	Chang Gung Memorial Hospital - Keelung	Keelung
Taiwan	Chang Gung Memorial Hospital - Linkou	Linkou	Taoyuan
Taiwan	Chang Gung Memorial Hospital - Kao Shiung	Niaosong	Kaohsiung County
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Thailand	King Chulalongkorn Memorial Hospital	Bangkok
Thailand	Siriraj Hospital	Bangkok
Thailand	Songklanagarind Hospital	Hat Yai	Songkla
Thailand	Thammasat University Hospital	Pathumthani
United States	Cleveland Clinic	Cleveland	Ohio
United States	Mayo Clinic - Jacksonville, Florida	Jacksonville	Florida
United States	UCLA	Los Angeles	California
United States	University Of Louisville	Louisville	Kentucky
United States	Mount Sinai School of Medicine	New York	New York
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Texas Health Science Center	San Antonio	Texas
United States	Geisinger Health System	Wilkes-Barre	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Imunon

Countries where clinical trial is conducted

United States,  Canada,  China,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Philippines,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Overall Survival as Measured by Time From Randomization to Death or the End of the Study.		3 years
Secondary	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
Secondary	Number of Participants With Local Recurrence	Number of participants with local progression in the intent-to-treat (ITT) population.	3 years
Secondary	Evaluation of Safety		3 years