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A Phase 2 Study of Cabozantinib in Japanese Participants With Advanced Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03586973
Recruitment Status : Completed
First Posted : July 16, 2018
Last Update Posted : August 27, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda

Tracking Information
First Submitted Date  ICMJE June 29, 2018
First Posted Date  ICMJE July 16, 2018
Last Update Posted Date August 27, 2021
Actual Study Start Date  ICMJE August 6, 2018
Actual Primary Completion Date July 17, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 22, 2020)
24-Week Progression-Free Survival Rate (PFSR) [ Time Frame: Up to 24 weeks ]
24-week PFSR was defined as percentage of participants with progression-free survival (PFS) at Week 25 Day 1 plus 7 days. PFS was defined as time from the first day of study drug administration to the earlier of PD per RECIST 1.1 or death due to any cause as assessed by IRC. Per RECIST 1.1, PD was defined as at least a 20% increase in the baseline sum of the diameters (SoD) of target lesions, taking as a reference the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm.
Original Primary Outcome Measures  ICMJE
 (submitted: July 12, 2018)
24-Week Progression-Free Survival Rate (PFSR) [ Time Frame: Baseline up to 3 years (approximately 2 years after enrollment of the last participant) ]
24-week PFSR is defined as Progression-Free Survival (PFS) proportion at Study Day of Week 25 Day 1 plus 7 days. PFS is defined as time from the first day of study drug administration to the earlier of progressive disease (PD) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause. PFS will be assessed by independent radiology committee (IRC) per RECIST 1.1 where PD: At least a 20% increase in the baseline sum of the diameters (SoD) of target lesions, taking as a reference the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2020)
  • Progression-Free Survival (PFS) [ Time Frame: Until disease progression, death or data cut-off (Approximately 11 months) ]
    PFS was defined as time from the first day of study drug administration to the earlier of PD per RECIST 1.1 or death due to any cause as assessed by IRC. Per RECIST 1.1, PD was defined as at least a 20% increase in the baseline SoD of target lesions, taking as a reference the smallest (nadir) SoD since (and including) Baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm.
  • Objective Response Rate (ORR) [ Time Frame: Up to data cut-off (Approximately 11 months) ]
    ORR was defined as the percentage of participants whose best overall response was complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by IRC, which was confirmed by a subsequent evaluation conducted >= 28 days later. CR was defined as disappearance of all target lesions; PR was defined as at least a 30% decrease in SoD of target lesions, taking as a reference the baseline SoD.
  • Disease Control Rate (DCR) [ Time Frame: Up to data cut-off (Approximately 11 months) ]
    DCR was defined as the percentage of participants whose best overall response is CR, PR or SD, per RECIST 1.1 by IRC, CR and PR require confirmation by a subsequent evaluation conducted >=28 days later, and SD have to be maintained for at least 8 weeks (51 days) after the first day of study drug administration. CR was defined as disappearance of all target lesions; PR was defined as at least a 30% decrease in SoD of target lesions, taking as a reference the baseline SoD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
  • Overall Survival (OS) [ Time Frame: Up to data cut-off (Approximately 11 months) ]
    OS was defined as time from the first day of study drug administration to death due to any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2018)
  • Progression-Free Survival (PFS) [ Time Frame: Baseline up to 3 years (approximately 2 years after enrollment of the last participant) ]
    PFS is defined as time from the first day of study drug administration to the earlier of PD as assessed by the IRC per RECIST 1.1, or death due to any cause. PD: At least a 20% increase in the SoD of target lesions, taking as a reference the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm.
  • Objective Response Rate (ORR) [ Time Frame: Baseline up to 3 years (approximately 2 years after enrollment of the last participant) ]
    ORR is defined as the percentage of participants whose best overall response is complete response (CR) or partial response (PR) per RECIST 1.1 by IRC, which is confirmed by a subsequent evaluation conducted >= 28 days later. CR: Disappearance of all target lesions; PR: At least a 30% decrease in SoD of target lesions, taking as a reference the baseline SoD.
  • Disease Control Rate (DCR) [ Time Frame: Baseline up to 3 years (approximately 2 years after enrollment of the last participant) ]
    DCR is defined as the percentage of participants whose best overall response is CR, PR or SD, per RECIST 1.1 by IRC, CR and PR require confirmation by a subsequent evaluation conducted >=28 days later, and SD have to be maintained for at least 8 weeks (51 days) after the first day of study drug administration. CR: Disappearance of all target lesions; PR: At least a 30% decrease in SoD of target lesions, taking as a reference the baseline SoD. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
  • Overall Survival (OS) [ Time Frame: Baseline up to 3 years (approximately 2 years after enrollment of the last participant) ]
    OS is defined as time from the first day of study drug administration to death due to any cause.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Study of Cabozantinib in Japanese Participants With Advanced Hepatocellular Carcinoma
Official Title  ICMJE A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients With Advanced Hepatocellular Carcinoma Who Have Received Prior Systemic Anticancer Therapy
Brief Summary The purpose of this study is to evaluate the efficacy and safety of cabozantinib in Japanese participants with advanced hepatocellular carcinoma (HCC) who have received prior systemic anticancer therapy.
Detailed Description

