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

Sponsor

Celsion (Industry)

Overall Status

Completed

CT.gov ID

NCT02112656

Collaborator

(none)

556

Enrollment

Locations

Arms

Duration (Months)

9.1

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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

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 :

Jun 1, 2014

Actual Primary Completion Date :

Aug 31, 2018

Actual Study Completion Date :

Aug 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

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

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

Secondary Outcome Measures

Progression-free survival (PFS) [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female ≥ 18 years of age.
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.

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.

Child-Pugh Class A without either current encephalopathy or ascites.
Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
Eastern Cooperative Oncology Group (ECOG) performance status 0.
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:

Is scheduled for liver transplantation
Expected ablation volume > 30% of total liver volume or removal of 3 hepatic segments
More than 1 lesion identified during baseline.
Have previously received therapeutic treatment for HCC outside the study protocol or is expected to receive concomitant HCC treatment prior to PFS event.
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.
Have previously received any anthracycline outside the protocol
Have extrahepatic metastasis.
Have portal or hepatic vein tumor invasion/thrombosis.
Have body temperature >101ºF (38.3ºC) immediately prior to study treatment.
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.

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.

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.
Are pregnant or breast-feeding. In women of childbearing potential, a negative serum pregnancy test is required prior to study treatment.
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).
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 contraindications to receiving doxorubicin hydrochloride (HCl).
Are being treated with other investigational agents.
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.
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.
HIV positive.
NYHA class III or IV functional classification for heart failure.
Evidence of hemachromatosis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Department of Medicine	Los Angeles	California	United States	90095
2	Toronto General Hospital	Toronto	Ontario	Canada
3	Mengchao Hepatobiliary Hospital of Fujian Medicatl University	Fuzhou	Fujian	China	350005
4	Peking University First Hospital	Beijing		China	100034
5	Beijing Cancer Hospital, School of Oncology, Peking	Beijing		China	100036
6	302 Military Hospital of China	Beijing		China	100039
7	Beijing Hospital of the Ministry of Health	Beijing		China	100730
8	Chinese PLA General Hospital	Beijing		China
9	West China Hospital of Sichuan University	Chengdu		China	610041
10	The Second Hospital of Dalian Medical University	Dalian		China	116023
11	Guangdong General Hospital	Guangdong		China	510080
12	Hunan Cancer Hospital	Hunan		China	410013
13	The First Hospital of Jilin University	Jilin		China	130021
14	Xijing Hospital	Shaanxi Province		China	710032
15	Zhongshan Hospital, Fudan University	Shanghai		China	200032
16	The Sixth People's Hospital of Shenyang	Shenyang		China	110006
17	The 3rd Hospital of Tianjing	Tianjin		China	300170
18	The First Hospital of Zhejiang	ZheJiang		China	310013
19	Zhejiang Cancer Hospital	Zhejiang		China	310022
20	Institut für Diagnostische und Radiologische Therapie del Uniklinik Frankfurt	Frankfurt		Germany
21	Klinikum rechts der Isar, II. Medizinische Klinik und Poliklinik (Gastroenterologie)	München		Germany
22	Universitätsklinikum Regensburg, Institut für Röntgendiagnostik	Regensburg		Germany
23	Universitaetsklinikum des Saarlandes, Klik fuer Allgemeine Chirurgie, Viszeral-, Gefaess und Kinderchirurgie	Saar		Germany	66421
24	Queen Mary Hospital	Hong Kong		Hong Kong
25	Cisanello Hospital, Division of Diagnostic Imaging and Intervention	Pisa		Italy
26	Department of Radiological Sciences and Bioimaging Catholic University of Rome, "A. Gemelli" Hospital	Rome		Italy
27	Pusan National University Hospital	Busan		Korea, Republic of	602-739
28	Kyungpook National University Hospital	Daegu		Korea, Republic of	700-721
29	Kyungpook National University Medical Center	Daegu		Korea, Republic of	702-210
30	Inha University Hospital	Incheon		Korea, Republic of	400-711
31	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
32	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	120-752
33	Samsung Medical Center	Seoul		Korea, Republic of	135-710
34	The Catholic University of Korea, Seoul St.Mary's Hospital	Seoul		Korea, Republic of	137-701
35	University Malaya Medical Centre	Kuala Lumpur		Malaysia	59100
36	Chinese General Hospital and Medical Center	Manila		Philippines	1003
37	St. Lukes Medical Center	Quezon City		Philippines	1112
38	Cardinal Santos Medical Center	San Juan		Philippines	1503
39	Singapore General Hospital	Singapore		Singapore	169608
40	Hospital Madrid Norte Sanchinarro	Madrid		Spain
41	Hospital Universitario Marqués de Valdecilla	Santander		Spain
42	National Taiwan University Hospital, Yun-Lin Branch	Douliou City		Taiwan	640
43	Chang Gung Memorial Hospital - Kaohsiung	Kaohsiung		Taiwan	833
44	Taipei Medical University-Shuang Ho Hospital	New Taipei City		Taiwan	235
45	Taichung Veteran General Hospital	Taichung		Taiwan	407
46	National Cheng Kung University (NCKU) Hospital	Tainan		Taiwan	704
47	National Taiwan University Hospital	Taipei City		Taiwan	100
48	Chang Gung Memorial Hospital - Linkou	Taoyuan		Taiwan	333
49	Siriraj Hospital	Bangkok		Thailand	10700
50	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai		Thailand
51	Srinagarind Hospital	Khon Kaen		Thailand	40002
52	Thammasat University Hospital	Pathumthani		Thailand	12120
53	Songklanagarind Hospital	Songkhla		Thailand	90110
54	Bach Mai Hospital	Hà Nội	Dong Da District	Vietnam
55	108 Military Central Hospital	Hà Nội	Hai Ba Trung District	Vietnam
56	Hue Central Hospital	Huế	Vin Ninh Ward	Vietnam
57	Bach Mai Hospital (Hepato-gastroenterology Department)	Hanoi		Vietnam
58	Can Tho Oncology Hospital	Hanoi		Vietnam
59	National Cancer Hospital	Hanoi		Vietnam
60	Viet Duc University Hospital	Hanoi		Vietnam
61	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, Peking University Cancer Hospital & Institute