Dose Escalation Study of Cabozantinib for Advanced HCC Patients With Compensated Liver Cirrhosis

• ClinicalTrials.gov Identifier: NCT04522908
• Recruitment Status: Recruiting
• First Posted: August 21, 2020
• Last Update Posted: February 18, 2021
• Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Information provided by (Responsible Party): Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Study Description

Brief Summary:

Open-label, single arm, multicenter phase II trial assessing the tolerability of a reduced starting dose of 40 mg cabozantinib for 4 weeks and subsequent dose escalation to 60 mg cabozantinib until disease progression or intolerable toxicities.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma (HCC); Compensated Liver Cirrhosis; Second Line Treatment	Drug: Cabozantinib Oral Tablet	Phase 2

Detailed Description:

The primary objective is to assess the tolerability of a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. Using the same study treatment discontinuation criteria as in the pivotal CELESTIAL trial will allow for comparison of treatment discontinuation rates due to treatment related adverse events (TRAEs) defined as unresolved intolerable Grade 2 TRAEs or any unresolved Grade 3 TRAEs (see Section 6).

Patients eligible for this trial are cirrhotic HCC patients treated with sorafenib or lenvatinib in first line.

Secondary objectives comprise the assessment of overall survival (OS), progression free survival (PFS) at 10 weeks, objective response rate (ORR), time on treatment, treatment exposure (dose intensity/dose reductions), toxicity, and quality of life (QLQ-C30).

In addition, tissue samples (optional) will be analyzed for molecular parameters and immune cell composition to identify biomarkers potentially associated with clinical efficacy (OS, PFS and ORR).

This is an open label, single-arm, multicenter phase II trial. 40 patients suffering from advanced stage hepatocellular carcinoma (HCC) with compensated liver cirrhosis in second line treatment, after first line treatment with sorafenib or lenvatinib, will be enrolled in this trial.

Patients will be recruited from up to 10 sites and patients withdrawn from the trial will not be replaced.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Clinical trials with a single arm, all eligible patients will receive Cabozantinib starting dose of 40 mg, oral, once daily for 4 weeks, followed by Cabozantinib escalated dose of 60 mg, oral, once daily from week 5 onwards
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Evaluating Reduced Starting Dose and Dose Escalation of Cabozantinib as Second-line Therapy for Advanced HCC in Patients With Compensated Liver Cirrhosis
• Actual Study Start Date: October 12, 2020
• Estimated Primary Completion Date: November 2022
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cabozantinib - Single Arm; Single Arm with Cabozantinib starting dose 40 mg for 4 weeks and dose escalation to 60 mg afterwards.	Drug: Cabozantinib Oral Tablet; Cabozantinib starting dose of 40 mg, oral, once daily for 4 weeks followed by Cabozantinib escalated dose of 60 mg, oral, once daily from week 5 onwards; Other Name: CABOMETYX

Outcome Measures

Primary Outcome Measures :

1. Treatment discontinuation rate due to treatment-related adverse events [ Time Frame: 27 months ]
   Any unresolved intolerable Grade 2 TRAE or unresolved Grade ≥ 3 TRAE after 60 mg or 40 mg or any intolerable Grade 2 TRAE or Grade ≥ 3 TRAE after 20 mg will count as treatment discontinuation due to AE.

Secondary Outcome Measures :

1. Overall survival [ Time Frame: 27 months ]
   Time from the date of enrollment to the date of death from any cause. Subjects who have not died by the date of data cutoff will be right censored at the last known date alive.
2. Progression free survival (PFS) according to RECIST 1.1 [ Time Frame: at 10 weeks ]
   Time from the date of enrollment to the date of first observed disease progression (investigator assessment according to RECIST 1.1) or death from any cause. Subjects who have died without a reported disease progression will be considered to have progressed on the date of their death. Subjects who did not progress or have died will be right censored on the date of their last evaluable tumor assessment.
3. Objective response rate (ORR) according to RECIST 1.1 [ Time Frame: 27 months ]
   Objective response rate will be assessed according to RECIST 1.1 (refer to Appendix 5). 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. Time on treatment [ Time Frame: 27 months ]
   Time on treatment defined as the interval from therapy initiation until premature discontinuation.
5. Treatment exposure [ Time Frame: 27 months ]
   Treatment exposure defined as summary of specific dose intensities on treatment (including dose reductions and interruptions).
6. Treatment-related and -unrelated toxicities (AEs, SAEs) according to NCI CTCAE v5.0 [ Time Frame: 27 months ]
   All observed treatment-related and -unrelated toxicities (type, incidence and severity of AEs and SAEs) 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. The treatment related serious adverse events rate (SAE) will be determined.
7. Quality of Life with the EORTC QLQ-C30 patient questionnaire [ Time Frame: 27 months ]
   Patient reported outcome assessed by the validated EORTC patient quality of life questionnaire QLQ-C30. The questionnaire evaluates the patient's health and activities in everyday life. Values reach from 1 (not at all) to 4 (very much). Low values mean a better outcome.
8. Correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) [ Time Frame: 27 months ]

   The TR projects might include the assessment of the following:

   FFPE tissue for IHC staining; FFPE tissue for nucleic isolation to assess the expression of biomarkers, determination of genetic alterations in HCC (panel sequencing) or to determine the mutational load.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Fully-informed written consent.

• 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.

• Patients with HCC who have been previously treated with sorafenib or lenvatinib in first line.
• Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/cytology or clinically by guideline criteria in cirrhotic patients.
• Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and/or locoregional therapies.
• ECOG performance status ≤ 2.
• Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade 1 prior to study entry, with the exception of alopecia.
• Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
• For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods from the time of signing the informed consent through at least 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Male patients, even if surgically sterilized (i.e. status post-vasectomy) must agree to practice effective barrier contraception (e.g. condom) and to refrain from sperm donation during the entire study treatment period and through at least 4 months after the last dose of study drug or agree to completely abstain from heterosexual intercourse.

Exclusion Criteria:

• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 4 months.
• Significant portal hypertension (moderate or severe ascites). Significant hypertension, defined as blood pressure ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic) in repeated measurements.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Liver cirrhosis Child-Pugh B or C.
• Severely impaired kidney function.
• Elevations of AST/ALT > 5 x ULN at baseline.
• History of encephalopathy in past 12 months.
• Significant cardiovascular disease (such as NYHA 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.
• Baseline QTcF > 500 ms.
• 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.
• 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.
• 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.
• Treatment with investigational systemic therapy within 28 days or five times the elimination half-life of the investigational product, whichever is longer, prior to initiation of study treatment.
• Prior cabozantinib use.
• Known or suspected hypersensitivity to cabozantinib or any other excipients of the IMP.
• Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
• Is currently participating in 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.
• Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
• 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].

Contacts and Locations

Contacts

Contact: Joerg Trojan, Prof. Dr.; 0049 69 6301 - 7860; trojan@em.uni-frankfurt.de

Contact: Christina Kopp; 0049 69 7601 4287; kopp.christina@ikf-khnw.de

Locations

Germany

HELIOS Klinikum Bad Saarow; Recruiting

Bad Saarow, Germany

Contact: Daniel Pink, MD

Principal Investigator: Daniel Pink, MD

BAG / Onkologische Gemeinschaftspraxis; Recruiting

Dresden, Germany

Contact: Lutz Jacobasch, MD

Principal Investigator: Lutz Jacobasch, MD

Ev. Kliniken Essen-Mitte, Klinik für Internistische Onkologie; Recruiting

Essen, Germany, 45136

Contact: Stefan Pluntke, MD

Principal Investigator: Stefan Pluntke, MD

Institute for Clinical Cancer Research Krankenhaus Nordwest; Recruiting

Frankfurt, Germany, 60488

Contact: Thorsten O Götze, MD

Principal Investigator: Thorsten Götze, MD

Klinikum der Johann-Wolfgang-Goethe Universität; Recruiting

Frankfurt, Germany

Contact: Jörg Trojan, MD

Principal Investigator: Jörg Trojan, MD

Universität Leipzig KöR, Medizinische Fakultät Department für Innere Medizin, Neurologie Klinik für Gastroenterologie; Recruiting

Leipzig, Germany

Contact: Florian van Bömmel, MD

Principal Investigator: Florian van Bömmel, MD

Klinikum rechts der Isar Technische Universität München Klinik und Poliklinik für Innere Medizin II; Recruiting

Müchen, Germany

Contact: Ursula Ehmer, MD

Principal Investigator: Ursula Ehmer, MD

Sponsors and Collaborators

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Investigators

• Principal Investigator: Joerg Trojan, Prof. Dr.; Universitätsklinikum Frankfurt Goethe-Universität

More Information

• Responsible Party: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• ClinicalTrials.gov Identifier: NCT04522908
• Other Study ID Numbers: CaboRISE
• First Posted: August 21, 2020
• Last Update Posted: February 18, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: No IPD will be shared

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

Keywords provided by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest:

hepatocellular carcinoma; HCC; liver cirrhosis

Additional relevant MeSH terms:

Carcinoma, Hepatocellular; Liver Cirrhosis; Fibrosis; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pathologic Processes