The drug being tested in this study is called Cabozantinib. Cabozantinib is being tested to treat advanced hepatocellular carcinoma in Japanese patients. This study will look at the efficacy and safety of Cabozantinib.

The study will enroll 34 patients. Participants will be assigned to Cohort A (at least 17 participants) or Cohort B (approximately 15 participants) and will receive the following treatment. Participants who have received prior sorafenib will enroll to Cohort A and participants who have not received prior sorafenib will enroll to Cohort B.

- Cabozantinib 60 mg

All participants will be asked to take one tablet of cabozantinib once daily in the fasted state (dose at least 2 hours after meal and no more food intake for 1 hour postdose) throughout the study.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately at most 3 years. Participants will make multiple visits to the clinic during the treatment and posttreatment period, including a follow-up assessment after last dose of study drug.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Hepatocellular Carcinoma
Intervention  ICMJE Drug: Cabozantinib
Cabozantinib tablet
Other Name: XL184
Study Arms  ICMJE
  • Experimental: Cohort A: Cabozantinib 60 mg
    Cabozantinib 60 milligrams (mg), tablet, orally, once daily in the fasted state. Participants received first/second line anticancer therapy with sorafenib before this study were assigned to Cohort A.
    Intervention: Drug: Cabozantinib
  • Experimental: Cohort B: Cabozantinib 60 mg
    Cabozantinib 60 mg, tablet orally, once daily in the fasted state. Participants who did not receive first/second line anticancer therapy with sorafenib before this study were assigned to Cohort B.
    Intervention: Drug: Cabozantinib
Publications * Kudo M, Tsuchiya K, Kato N, Hagihara A, Numata K, Aikata H, Inaba Y, Kondo S, Motomura K, Furuse J, Ikeda M, Morimoto M, Achira M, Kuroda S, Kimura A. Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: a phase 2 multicenter study. J Gastroenterol. 2021 Feb;56(2):181-190. doi: 10.1007/s00535-020-01753-0. Epub 2021 Jan 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 22, 2020)
34
Original Estimated Enrollment  ICMJE
 (submitted: July 12, 2018)
32
Actual Study Completion Date  ICMJE June 29, 2021
Actual Primary Completion Date July 17, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female Japanese participants 20 years of age or older on the day of consent.
  2. Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted).
  3. Measurable disease per response evaluation criteria in solid tumors (RECIST) 1.1 as determined by the investigator.
  4. Participants who have disease that is not amenable to a curative treatment approach (eg, transplant, surgery, radiofrequency ablation).
  5. Participants who have received 1 or 2 prior anticancer therapies for advanced HCC.

    • Cohort A: participants who have received prior sorafenib.
    • Cohort B: participants who have not received prior sorafenib. Note: Additional prior systemic therapies used as adjuvant or local therapy are allowed.
  6. Radiographic progression following prior systemic anticancer therapy for advanced HCC.
  7. Recovery to =<Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 from toxicities related to any prior treatments, unless the Adverse Events (AEs) are clinically nonsignificant and/or stable on supportive therapy.
  8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and life expectancy of at least 3 months.
  9. Child-Pugh Score of A.
  10. Adequate organ and marrow function at Screening (within 10 days before Week 1 Day 1):

    1. Absolute neutrophil count (ANC) >=1,200/mm^3.
    2. Platelets >=60,000/mm^3.
    3. Hemoglobin >=8 g/dL.
    4. Serum creatinine =<1.5 × upper limit of normal (ULN) or calculated creatinine clearance >=40 mL/min using the Cockroft-Gault equation.
    5. Urine protein-to-creatinine ratio (UPCR) =<1 mg/mg Cr.
    6. Total bilirubin =<2 mg/dL.
    7. Serum albumin >=2.8 g/dL.
    8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =<5.0 × ULN.
    9. Hemoglobin A1c (HbA1c) =<8% (if HbA1c results are unavailable [eg, hemoglobin variant], a fasting serum glucose =<160 mg/dL).
  11. Antiviral therapy per local standard of care if active hepatitis B virus (HBV) infection.
  12. Female participants who:

