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Advanced Hepatocellular CarcinomaPhase 2NCT03586973

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

A Phase 2 study testing Cabozantinib in people with Advanced Hepatocellular Carcinoma, run by Takeda at 17 sites in Japan.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 20 years and older
Conditions the study is for
Advanced Hepatocellular Carcinoma
What is being tested?
Cabozantinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
17 sitesJapan
Study dates
6 Aug 2018to 29 Jun 2021
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female Japanese participants 20 years of age or older on the day of consent.
  • Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted).
  • Measurable disease per response evaluation criteria in solid tumors (RECIST) 1.1 as determined by the investigator.
  • Participants who have disease that is not amenable to a curative treatment approach (eg, transplant, surgery, radiofrequency ablation).
  • Participants who have received 1 or 2 prior anticancer therapies for advanced HCC.
  • Cohort A: participants who have received prior sorafenib.
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  • Cohort B: participants who have not received prior sorafenib. Note: Additional prior systemic therapies used as adjuvant or local therapy are allowed.
  • Radiographic progression following prior systemic anticancer therapy for advanced HCC.
  • 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.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and life expectancy of at least 3 months.
  • Child-Pugh Score of A.
  • Adequate organ and marrow function at Screening (within 10 days before Week 1 Day 1):
  • Absolute neutrophil count (ANC) >=1,200/mm^3.
  • Platelets >=60,000/mm^3.
  • Hemoglobin >=8 g/dL.
  • Serum creatinine =<1.5 × upper limit of normal (ULN) or calculated creatinine clearance >=40 mL/min using the Cockroft-Gault equation.
  • Urine protein-to-creatinine ratio (UPCR) =<1 mg/mg Cr.
  • Total bilirubin =<2 mg/dL.
  • Serum albumin >=2.8 g/dL.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =<5.0 × ULN.
  • Hemoglobin A1c (HbA1c) =<8% (if HbA1c results are unavailable [eg, hemoglobin variant], a fasting serum glucose =<160 mg/dL).
  • Antiviral therapy per local standard of care if active hepatitis B virus (HBV) infection.
  • Female participants who:
  • Are postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 year before the Screening visit, OR
  • Are surgically sterile, OR
  • 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
  • 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:
  • 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
  • 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.)
  • 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.
  • Participant is willing and able to adhere to the study visit schedule and other protocol requirements.

Who cannot join

  • Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
  • Any type of anticancer agent within 14 days before the first day of study drug administration (Week 1 Day 1).
  • 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).
  • Prior Cabozantinib treatment.
  • Treatment with any investigational products (excluding anticancer products approved in Japan) within 28 days before Week 1 Day 1.
  • 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.
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  • 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.
  • Participants who have uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
  • 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%.
  • 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.
  • 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.
  • Cavitating pulmonary lesion(s) or endobronchial disease.
  • 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.
  • 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.
  • 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.
  • 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.
  • Moderate or severe ascites.
  • 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.
  • Inability to swallow tablets.
  • Previously identified allergy or hypersensitivity to components of the study treatment formulations.
  • 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.
  • 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.
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of Cabozantinib.
  • Use of strong cytochrome P450 (CYP) 3A inhibitors and CYP3A inducers within 14 days before Week 1 Day 1.
  • Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.

Trial locations and contacts

17 sites in 1 country.

17 sites in 1 country

Japan17 sites

  • Chiba University Hospital

    Chiba

  • National Cancer Center Hospital

    Chuo-ku, Tokyo

  • Hiroshima University Hospital

    Hiroshima

  • Iizuka Hospital

    Iizuka, Fukuoka

  • Kanazawa University Hospital

    Kanazawa, Ishikawa-ken

  • National Cancer Center Hospital East

    Kashiwa, Chiba

  • Kurume University Hospital

    Kurume, Fukuoka

  • Kyorin University Hospital

    Mitaka, Tokyo

  • Japanese Red Cross Musashino Hospital

    Musashino, Tokyo

  • Aichi Cancer Center Hospital

    Nagoya, Aichi-ken

  • Okayama University Hospital

    Okayama

  • Osaka City University Hospital

    Osaka

  • Osaka International Cancer Institute

    Osaka

  • Sapporo-Kosei General Hospital

    Sapporo, Hokkaido

  • Kindai University Hospital

    Sayama, Osaka

  • Kanagawa Cancer Center

    Yokohama, Kanagawa

  • Yokohama City University Medical Center

    Yokohama, Kanagawa

Other trials in Japan

About this study

Official title: A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients With Advanced Hepatocellular Carcinoma Who Have Received Prior Systemic Anticancer Therapy

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.

