Efficacy and Safety Doxorubicin Transdrug Study in Patients Suffering From Advanced Hepatocellular Carcinoma (ReLive)

• ClinicalTrials.gov Identifier: NCT01655693
• Recruitment Status: Completed
• First Posted: August 2, 2012
• Results First Posted: June 2, 2021
• Last Update Posted: June 2, 2021
• Sponsor: Valerio Therapeutics
• Information provided by (Responsible Party): Valerio Therapeutics

Tracking Information

• First Submitted Date: July 26, 2012
• First Posted Date: August 2, 2012
• Results First Submitted Date: November 12, 2020
• Results First Posted Date: June 2, 2021
• Last Update Posted Date: June 2, 2021
• Actual Study Start Date: June 2012
• Actual Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 28, 2021)

Overall Survival (OS) [ Time Frame: Time from date of randomization to the date of death from any cause with initial assessment up to 24 months and follow-up assessment up to 45 months. ]

OS is defined as the time from date of randomization to the date of death from any cause.

Original Primary Outcome Measures (submitted: July 31, 2012)

Overall survival(OS) in each group [ Time Frame: at 1 year (expected average) ]

Survival status will be collected at each visit (at least every 2 weeks) during the study treatment period and then every 3 months until death for an expected average of 1 year.

Current Secondary Outcome Measures (submitted: May 28, 2021)

• Progression-free Survival (PFS) [ Time Frame: Time from date of randomization to date of first documented progression or death from any cause, which ever came first, assessed up to 20 months. ]
  PFS is defined as time from the date of randomisation to the date of the first documented progression or death from any cause. PFS determined by independent radiological review according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 is determine by at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.
• Objective Response Rate (ORR) [ Time Frame: Time from date of first treatment cycle to date of last cycle of treatment for the full duration of study treatment up to 24 months. ]
  ORR is defined as percent of patients whose best overall response is complete response (CR) or partial response (PR) during the study treatment period and based on the evaluation of independent radiological review according to RECIST 1.1 for target lesions and assessed by MRI: CR is disappearance of all targets extra nodal lesions and the regression of all nodal lesions to < 10 mm; PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. PD is at least a 20% increase in the sum of diameters of target lesions, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.

Original Secondary Outcome Measures (submitted: July 31, 2012)

Incidence and severity of all Treatment Emergent Adverse Events according to NCI-CTC v4.0 scale in each groups [ Time Frame: until 2 months after last treatment intake ]

Adverse events will be collected at each visit (at least every 2 weeks) during the study treatment period, and then 2 months after the last treatment intake for an expected average of 6 months.

Current Other Pre-specified Outcome Measures (submitted: May 28, 2021)

• Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, Withdrawal From Study, or Death [ Time Frame: Time from date of initial treatment to date of death, disease progression, or participant withdrawal from the study. ]
  The number of participants experiencing TEAEs considered related to treatment and categorized by severity of all related TEAEs according to National Cancer Institute/Common Toxicity Criteria (NCI-CTCAE) v4.0 and resulting in patient withdrawal from study or death.
• Number of Participants With Cardiovascular and Respiratory Events Related to Study Drug [ Time Frame: Time from date of initial treatment to date of death, disease progression, or patient withdrawal from the study. ]
  The number of participants with cardiovascular and respiratory adverse events (AEs) were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The AE numbers reported are those considered related to treatment. Related AEs are those that are judged unlikely, possibly, probably or definitely related to the study or study drug by the investigator.
• Number of Participants Experiencing a Reduction of Oxygen Saturation (SaO2) During and After Doxorubicin Transdrug (DT) Infusion [ Time Frame: Time from start of infusion to resolution of reduction in oxygen saturation. ]
  Number of participants experiencing an SaO2 reduction defined as a decrease =< 90% during or after DT infusion until resolution to =>93%. Participants had continuous monitoring of SaO2 saturation with pulse oximeter during 6 hour infusion and up to 24 hour after infusion start. SaO2 measures the amount of oxygen (in percent) bound to hemoglobin in red blood cells. SaO2 saturation was only monitored and reported in the DT infusion group. Reduction in SaO2 could result in modify DT dosing regimen. Decreases in SaO2 are a known and expected occurrence with DT infusions, and close monitoring of SaO2 was specified by the protocol to protect patients from potential respiratory distress during infusions.
• Number of Participants With Clinically Significant Abnormal Change in Respiratory Function [ Time Frame: Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study. ]
  Number of participants with any clinically significant abnormal change in respiratory function test over the study to include carbon monoxide diffusing capacity to measure lung function, forced expiratory volume in 1 second to measure ability to expel air from your lungs, total lung capacity to measure total amount of air in the lungs after taking the deepest breath possible, and vital capacity to measure the greatest volume of air that can be expelled from the lungs after taking the deepest breath possible. Clinically significant abnormal changes in respiratory function was determined by the investigator.
• Number of Participants Experiencing Clinically Significant Abnormal Electrocardiogram (ECG) Changes From Baseline [ Time Frame: Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study. ]
  Number of participants experiencing clinically significant abnormal ECG changes from baseline over the course of the study. ECG were completed every month before each infusion. ECG will detect changes in heart rhythm. Clinically significant abnormal changes in ECG were determined by the investigator.
• Number of Participants Experiencing Clinically Significant Changes in Left Ventricular Ejection Fraction (LVEF) and the Severity of the Event [ Time Frame: Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study. ]
  Number of participants that experienced a change from baseline in LVEF with severity of LVEF noted as follows: Normal: 100 - 50%, 0 - 9% drop from baseline resting ejection fraction (EF), Grade 2 = 50 - 40%, 10 - 19% drop from baseline resting EF; Grade 3 = 39 - 20%, >20% drop from baseline; Grade 4 = <20%. LVEF was monitored every other month. LVEF measures how much blood the left ventricle of the heart pumps out with each contraction and is used to assess the severity of left ventricle dysfunction in the heart. Clinical significance changes were determined by the investigator.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety Doxorubicin Transdrug Study in Patients Suffering From Advanced Hepatocellular Carcinoma
• Official Title: Multicentre, Randomised, Controlled, Open-label Study Comparing the Efficacy and Safety of Doxorubicin Transdrug™ to Best Standard of Care in Patients With Advanced Hepatocellular Carcinoma. ReLive Study.

Brief Summary

The purpose of this phase III study is to determine whether Doxorubicin Transdrug (DT) is effective in the treatment of patients suffering from advanced Hepatocellular Carcinoma (HCC) after failure or intolerance to Sorafenib. Patients with HCC with or without cirrhosis and with good liver functions are eligible. Only those who can not benefit from treatment for which efficacy is demonstrated are eligible.

These patients are usually proposed either best standard of care (BSC) or participation to clinical trials. Patients eligible for the RELIVE study will receive either DT at 20 mg/m2 or DT at 30 mg/m2 or the BSC.

• Detailed Description: Doxorubicin-Transdrug™ (DT) is a nanoparticle formulation of doxorubicin.In in vitro and in vivo models, DT was shown to overcome the multidrug resistance (MDR) and to be more effective than doxorubicin on both sensitive and resistant tumour models and in particular in the X/myc bi-transgenic MDR murine model of HCC.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• Drug: Doxorubicin 20 mg/m2
  Other Name: Doxorubicin Transdrug (DT) at 20 mg/m2
• Drug: Doxorubicin 30 mg/m2
  Other Name: Doxorubicin Transdrug (DT) at 30 mg/m2
• Drug: Best Standard of Care
  Other Name: BSC

Study Arms

• Experimental: Doxorubicin Transdrug (DT) at 20 mg/m2
  DT will be infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity
  Intervention: Drug: Doxorubicin 20 mg/m2
• Experimental: Doxorubicin Transdrug (DT) at 30 mg/m2
  DT will be infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity
  Intervention: Drug: Doxorubicin 30 mg/m2
• Active Comparator: Best Standard of Care
  Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or unacceptable toxicity
  Intervention: Drug: Best Standard of Care

• Publications *: Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Mole A, Attali P, Le Boulicaut J, Vasseur B; RELIVE Investigators. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol. 2019 Jun;4(6):454-465. doi: 10.1016/S2468-1253(19)30040-8. Epub 2019 Apr 4. Erratum In: Lancet Gastroenterol Hepatol. 2019 Jul;4(7):e6. Lancet Gastroenterol Hepatol. 2020 Feb;5(2):e1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 28, 2021): 397
• Original Estimated Enrollment (submitted: July 31, 2012): 390
• Actual Study Completion Date: May 2019
• Actual Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or non-pregnant, non-breast feeding female;
• Aged ≥ 18 years;

• Patient with:

  • advanced HCC (BCLC-C according to BCLC staging classification) having progressed under Sorafenib therapy or intolerant to Sorafenib, or;
  • intermediate HCC (BCLC-B) non eligible or non responders to transarterial chemoembolization (TACE), and having progressed under or intolerant to Sorafenib therapy
• Patients with porta hepatis lymph nodes, extrahepatic metastases, or portal/suprahepatic vein thrombosis without extension in inferior/superior vena cava, are eligible;

• HCC diagnosed according to the American Association for Study of Liver Diseases (AASLD) and/or European Association for the Study of the Liver (EASL) criteria:

  • Radiological Criteria applicable in cirrhotic liver:
• Nodule ≥ 10 mm: one imaging technique among MRI and CT-scan showing typical appearances for HCC defined as arterial enhancement and rapid washout in portal venous or delayed phase;

• If appearance not typical for HCC on initial imaging: second contrast enhanced study (CT or MRI) showing typical appearances for HCC defined as arterial enhancement and rapid wash-out in portal venous or delayed phase;

  • And/Or cyto-histology criteria (e.g. in case of atypical lesions for HCC at imaging, absence of cirrhosis);
• Without cirrhosis or with a non decompensated cirrhosis (Child-Pugh score from A5 to B7 included);
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;

• Laboratory tests as follows:

  • Platelets ≥ 50,000 /mm3
  • Neutrophil count ≥ 1000/mm3
  • Hemoglobin ≥ 10g/dL
  • Serum transaminases < 5 upper limit normal (ULN) (NCI/common toxicity criteria (CTC) grades 0, 1, or 2)
  • Alkaline phosphatases < 5 ULN (NCI/CTC grades 0, 1, or 2)
  • Serum bilirubin < 35 micromolar (µM)/L (or 2.0 mg/dL);
• Signed and dated written informed consent form.

Exclusion Criteria:

• Cirrhosis with a Child-Pugh score B8-C15;
• Untreated chronic hepatitis B;
• Patients eligible for curative treatments (transplantation, surgical resection, percutaneous treatment);
• Patients eligible for palliative treatments with demonstrated efficacy: TACE, Sorafenib; Patients who failed to Sorafenib treatment or intolerant to sorafenib are eligible and can be included if Sorafenib has been stopped at least 2 weeks before randomization;
• Prior history of malignancy with the exception of adequately treated basal cell carcinoma or in situ cervical cancer in complete remission since five years at least;
• HCC developed on transplanted liver;
• HIV infection;
• Risk of variceal bleeding;
• Oxygen saturation (SaO2) < 95%;
• Presence of a significant acute or chronic respiratory disease defined as NCI/CTCAE > grade 2;
• Presence of recent (< 6 months) or current cardiac failure (class III or IV New York Heart Association (NYHA) classification), recent (< 6 months) acute coronary syndrome, clinically significant ECG abnormalities or recent (less than 6 months) acute vascular diseases (stroke, myocardial infarction (MI)…);
• Prior cumulative dose of 300 mg/m² of doxorubicin or equivalent;
• Patients currently treated with immunosuppressive agents that cannot be stopped;
• Patients whose medical or surgical conditions are unstable and may not allow the study completion or compliance, and specially patients with uncontrolled diabetes;
• Uncontrolled systemic infection;
• Patients with a life expectancy of less than 2 months;
• Patients who have received an experimental drug in another clinical trial in the last 30 days prior to randomization in the present clinical trial;
• Women of child-bearing age who are unwilling or unable to use an effective contraception method during the study treatment period and for 6 months after the last administration of study drug, and their male partner(s) refusing to use a condom (if applicable);
• Men who are unwilling or unable to use a condom during the study treatment period and for 6 months after the last administration of study drug, and their female partner(s) refusing to use one of the appropriate effective contraception methods (if applicable);
• Patients unwilling or unable to comply with protocol requirements and scheduled visits.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Egypt, France, Germany, Hungary, Italy, Lebanon, Spain, Turkey, United States
• Removed Location Countries: Russian Federation, Saudi Arabia

Administrative Information

• NCT Number: NCT01655693
• Other Study ID Numbers: BA2011/03/04; 2011-002843-92 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Valerio Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Valerio Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Philippe Merle, MD; Croix-Rousse Hospital - Lyon-France

• PRS Account: Valerio Therapeutics
• Verification Date: May 2021