    1. Are postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 year before the Screening visit, OR
    2. Are surgically sterile, OR
    3. If they are of childbearing potential, agree to practice 1 highly effective method of birth control with a condom, which is an effective barrier method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR
    4. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, from the time of signing the informed consent through 4 months after the last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

      Male participants, even if surgically sterilized (ie, status postvasectomy), who:

    5. Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug. If their partner are of childbearing potential, their female partner should use 1 highly effective method of birth control at the same time, OR
    6. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, from the time of signing the informed consent through 4 months after the last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
  13. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
  14. Participant is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

  1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
  2. Any type of anticancer agent within 14 days before the first day of study drug administration (Week 1 Day 1).
  3. Radiation therapy within 28 days (14 days for radiation for bone metastases) or radionuclide treatment (eg, I-131 or Y-90) within 42 days before Week 1 Day 1 (participant is excluded if there are any clinically relevant ongoing complications from prior radiation therapy).
  4. Prior Cabozantinib treatment.
  5. Treatment with any investigational products (excluding anticancer products approved in Japan) within 28 days before Week 1 Day 1.
  6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before Week 1 Day 1. Eligible participants must be without corticosteroid treatment at Week 1 Day 1.
  7. Concomitant anticoagulation, with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).

    Note: Low-dose aspirin for prophylactic use (per local applicable guidelines) and low-dose, low molecular weight heparins (LMWH) are permitted (LMWH has not been approved for the use for cardioprotection in Japan). Anticoagulation with therapeutic doses of LMWH is allowed in participants without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before Week 1 Day 1, and who have had no complications from a thromboembolic event or the anticoagulation regimen.

  8. Participants who have uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    1. Cardiovascular disorders including

      • Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias.
      • Uncontrolled hypertension defined as sustained blood pressure (BP) >150 mm Hg systolic, or >100 mm Hg diastolic despite optimal antihypertensive treatment.
      • Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event within 6 months before Week 1 Day 1.
      • Thromboembolic event within 3 months before Week 1 Day 1.
      • A left-ventricular ejection fraction =<50%.
    2. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:

      • Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
      • Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before Week 1 Day 1.

      Note: Complete healing of an intra-abdominal abscess must be confirmed prior to Week 1 Day 1.

    3. Major surgery within 2 months before Week 1 Day 1. Complete healing from major surgery must have occurred 1 month before Week 1 Day 1. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before Week 1 Day 1. Participants with clinically relevant complications from prior surgery are not eligible.
    4. Cavitating pulmonary lesion(s) or endobronchial disease.
    5. Lesion invading a major blood vessel including, but not limited to: inferior vena cava, pulmonary artery, or aorta. Participants with invasion or thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor are eligible.
    6. Clinically significant bleeding risk including the following within 3 months before Week 1 Day 1: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors.
    7. Other clinically significant disorders such as:

      • Active infection requiring systemic treatment.
      • Known infection with human immunodeficiency virus, or known acquired immunodeficiency syndrome -related illness.
      • Active hepatitis B and/or C. Participants with active hepatitis virus infection controlled with antiviral therapy are eligible.
      • Serious non-healing wound/ulcer/bone fracture.
      • Malabsorption syndrome.
      • Uncompensated/symptomatic hypothyroidism.
      • Requirement for hemodialysis or peritoneal dialysis.
      • History of solid organ transplantation.
  9. Participants with untreated or incompletely treated varices with bleeding or high risk for bleeding. Participants treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months before Week 1 Day 1 are eligible.
  10. Moderate or severe ascites.
  11. Corrected QT interval calculated by the Fridericia formula (QTcF) >500 msec within 14 days before Week 1 Day 1.

    Note: If the QTcF is >500 msec in first electrocardiogram (ECG), a total of 3 ECGs each separated by at least 3 minutes should be performed within 30 minutes. If the average of these 3 consecutive results for QTcF is =<500 msec, the participant meets eligibility in this regard.

  12. Inability to swallow tablets.
  13. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
  14. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.

    Note: Female participants who are in the lactation period, even if they discontinue breastfeeding, will be excluded from the study.

  15. Previously diagnosed with another malignancy and have any evidence of residual disease within 2 years before Week 1 Day 1.

    Note: Participants with superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy are not excluded.

  16. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  17. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of Cabozantinib.
  18. Use of strong cytochrome P450 (CYP) 3A inhibitors and CYP3A inducers within 14 days before Week 1 Day 1.
  19. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03586973
Other Study ID Numbers  ICMJE Cabozantinib-2003
U1111-1214-6141 ( Other Identifier: WHO )
JapicCTI-184018 ( Registry Identifier: JapicCTI )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/
Current Responsible Party Takeda
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Takeda
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Takeda
PRS Account Takeda
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP