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Phase 2, Randomized, Double-Blind, Placebo-Controlled of the Efficacy and Safety of CF102 in Hepatocellular Carcinoma (HCC)

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ClinicalTrials.gov Identifier: NCT02128958
Recruitment Status : Completed
First Posted : May 1, 2014
Results First Posted : December 29, 2021
Last Update Posted : October 4, 2022
Sponsor:
Information provided by (Responsible Party):
Can-Fite BioPharma

Study Description
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Brief Summary:
This is a multicenter, randomized, double-blind, placebo-controlled clinical trial in subjects with advanced HCC and CPB cirrhosis whose disease has progressed while taking 1 prior systemic drug therapy for HCC.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: CF102 Drug: Placebo Phase 2

Detailed Description:
The trial will evaluate the efficacy and safety of CF102 as compared to placebo. Subjects will be randomly assigned in a 2:1 ratio to treatment with oral doses of either CF102 25 mg or matching placebo administered twice daily (BID) for consecutive, 28-day cycles. Subjects will be evaluated regularly for safety. Tumor imaging will be performed every 8 weeks. Treatment will continue until the subject experiences unacceptable drug-related intolerability. Subjects will return for a follow-up visit 28 days after completion of the last dose of study drug, and every attempt will be made to obtain survival data on all randomized subjects. Subjects who discontinue will be followed indefinitely for survival status. The trial will continue until 75 deaths have been recorded.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2 Study in the Second-Line Treatment of Advanced Hepatocellular Carcinoma in Subjects With Child-Pugh Class B Cirrhosis
Actual Study Start Date : September 2014
Actual Primary Completion Date : November 27, 2017
Actual Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: CF102
orally q12h
 Drug: CF102
orally q12h
Other Name: IB-MECA
Placebo Comparator: Placebo tablets of CF102
orally q12h
 Drug: Placebo
orally q12 hours
Other Name: Inactive pill


Outcome Measures
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Primary Outcome Measures :
  1. Number of Subjects With Overall Survival [ Time Frame: From date of first treatment (Cycle 1 Day 1) until date of death from any cause, assessed up to 12 months ]
    Evaluate the efficacy of orally administered CF102 25 mg twice daily (BID) as compared to placebo, as determined by Overall Survival (OS), when used as second-line therapy in subjects with advanced hepatocellular carcinoma (HCC) and Child-Pugh Class B (CPB) cirrhosis. Overall Survival is defined as the time from Baseline (Cycle 1 Day 1) to death due to any cause, calculated as (date of death- date of Cycle 1 Day 1) +1.OS will be summarized in months, which will be obtained by dividing OS in days by 30 days/month. Summary statistics will be determined using the Kaplan-Meier (KM) estimate of the survival function and the between-treatment comparison will be performed using the logrank test as the primary analysis.


Secondary Outcome Measures :
  1. Time to Progression (TTP) [ Time Frame: From date of first treatment (Cycle 1 Day 1) until the date of first documented progression, assessed up to 36 months ]
    Time to Progression (TTP) is the time from Baseline to the first Overall Response of Progressive Disease (PD), calculated as date of first PD - date of Cycle 1 Day 1+1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. TTP will be summarized in months, which will be obtained by dividing TTP in days by 30 days/month. Summary statistics will be determined using the KM estimate of the survival function for TTP. The between-treatment comparison will be performed using the logrank test.

  2. Time to Progression-Free Survival (PFS) [ Time Frame: From date of first treatment (Cycle 1 Day 1) until the date of first documented disease progression or date of death, which occurred first, assessed up to 36 months ]
    Time to Progression-Free Survival (PFS) is the time from Baseline to the first Overall Response of Progressive Disease (PD) or death due to any cause if the subject dies without experiencing PD, calculated as date of first PD or date of death - date of Cycle 1 Day 1+1. PFS will be summarized in months, which will be obtained by dividing PFS in days by 30 days/month. Summary statistics will be determined using the KM estimate of the survival function for PFS. The between-treatment comparison will be performed using the logrank test.