Read the 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 approximately 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.

Being tested
Cabozantinib

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT03586973
Study groupRoleWhat they receive
Cohort A: Cabozantinib 60 mgExperimentalParticipants who have received first/second line anticancer therapy with sorafenib were assigned to Cohort A and received cabozantinib 60 milligrams (mg), tablet, orally, once daily in the fasted state, up to approximately 2 years.
Receives: Drug: Cabozantinib
Cohort B: Cabozantinib 60 mgExperimentalParticipants who did not receive first/second line anticancer therapy with sorafenib were assigned to Cohort B and received cabozantinib 60 mg, tablet orally, once daily in the fasted state, up to approximately 2 years.
Receives: Drug: Cabozantinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 24-Week Progression-Free Survival Rate (PFSR)

    24-week PFSR=percentage of participants with progression-free survival (PFS) of at least 24 weeks at Week 25 Day 1 plus 7 days. PFS=time from first day of study drug administration to earlier of progressive disease (PD) or death due to any cause per Response Evaluation Criteria in Solid Tumors Version 1.1(RECIST 1.1). PD=at least a 20% increase in sum of target lesion diameters (SoD) with reference to smallest(nadir) SoD. In addition to relative increase of 20%, SoD must also demonstrate an absolute increase of at least 5 mm. For nontarget lesion time Point Response, unequivocal progression of nontarget lesions. Modest 'increase' in size of one or more nontarget lesions is usually not sufficient to quality for unequivocal progression status, it must not be representative of single lesion increase. Lesion in an anatomical location and not scanned at baseline is considered new lesion. Lesion qualifies as PD if finding is unequivocally not due to change in imaging technique or modality.

    Measured: Week 25 Day 1 plus 7 days

Secondary outcomes (4)

  1. Progression-Free Survival (PFS)

    PFS was defined as time from the first day of study drug administration to the earlier of PD per RECIST 1.1 as assessed by IRC or death due to any cause. Per RECIST 1.1, for target lesion time point response, PD was defined 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. For nontarget lesion time point response, unequivocal progression of nontarget lesions. A modest 'increase' in the size of one or more nontarget lesions is usually not sufficient to quality for unequivocal progression status. It must be representative of overall disease status change, not a single lesion increase. The lesion qualifies as a PD if the finding is unequivocally not due to a change in the imaging technique or modality.

    Measured: Until disease progression, or death or end of study (Up to approximately 2.8 years)

  2. Objective Response Rate (ORR)

    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. Per RECIST 1.1, for target lesion time point response, CR was defined disappearance of all target lesions. All pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. For nontarget lesion time point response, disappearance of all nontarget lesions. All lymph nodes must be nonpathological in size (<10 mm short axis); PR was defined as at least a 30% decrease in SoD of target lesions, taking as a reference the baseline SoD.

    Measured: Up to approximately 2 years

  3. Disease Control Rate (DCR)

    DCR=percentage of participants whose best overall response is CR,PR or SD, per RECIST 1.1, CR and PR require confirmation by subsequent evaluation conducted >=28 days later, and SD have to be maintained for at least 8 weeks after first day of study drug administration. CR=disappearance of all target lesions. All pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. For nontarget lesion time point response, disappearance of all nontarget lesions. All lymph nodes must be nonpathological in size (<10 mm short axis); PR=at least a 30% decrease in SoD of target lesions, taking as reference baseline SoD; SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; SoD must also demonstrate an absolute increase of at least 5 mm; PD=at least a 20% increase in SoD of target lesions, taking as a reference smallest (nadir) SoD.

    Measured: Up to approximately 2 years

  4. Overall Survival (OS)

    OS was defined as time from the first day of study drug administration to death due to any cause. Participants without documentation of death were censored on the date they were last known to be alive.

    Measured: Up to end of study (Up to approximately 2.8 years)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jul 2018
  2. Study start6 Aug 2018
  3. Primary completion17 Jul 2019
  4. Study completion29 Jun 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
34 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03586973
Sponsor's protocol ID
Cabozantinib-2003
Other IDs
U1111-1214-6141, JapicCTI-184018
Status last verified
Apr 2023
First submitted
29 Jun 2018
Last updated
18 Apr 2023
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

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.

    PubMed 33392749

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cabozantinib in people with Advanced Hepatocellular Carcinoma, run by Takeda at 17 sites in Japan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 46 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in Japan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Apr 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

24-Week Progression-Free Survival Rate (PFSR) (time frame: Week 25 Day 1 plus 7 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03586973, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2023.

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