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A Phase II, Non-randomized, Single Arm, Translational Study of Cabozantinib for Patients With Hepatocellular Carcinoma (HCC) Refractory to Lenvatinib Treatment

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ClinicalTrials.gov Identifier: NCT04511455
Recruitment Status : Recruiting
First Posted : August 13, 2020
Last Update Posted : December 24, 2020
Sponsor:
Collaborator:
Ipsen
Information provided by (Responsible Party):
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Brief Summary:
Patients suffering from advanced stage hepatocellular carcinoma (HCC) who have shown disease progression during lenvatinib-based first line treatment, will be enrolled in this trial. Patients who progressed either during lenvatinib monotherapy or lenvatinib-IO (immuno-oncology) combination therapy will be eligible for study participation, whereas at least 50% of the enrolled patients should be in favor of lenvatinib monotherapy.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Non-resectable Metastatic Hepatocellular Carcinoma Drug: Cabozantinib Phase 2

Detailed Description:

This is a open-label, single-arm, multicenter phase II trial for patients with locally advanced and/or metastatic and/or unresectable hepatocellular carcinoma (HCC).

Patients who have histologically proven or were clinically diagnosed (by guideline criteria in cirrhotic patients) with locally advanced or metastatic and/or unresectable HCC will be included to receive cabozantinib peroral 60 mg/day. A stepwise dose de-escalation schedule on individual level is available for patients with lower tolerability against cabozantinib.

The study treatment will be limited to a maximum of 12 months (including temporary interruptions).

Tumor tissue will be collected for accompanying research project. (Participation is optional for participant).

During treatment, clinical visits (blood cell counts, ECG, detection of toxicity) occur every four weeks during treatment phase. Safety will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.

During treatment, tumor response will be assessed by the Investigator according to RECIST 1.1 (radiological imaging by CT and/or MRI of the chest, abdomen, pelvis and all other sites of disease every 10 weeks until end of treatment (EOT) and every 12 weeks during follow-up (FU), in case of EOT due to other reasons than progressive disease. Safety-FU visit and Survival FU visits will be assessed 30 days-, and every 12 weeks after EOT.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Translational Study of Cabozantinib for Patients With Hepatocellular Carcinoma (HCC) Refractory to Lenvatinib Treatment
Actual Study Start Date : December 8, 2020
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : March 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental

Cabozantinib peroral 60 mg/day

A stepwise dose de-escalation schedule on individual level is available for patients with lower tolerability against cabozantinib.

The study treatment will be limited to a maximum of 12 months (including interruptions).

Drug: Cabozantinib
Cabozantinib 60 mg/day peroral




Primary Outcome Measures :
  1. Time-on-treatment [ Time Frame: at study end (approx. 30 months after FPI) ]
    Time on treatment will be assessed as time from date of first dose of cabozantinib intake till date of permanent discontinuation of treatment.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: at 18 months after last patient randomized ]
    Survival rates will be assessed from the date of first dose of cabozantinib intake to the date of death from any cause using Kaplan-Meier methods.

  2. Progression free survival (PFS) [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Survival rates for the different time points will be determined using the Kaplan-Meier analysis and RECIST 1.1.

  3. Objective response rate (ORR) [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Objective response rate will be defined as the proportion of subjects experiencing a confirmed complete response (CR) or confirmed partial response (PR) per RECIST 1.1.

  4. Duration of response [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Time from documentation of tumor response to disease progression.

  5. Treatment exposure [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Time on treatment/dose intensity/dose reductions

  6. Toxicity: o Treatment-related adverse events (TRAEs) o TRAE related treatment interruptions o TRAE related treatment modifications o TRAE related treatment discontinuations [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    All observed toxicities and side effects will be graded according to NCI CTCAE v5.0 and the degree of association of each with the study treatment assessed and summarized.

  7. Change in ECOG Performance Status [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Eastern Cooperative Oncology Group patient performance status (Grading from 0 to 5)

  8. Change in ALBI Grade [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    ALBI score = -0.085 × (albumin g/L) + 0.66 × l g(TBil μmol/L)

  9. Change in Child Pugh Score [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Child-Pugh Classification Score (Grading from A to C)

  10. Translational research [ Time Frame: at study end (approx. 18 months after last patient randomized) ]
    Correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) of cabozantinib by NGS Oncopanel analysis and VEGF module expression analysis.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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. Fully-informed written consent.
  2. Males and females ≥ 18 years of age.

    *There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.

  3. Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by guideline criteria in cirrhotic patients
  4. Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies.
  5. Patients who have shown progressive disease despite of lenvatinib treatment (in terms of lenvatinib monotherapy or combination therapy with IO) OR patients must have had their treatment interrupted after at least 1 administration, as treatment with lenvatinib is no longer clinically indicated due to the level of toxicities.
  6. ECOG performance status ≤ 2.
  7. Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade 1 prior to study entry, with the exception of alopecia.
  8. For women of childbearing potential and men who are sexually active with women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods.

Exclusion Criteria:

  1. Unwillingness to give informed consent for participation in the study.
  2. Prior sorafenib treatment.
  3. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after last dose of study treatment.
  4. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
  5. Significant portal hypertension (moderate or severe ascites).
  6. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
  7. Liver cirrhosis Child-Pugh B (> 7 points).
  8. Severely impaired kidney function.
  9. History of encephalopathy in past 12 months.
  10. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
  11. Baseline QTcF >500 ms.
  12. Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study.
  13. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  14. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
  15. Elevations of AST/ALT exceeding 5 X ULN.
  16. Treatment with investigational systemic therapy within 28 days prior to initiation of study treatment.
  17. Prior cabozantinib use.
  18. Is currently participating or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
  19. Patients who have been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
  20. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

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): NCT04511455


Contacts
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Contact: Arndt Vogel, MD +49 176 ext 1 532 9590 vogel.arndt@mh-hannover.de
Contact: Johanna Riedel, PhD +49 69 7601 ext 4635 riedel.johanna@ikf-khnw.de

Locations
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Germany
Universitätsklinikum Schleswig-Holstein Campus Lübeck Recruiting
Lübeck, Germany, 23538
Contact: Jens Marquardt, Prof.         
Sponsors and Collaborators
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Ipsen
Investigators
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Principal Investigator: Arndt Vogel, MD Hannover Medical School Department of Gastroenterology, Hepatology and Endocrinology
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Responsible Party: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
ClinicalTrials.gov Identifier: NCT04511455    
Other Study ID Numbers: AURORA
First Posted: August 13, 2020    Key Record Dates
Last Update Posted: December 24, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No IPD will be shared.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
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