  3. Objective Response Rate (ORR) [ Time Frame: The end of even-numbered cycles (Cycle 3 Day 1,Cycle 5 Day 1,Cycle 7 Day 1, Cycle 9 Day 1, Cycle 11 Day 1) assessed up to 12 months ]
    Objective Response Rate (ORR) is assessed as the percentage of subjects who achieved a Complete Response (CR) or Partial Response (PR). Per RECIST criteria v1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm; PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response is the sum of subjects achieving CR or PR.

  4. Disease Control Rate (DCR) [ Time Frame: The end of even-numbered cycles (Cycle 3 Day 1,Cycle 5 Day 1,Cycle 7 Day 1, Cycle 9 Day 1, Cycle 11 Day 1) assessed up to 12 months ]
    Disease Control Rate (DCR) is assessed as the percentage of subjects who achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) using RECIST criteria. Per RECIST criteria v1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm; PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm) taking as reference the smallest sum diameters while on study.

  5. Summary Statistics of Laboratory Parameters Associated With Viral Hepatitis, Hepatic Dysfunction, and Cirrhosis [ Time Frame: Baseline (Cycle 1 Day 1); Cycle 11 Day 15 ]
    The raw and change from baseline (CFB) for each laboratory parameter (alanine aminotransferase (ALT), albumin, aspartate aminotransferase (AST), bilirubin (direct and total), International Normalized Ratio (INR),and prothrombin time (PT)) will be summarized by treatment and visit. CFB is calculated as (Value at Post-Baseline visit - Value at Baseline). The baseline value used in the calculations of CFB is the value taken at Cycle 1 Day 1.

  6. Summary Statistics of White Blood Cell (WBC) Adenosine A3 Receptor (A3AR) Expression and Clinical Response - WBC Adenosine A3 Receptor (A3AR) Expression [ Time Frame: Baseline (Cycle 1 Day 1) and Cycle 11 Day 1 ]
    Summary statistics for WBC adenosine A3 receptor (A3AR) expression and CFB in WBC A3AR expression will be provided by treatment and visit. A3AR mRNA expression in WBC was determined from blood collected to a PAXgene RNA tubes (Qiagen, Venlo, The Netherlands), using the QuantiGene Plex 2.0® assay (Thermo Fisher, Waltham, MA, USA). β-actin was used as a reference control, and the oligonucleotide probe sets were designed by Thermo Fisher. Luminescence from each specific probe set was captured by Glomax Multi (Promega, Madison, WI, USA). A3AR was expressed in units, where 1 unit was defined as the mean of A3AR expression in healthy subjects (n = 50). Healthy subjects were 20-70 years of age with no known illness and no prior treatment.

  7. Pharmacokinetics (PK) Parameters of CF102 - CL/F (L/h) [ Time Frame: Cycle 1 Days 1, 8 and 15; Cycle 2 day 1 ]
    Describe the PK parameter CL/F (L/h) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

  8. Pharmacokinetics (PK) Parameters of CF102 - Vc/F (L) [ Time Frame: Cycle 1 Days 1, 8 and 15; Cycle 2 day 1 ]
    Describe the PK parameter Vc/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

  9. Pharmacokinetics (PK) Parameters of CF102 - Vp/F (L) [ Time Frame: Cycle 1 Days 1, 8 and 15; Cycle 2 day 1 ]
    Describe the PK parameter Vp/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

  10. Pharmacokinetics (PK) Parameters of CF102 - Vss/F (L) [ Time Frame: Cycle 1 Days 1, 8 and 15; Cycle 2 day 1 ]
    Describe the PK parameter Vss/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

  11. Pharmacokinetics (PK) Parameters of CF102 - Elimination Half-life (Hours) [ Time Frame: Cycle 1 Days 1, 8 and 15; Cycle 2 day 1 ]
    Describe the PK parameter Elimination half-life (hours) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

  12. Pharmacokinetics (PK) Parameters of CF102 - AUC_0-12, Steady State (ng*h/mL) [ Time Frame: Cycle 1 Days 1, 8 and 15; Cycle 2 day 1 ]
    Describe the PK parameter AUC_0-12, steady state (ng*h/mL) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).


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

Inclusion Criteria:

  1. Males and females at least 18 years of age.

  2. Diagnosis of HCC:

    • For subjects without underlying cirrhosis at the time of diagnosis, diagnosis of HCC documented by cytology and/or histology.
    • For subjects with underlying cirrhosis at the time of diagnosis, diagnosis of HCC established according to the American Association for the Study of Liver Diseases Practice Guideline algorithm (Appendix E).
  3. HCC is advanced, ie, treatment-refractory or metastatic, and no standard therapies are expected to be curative.
  4. Receipt of 1 previous systemic drug therapy for at least 3 weeks and withdrawal from treatment due either to intolerability or to radiographic disease progression. If treatment was withdrawn due to intolerability manifested as a Grade 3 or 4 event by National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE v4.0), less than 3 weeks of continuous prior administration prior to withdrawal is acceptable (see also Exclusion Criterion #3).
  5. Prior systemic treatment was discontinued for at least 2 weeks prior to the Baseline Visit.
  6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2 (Appendix B).
  7. Cirrhosis classified as Child-Pugh Class B (Appendix C).

  8. The following laboratory values must be documented within 3 days prior to the first dose of study drug:

    • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
    • Platelet count ≥ 75 × 109/L
    • Serum creatinine ≤ 2.0 mg/dL
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × the upper limit of normal (ULN)
    • Total bilirubin ≤ 3.0 mg/dL
    • Serum albumin ≥ 2.8 g/dL
    • Prothrombin time (PT) no greater than 6 seconds longer than control.
  9. Life expectancy of ≥ 6 weeks.

Exclusion Criteria:

  1. Receipt of no, or of >1, prior systemic drug therapies for HCC.
  2. Receipt of systemic cancer therapy, immunomodulatory drug therapy, immunosuppressive therapy, or corticosteroids > 20 mg/day prednisone or equivalent within 14 days prior to the Baseline Visit or concurrently during the trial.
  3. Presence of an acute or chronic toxicity of prior chemotherapy that has not resolved to ≤ Grade 1, as determined by CTCAE v 4.0.
  4. Locoregional treatment within 4 weeks prior to the Baseline Visit.
  5. Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit.
  6. Use of any investigational agent within 4 weeks prior to the Baseline Visit.
  7. Child-Pugh Class A or C cirrhosis, or hepatic encephalopathy.
  8. Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion within 4 weeks prior to the Baseline Visit.
  9. Active bacterial, viral, or fungal infection requiring systemic therapy or operative or radiological intervention.
  10. Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related illness.
  11. Liver transplant.
  12. Active malignancy other than HCC.
  13. Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4) (Appendix B).
  14. Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of study drug.
  15. History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation of any grade, or persistent prolongation of the QTc (Fridericia) interval to > 450 msec for males or > 470 msec for females.
  16. Pregnant or lactating female.
  17. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with trial participation or study drug administration; may interfere with the informed consent process and/or with compliance with the requirements of the trial; or may interfere with the interpretation of trial results and, in the Investigator's opinion, would make the subject inappropriate for entry into this trial.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02128958


Locations
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Sponsors and Collaborators
Can-Fite BioPharma
Investigators
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Study Director: Michael H Silverman Can-Fite BioPharma Ltd
  Study Documents (Full-Text)

Documents provided by Can-Fite BioPharma:
Study Protocol  [PDF] November 6, 2018
Statistical Analysis Plan  [PDF] August 29, 2019

More Information
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Publications:

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Responsible Party: Can-Fite BioPharma
ClinicalTrials.gov Identifier: NCT02128958    
Other Study ID Numbers: CF102-201HCC
First Posted: May 1, 2014    Key Record Dates
Results First Posted: December 29, 2021
Last Update Posted: October 4, 2022
Last Verified: September 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Can-Fite BioPharma:
Hepatocellular Carcinoma
Child-Pugh Class B Cirrhosis
Additional relevant MeSH terms:
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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