Cabozantinib for Patients With Hepatocellular Carcinoma (HCC) Refractory to First Line Treatment

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma Non-resectable; Metastatic Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Cabozantinib

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.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Arndt Vogel, Prof. Dr.; Phone Number: +49 511 532 9590; Email: vogel.arndt@mh-hannover.de
• Study Contact Backup: Name: Johanna Riedel, Dr.; Phone Number: +49 69 7601 4635; Email: riedel.johanna@ikf-khnw.de

Study Locations

• Germany
  • Bad Saarow, Germany, 15526
    • Recruiting
    • HELIOS Klinikum Bad Saarow
    • Contact: Daniel Pink, Dr.
  • Halle, Germany, 06120
    • Recruiting
    • Universitätsklinikum Halle (Saale)
    • Contact: Marko Damm, Dr.
  • Hannover, Germany, 30625
    • Recruiting
    • Medizinische Hochschule Hannover
    • Contact: Arndt Vogel, Prof. Dr.
  • Kiel, Germany, 24105
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein
    • Contact: Rainer Günther, Dr.
  • Köln, Germany, 50937
    • Recruiting
    • Universitätsklinikum Köln
    • Contact: Dirk Waldschidt, Dr.
  • Landshut, Germany, 84036
    • Recruiting
    • VK&K Studien
    • Contact: Florian Kaiser, Dr.
  • Lübeck, Germany, 23538
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein
    • Contact: Jens Marquardt, Prof.
  • München, Germany, 81675
    • Recruiting
    • Klinikum Rechts Der Isar Der Technischen Universität München
    • Contact: Ursula Ehmer, PD Dr.
  • Neuss, Germany, 41462
    • Recruiting
    • Johanna Etienne Krankenhaus
    • Contact: Wolf Köster, Dr.
  • Ulm, Germany, 89081
    • Recruiting
    • Universitatsklinikum Ulm
    • Contact: Thomas Ettrich, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 during or after first line therapy OR patients must have had their treatment interrupted due to the level of toxicities AND cabozantinib therapy is intended as second line therapy.
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 with > 7 points and Child-Pugh C.
8. Severely impaired kidney function.
9. History of encephalopathy in past 12 months, if not completely regressive or more than one episode within the last 6 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].

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	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.	at 18 months after last patient randomized
Progression free survival (PFS)	Survival rates for the different time points will be determined using the Kaplan-Meier analysis and RECIST 1.1.	at study end (approx. 18 months after last patient randomized)
Objective response rate (ORR)	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.	at study end (approx. 18 months after last patient randomized)
Duration of response	Time from documentation of tumor response to disease progression.	at study end (approx. 18 months after last patient randomized)
Treatment exposure	Time on treatment/dose intensity/dose reductions	at study end (approx. 18 months after last patient randomized)
Toxicity: o Treatment-related adverse events (TRAEs) o TRAE related treatment interruptions o TRAE related treatment modifications o TRAE related treatment discontinuations	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.	at study end (approx. 18 months after last patient randomized)
Change in ECOG Performance Status	Eastern Cooperative Oncology Group patient performance status (Grading from 0 to 5)	at study end (approx. 18 months after last patient randomized)
Change in ALBI Grade	ALBI score = -0.085 × (albumin g/L) + 0.66 × l g(TBil μmol/L)	at study end (approx. 18 months after last patient randomized)
Change in Child Pugh Score	Child-Pugh Classification Score (Grading from A to C)	at study end (approx. 18 months after last patient randomized)
Translational research	Correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) of cabozantinib by NGS Oncopanel analysis and VEGF module expression analysis.	at study end (approx. 18 months after last patient randomized)

Collaborators and Investigators

• Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Collaborators: Ipsen
• Investigators: Principal Investigator: Arndt Vogel, Prof. Dr., Hannover Medical School; Study Director: Salah-Eddin Al-Batran, Prof. Dr., Institut für Klinische Krebsforschung IKF GmbH

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2020
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: August 4, 2020
• First Submitted That Met QC Criteria: August 10, 2020
• First Posted (Actual): August 13, 2020

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 24, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: AURORA (Other Identifier: Mayo Clinic); 2019-004728-39 (EudraCT Number); AIO-HEP-0419/ass (Other Identifier: AIO-Studien-gGmbH); IKF-t018 (Other Identifier: IKF Trial ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No IPD will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No