Study of ThermoDox With Standardized Radiofrequency Ablation (RFA) for Treatment of Hepatocellular Carcinoma (HCC) (OPTIMA)

• ClinicalTrials.gov Identifier: NCT02112656
• Recruitment Status: Completed
• First Posted: April 14, 2014
• Last Update Posted: October 24, 2018
• Sponsor: Celsion
• Information provided by (Responsible Party): Celsion

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma	Drug: ThermoDox; Drug: Dummy infusion	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 556 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 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 Start Date: June 2014
• Actual Primary Completion Date: August 31, 2018
• Actual Study Completion Date: August 31, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: ThermoDox 50 mg/m2; ThermoDox plus standardized RFA using standardized treatment dwell time for solitary HCC lesions ≥ 3.0 cm to ≤ 7.0 cm	Drug: ThermoDox; Thermally Sensitive Liposomal Doxorubicin 50 mg/m2 Single 30 minute intravenous infusion
Placebo Comparator: Dummy infusion; standardized RFA alone using standardized treatment dwell time for solitary HCC lesions ≥ 3.0 cm to ≤ 7.0 cm	Drug: Dummy infusion; Sodium Chloride 0.9% or 5% Dextrose (D5W), Single 30 minute intravenous infusion

Outcome Measures

Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: 5 years ]
   Overall survival is defined as the time (in months) from the date of randomization to the death date.

Secondary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: 5 years ]
   Progression-free survival is defined as the time (in months) from the date of randomization until the date of the Investigator-assessed radiological disease progression or death due to any cause.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, California

UCLA Department of Medicine

Los Angeles, California, United States, 90095

Canada, Ontario

Toronto General Hospital

Toronto, Ontario, Canada

China, Fujian

Mengchao Hepatobiliary Hospital of Fujian Medicatl University

Fuzhou, Fujian, China, 350005

China

Peking University First Hospital

Beijing, China, 100034

Beijing Cancer Hospital, School of Oncology, Peking

Beijing, China, 100036

302 Military Hospital of China

Beijing, China, 100039

Beijing Hospital of the Ministry of Health

Beijing, China, 100730

Chinese PLA General Hospital

Beijing, China

West China Hospital of Sichuan University

Chengdu, China, 610041

The Second Hospital of Dalian Medical University

Dalian, China, 116023

Guangdong General Hospital

Guangdong, China, 510080

Hunan Cancer Hospital

Hunan, China, 410013

The First Hospital of Jilin University

Jilin, China, 130021

Xijing Hospital

Shaanxi Province, China, 710032

Zhongshan Hospital, Fudan University

Shanghai, China, 200032

The Sixth People's Hospital of Shenyang

Shenyang, China, 110006

The 3rd Hospital of Tianjing

Tianjin, China, 300170

The First Hospital of Zhejiang

ZheJiang, China, 310013

Zhejiang Cancer Hospital

Zhejiang, China, 310022

Germany

Institut für Diagnostische und Radiologische Therapie del Uniklinik Frankfurt

Frankfurt, Germany

Klinikum rechts der Isar, II. Medizinische Klinik und Poliklinik (Gastroenterologie)

München, Germany

Universitätsklinikum Regensburg, Institut für Röntgendiagnostik

Regensburg, Germany

Universitaetsklinikum des Saarlandes, Klik fuer Allgemeine Chirurgie, Viszeral-, Gefaess und Kinderchirurgie

Saar, Germany, 66421

Hong Kong

Queen Mary Hospital

Hong Kong, Hong Kong

Italy

Cisanello Hospital, Division of Diagnostic Imaging and Intervention

Pisa, Italy

Department of Radiological Sciences and Bioimaging Catholic University of Rome, "A. Gemelli" Hospital

Rome, Italy

Korea, Republic of

Pusan National University Hospital

Busan, Korea, Republic of, 602-739

Kyungpook National University Hospital

Daegu, Korea, Republic of, 700-721

Kyungpook National University Medical Center

Daegu, Korea, Republic of, 702-210

Inha University Hospital

Incheon, Korea, Republic of, 400-711

Seoul National University Hospital

Seoul, Korea, Republic of, 110-744

Severance Hospital, Yonsei University Health System

Seoul, Korea, Republic of, 120-752

Samsung Medical Center

Seoul, Korea, Republic of, 135-710

The Catholic University of Korea, Seoul St.Mary's Hospital

Seoul, Korea, Republic of, 137-701

Malaysia

University Malaya Medical Centre

Kuala Lumpur, Malaysia, 59100

Philippines

Chinese General Hospital and Medical Center

Manila, Philippines, 1003

St. Lukes Medical Center

Quezon City, Philippines, 1112

Cardinal Santos Medical Center

San Juan, Philippines, 1503

Singapore

Singapore General Hospital

Singapore, Singapore, 169608

Spain

Hospital Madrid Norte Sanchinarro

Madrid, Spain

Hospital Universitario Marqués de Valdecilla

Santander, Spain

Taiwan

National Taiwan University Hospital, Yun-Lin Branch

Douliou City, Taiwan, 640

Chang Gung Memorial Hospital - Kaohsiung

Kaohsiung, Taiwan, 833

Taipei Medical University-Shuang Ho Hospital

New Taipei City, Taiwan, 235

Taichung Veteran General Hospital

Taichung, Taiwan, 407

National Cheng Kung University (NCKU) Hospital

Tainan, Taiwan, 704

National Taiwan University Hospital

Taipei City, Taiwan, 100

Chang Gung Memorial Hospital - Linkou

Taoyuan, Taiwan, 333

Thailand

Siriraj Hospital

Bangkok, Thailand, 10700

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, Thailand

Srinagarind Hospital

Khon Kaen, Thailand, 40002

Thammasat University Hospital

Pathumthani, Thailand, 12120

Songklanagarind Hospital

Songkhla, Thailand, 90110

Vietnam

Bach Mai Hospital

Hà Nội, Dong Da District, Vietnam

108 Military Central Hospital

Hà Nội, Hai Ba Trung District, Vietnam

Hue Central Hospital

Huế, Vin Ninh Ward, Vietnam

Bach Mai Hospital (Hepato-gastroenterology Department)

Hanoi, Vietnam

Can Tho Oncology Hospital

Hanoi, Vietnam

National Cancer Hospital

Hanoi, Vietnam

Viet Duc University Hospital

Hanoi, Vietnam

People's Hospital 115

Ho Chi Minh City, Vietnam

Sponsors and Collaborators

Celsion

Investigators

• Study Chair: Ricardo Lencioni, MD; University of Pisa
• Study Chair: Ronnie Tung Ping Poon, MD; Hong Kong University
• Principal Investigator: Chen Min Hua, MD; Beijing Cancer Hospital

More Information

• Responsible Party: Celsion
• ClinicalTrials.gov Identifier: NCT02112656
• Other Study ID Numbers: 104-13-302
• First Posted: April 14, 2014
• Last Update Posted: October 24, 2018
• Last Verified: October 2018

Keywords provided by Celsion:

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

Additional relevant MeSH terms:

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