Clinical trial NCT02112656: Study of ThermoDox With Standardized Radiofrequency Ablation (RFA) for Treatment of Hepatocellular Carcinoma (HCC)
Official title: A Phase III, Randomized, Double Blind, Dummy-Controlled Study of ThermoDox® (Lyso-Thermosensitive Liposomal Doxorubicin-LTLD) in Hepatocellular Carcinoma (HCC) Using Standardized Radiofrequency Ablation (RFA) Treatment Time ≥ 45 Minutes for Solitary Lesions ≥ 3 cm to ≤ 7 cm
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Lead sponsor: Imunon
Sponsor class: INDUSTRY
First posted: 2014-04-14
Enrollment: 554
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 standardized radiofrequency ablation (sRFA).

Detailed description: This is a Phase III, randomized, double blind, dummy controlled safety and efficacy study of ThermoDox plus sRFA compared to sRFA plus dummy infusion using standardized treatment dwell time for solitary HCC lesions ≥ 3.0 cm to ≤ 7.0 cm. An sRFA treatment for this protocol is defined as the dwell time of ≥ 45 minutes measured from the first activation of the RFA probe through removal of the RFA probe after the final ablation cycle or deployment.

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 24 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 24 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 24 hours prior to infusion of the study medication, and a dummy infusion 30 minutes prior to dummy infusion of Sodium Chloride 0.9% or 5% Dextrose (D5W). 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 goal is to reach a \> 45 minute dwell time which can be achieved by employing at least four ablation cycles or deployments in order to ablate the tumor as well as a 360º 1.0 cm tumor-free margin surrounding the tumor.with an estimated overall procedure time of less than 3 hours.

A subject who has an incomplete ablation is eligible for 1 retreatment procedure within 21 days after the radiological imaging exam showing residual disease at Day 28. Subjects will be retreated only once with the same RFA equipment and treatment assigned at randomization. Subjects with a complete ablation after retreatment will be followed both for PFS and for OS.

If after 2 ablations the subject has local, distant intrahepatic, or extrahepatic HCC, then the subject will be considered a treatment failure and will have met the PFS endpoint. The subject will be followed for OS every 3 months. Among subjects who are not treatment failures, five repeat treatments are permitted to treat a recurrent lesion or to treat newly-identified local or distant intrahepatic lesions at the Investigator's discretion after the PFS endpoint is reported and with agreement from the Sponsor. The subject must be eligible for retreatment consistent with the safety eligibility criteria and will be retreated with the same randomized treatment.

CT or MRI imaging will be used to assess the effectiveness of the ablation therapy. The blind will be maintained at the level of the imaging reads. Investigator determined radiological progression must be observed and recorded prior to beginning alternate treatments for HCC. Posttreatment imaging will be obtained at months 1, 5, 9, 13, 17, 21, 25, then every 6 months (+/- 2 weeks) until radiological progression is seen. 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 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 if clinically indicated and based on the treating physician's medical judgment.

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

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥ 18 years of age.
2. Diagnosed with a single HCC lesion ≥ 3.0 cm but ≤ 7.0 cm in maximum diameter based on diagnosis at screening.

   * Subjects meeting the American Association for the Study of Liver Disease (AASLD) criteria may be randomized without a biopsy, but will undergo a biopsy during the RFA procedure unless contraindicated or unattainable.
   * Subjects not meeting the AASLD criteria for HCC will need a biopsy to confirm HCC prior to randomization.
3. Be an appropriate candidate for receiving RFA as a medically indicated treatment as evaluated by the following factors:

   * The position and accessibility of the target lesion allows for the safe administration of multiple ablation cycles or deployments to achieve a probe dwell time of ≥ 45 minutes.
   * Not a candidate for surgical resection according to the local guidelines for resection and in the Investigator's judgment.
4. Child-Pugh Class A without either current encephalopathy or ascites.
5. Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0.
7. Willing to sign an informed consent form, indicating awareness of the investigational nature of this study that is in keeping with the policies of the institution.

Exclusion Criteria:

1. Is scheduled for liver transplantation
2. Expected ablation volume \> 30% of total liver volume or removal of 3 hepatic segments
3. More than 1 lesion identified during baseline.
4. Have previously received therapeutic treatment for HCC outside the study protocol or is expected to receive concomitant HCC treatment prior to PFS event.
5. 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.
6. Have previously received any anthracycline outside the protocol
7. Have extrahepatic metastasis.
8. Have portal or hepatic vein tumor invasion/thrombosis.
9. Have body temperature \>101ºF (38.3ºC) immediately prior to study treatment.
10. Baseline laboratories (repeat lab tests are permitted to evaluate eligibility during the Screening Period. Lab results must be within protocol range prior to study treatment.)

    * Absolute neutrophil count \< 1500/mm3
    * Platelet count \< 75,000/mm3
    * 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) Note: If clinically indicated, subjects may receive platelets or packed red blood cell (RBC) transfusions and be re-evaluated after condition is treated.
11. Baseline Chemistry

    * Serum creatinine ≥ 2.5 mg/dL or calculated creatinine clearance (CrCl) ≤25.0 mL/min.
    * Serum bilirubin \> 3.0 mg/dL.
    * Serum albumin \< 2.8 g/dL.
12. Have any known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents that prohibit the ability to complete the imaging requirements.
13. Are pregnant or breast-feeding. In women of childbearing potential, a negative serum pregnancy test is required prior to study treatment.
14. Women of childbearing potential and men 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 or men who have undergone a vasectomy must use a second form of birth control).
15. 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.
16. Have contraindications to receiving doxorubicin hydrochloride (HCl).
17. Are being treated with other investigational agents.
18. Use of an investigational drug outside this study within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication.
19. 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.
20. HIV positive.
21. NYHA class III or IV functional classification for heart failure.
22. Evidence of hemachromatosis.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: All subjects to be contacted every 3 months after radiological progression for vital status reporting. Subjects were followed for OS up to 68 months from randomization.
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: CT or MRI scan (Chest, Abdomen, Pelvis) done at Baseline and Day 28. Additional imaging done at months 5, 9, 13, 17, 21, 25, then every 6 months until disease progression is seen. Study subjects were followed up to 63 months after randomization.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Department of Medicine
state: California
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Fuzhou
country: China
facility: Mengchao Hepatobiliary Hospital of Fujian Medicatl University
state: Fujian
city: Xi'an
country: China
facility: Xijing Hospital
state: Shaanxi
city: Beijing
country: China
facility: Peking University First Hospital
city: Beijing
country: China
facility: Beijing Cancer Hospital, School of Oncology, Peking
city: Beijing
country: China
facility: 302 Military Hospital of China
city: Beijing
country: China
facility: Beijing Hospital of the Ministry of Health
city: Beijing
country: China
facility: Chinese PLA General Hospital
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
city: Dalian
country: China
facility: The Second Hospital of Dalian Medical University
city: Guangdong
country: China
facility: Guangdong General Hospital
city: Hunan
country: China
facility: Hunan Cancer Hospital
city: Jilin
country: China
facility: The First Hospital of Jilin University
city: Shanghai
country: China
facility: Zhongshan Hospital, Fudan University
city: Shenyang
country: China
facility: The Sixth People's Hospital of Shenyang
city: Tianjin
country: China
facility: The 3rd Hospital of Tianjing
city: ZheJiang
country: China
facility: The First Hospital of Zhejiang
city: Zhejiang
country: China
facility: Zhejiang Cancer Hospital
city: Frankfurt
country: Germany
facility: Institut für Diagnostische und Radiologische Therapie del Uniklinik Frankfurt
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes, Klik fuer Allgemeine Chirurgie, Viszeral-, Gefaess und Kinderchirurgie
city: München
country: Germany
facility: Klinikum rechts der Isar, II. Medizinische Klinik und Poliklinik (Gastroenterologie)
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg, Institut für Röntgendiagnostik
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Pisa
country: Italy
facility: Cisanello Hospital, Division of Diagnostic Imaging and Intervention
city: Rome
country: Italy
facility: Department of Radiological Sciences and Bioimaging Catholic University of Rome, "A. Gemelli" Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Medical Center
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St.Mary's Hospital
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Manila
country: Philippines
facility: Chinese General Hospital and Medical Center
city: Quezon City
country: Philippines
facility: St. Lukes Medical Center
city: San Juan
country: Philippines
facility: Cardinal Santos Medical Center
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Madrid
country: Spain
facility: Hospital Madrid Norte Sanchinarro
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital - Kaohsiung
city: New Taipei City
country: Taiwan
facility: Taipei Medical University-Shuang Ho Hospital
city: Taichung
country: Taiwan
facility: Taichung Veteran General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University (NCKU) Hospital
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou
city: Yuanlin
country: Taiwan
facility: National Taiwan University Hospital, Yun-Lin Branch
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Pathumthani
country: Thailand
facility: Thammasat University Hospital
city: Songkhla
country: Thailand
facility: Songklanagarind Hospital
city: Hà Nội
country: Vietnam
facility: Bach Mai Hospital
state: Dong Da District
city: Hà Nội
country: Vietnam
facility: 108 Military Central Hospital
state: Hai Ba Trung District
city: Huế
country: Vietnam
facility: Hue Central Hospital
state: Vin Ninh Ward
city: Hanoi
country: Vietnam
facility: Bach Mai Hospital (Hepato-gastroenterology Department)
city: Hanoi
country: Vietnam
facility: Can Tho Oncology Hospital
city: Hanoi
country: Vietnam
facility: National Cancer Hospital
city: Hanoi
country: Vietnam
facility: Viet Duc University Hospital
city: Ho Chi Minh City
country: Vietnam
facility: People's Hospital 115
Study officials:
affiliation: University of Pisa
name: Ricardo Lencioni, MD
role: STUDY_CHAIR
affiliation: Hong Kong University
name: Ronnie Tung Ping Poon, MD
role: STUDY_CHAIR
affiliation: Peking University Cancer Hospital & Institute
name: Chen Min Hua, MD
role: PRINCIPAL_INVESTIGATOR
References: