Sorafenib and Nivolumab in Treating Participants With Unresectable, Locally Advanced or Metastatic Liver Cancer

NCT03439891 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 174523NCI-2018-00051
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

This phase II trial studies the best dose and side effects of sorafenib tosylate and nivolumab in treating patients with liver cancer that cannot be removed by surgery (unresectable), has spread to nearby tissues or lymph nodes (locally advanced) or to other places in the body (metastatic). Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sorafenib tosylate and nivolumab may work better in treating patients with liver cancer.

Conditions

Stage III Hepatocellular Carcinoma AJCC v8; Stage IIIA Hepatocellular Carcinoma AJCC v8; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Hepatocellular Carcinoma AJCC v8; Stage IVA Hepatocellular Carcinoma AJCC v8; Stage IVB Hepatocellular Carcinoma AJCC v8

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) (Part 1 Only)

  MTD is defined as the dose in which 1 or more dose limiting toxicities (DLT) is reported by study participants in Part 1 within the first cycle of treatment. Participants in Part 1 must receive at least 2 doses of nivolumab and at least 75% of sorafenib doses within 28 days (1 cycle), or experience a qualifying DLT event to be evaluable.

  28 days

• Proportion of Participants With Grade 3 or Higher Treatment-related Adverse Events (Part 2 Only)

  All adverse event (AE) will be summarized based on proportion of total participants in Part 2 to evaluate the safety of the treatment combination in participants with Child-Pugh B7-9 liver function as measured by proportion of participants with an AE of toxicity grade \>=3 as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and assessed as at least possibly related to sorafenib, nivolumab, or the combination of therapies.

  Up to 2 years

Secondary Outcomes (14)

• Proportion of Participants With Treatment-related Adverse Events

  Up to 2 years

• Proportion of Participants Reporting Immune-related Adverse Event (irAE) (Part 1 and Part 2 Combined)

  Up to 2 years

• Proportion of Participants With Child-Pugh B (CPB) Reporting Immune-related Adverse Event (irAE) (Parts 1 and 2 Combined)

  Up to 2 years

• Proportion of Participants With Dose Delays Due to Toxicity

  Up to 2 years

• Proportion of Participants With Dose Reductions Due to Toxicity

  Up to 2 years

Study Arms (3)

Part 1: Starting Dose Schedule (DL -1) Once a day

EXPERIMENTAL

Participants with Child-Pugh A or B7 receive a daily dose of 400mg sorafenib on days 1-28, and 240mg of nivolumab IV over 30 minutes beginning on day 15 of course 1, then on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Course will continue until 1 dose-limiting toxicity occurs to establish maximum tolerated dosing schedule.

Biological: Nivolumab; Drug: Sorafenib

Part 1: Escalated Dose Schedule (DL 1) Twice a day

EXPERIMENTAL

Participants with Child-Pugh A or B7 receive a daily dose of 400mg sorafenib twice a day on days 1-28, and 240mg of nivolumab IV over 30 minutes beginning on day 15 of course 1, then on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Course will continue until 1 dose-limiting toxicity occurs to establish maximum tolerated dosing schedule.

Biological: Nivolumab; Drug: Sorafenib

Part 2: Child-Pugh B (CPB) Expansion Cohort (sorafenib, nivolumab)

EXPERIMENTAL

Participants with Child-Pugh B7-9 receive sorafenib at the maximum tolerated dose (MTD) established in Part 1 on days 1-28, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Nivolumab; Drug: Sorafenib

Interventions

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Part 1: Escalated Dose Schedule (DL 1) Twice a day; Part 1: Starting Dose Schedule (DL -1) Once a day; Part 2: Child-Pugh B (CPB) Expansion Cohort (sorafenib, nivolumab)

Sorafenib DRUG

Given PO

Also known as: BAY 43-9006

Part 1: Escalated Dose Schedule (DL 1) Twice a day; Part 1: Starting Dose Schedule (DL -1) Once a day; Part 2: Child-Pugh B (CPB) Expansion Cohort (sorafenib, nivolumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic or cytologic diagnosis of unresectable, locally advanced and/or metastatic hepatocellular carcinoma (HCC) not amenable to curative surgery, transplantation, or ablative therapies based upon assessment of treating investigator.
• a. For patients without prior histologic or cytologic diagnosis, radiographic diagnosis is allowed provided patients meet American Association for the Study of Liver Diseases (AASLD) criteria for radiographic diagnosis.
• Radiographically measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in at least one site not previously treated with chemoembolization, radioembolization, radiation, or other local/liver-directed procedures (i.e. must have at least one measurable target lesion, either within the liver or in a measurable metastatic site); a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a radiologist, is acceptable.
• Untreated/pretreatment archival tumor tissue must be available for correlative analyses
• Age at least 18 years at enrollment.
• Eastern Cooperative Oncology Group (ECOG) 0 or 1 at enrollment
• At least 4 weeks after any prior chemoembolization, radioembolization, local ablative therapies, or hepatic radiation and recovery to =\< grade 1 treatment-related toxicity.
• At least 6 weeks after any major surgery including prior hepatic resection and recovery to =\< grade 1 treatment-related toxicity.
• At least 7 days after minor surgery (such as central venous access) or biopsy and recovery to =\< grade 1 treatment-related toxicity
• At least 2 weeks after any prior palliative radiation (e.g. to focal metastatic lesion such as bone metastases) and recovery to =\< grade 1 treatment-related toxicity.
• Blood pressure =\< 140/90 mm Hg with or without anti-hypertensive therapy
• a. Patients may be rescreened after initial ineligibility if due to elevated blood pressure, if adequately medically managed within approximately 30 days.
• Adequate baseline organ and marrow function as defined below:
• Adequate bone marrow function:
• Absolute neutrophil count at least 1,200/microliter (mcL).

You may not qualify if:

• Any prior systemic therapy for HCC.
• Known fibrolamellar or mixed HCC-cholangiocarcinoma histology.
• Requirement for paracentesis to control ascites within 6 months before enrollment.
• a. Ascites which is not clinically detectable or mild on stable doses of diuretics during screening is allowed provided meets criteria for Child Pugh A or B7 (Part 1) or B7-9 (Part 2).
• Symptomatic hepatic encephalopathy requiring medication (such as lactulose or rifaximin) (Part 1) or any hospitalization for encephalopathy within 6 months before enrollment (Part 1 or 2).
• Hepatic encephalopathy that is adequately controlled on stable doses of lactulose and/or rifaximin per assessment of treating investigator is allowed in Part 2, provided no hospitalization for encephalopathy within 6 months before enrollment.
• Medications such as lactulose used for other indications (e.g. constipation) are allowed in both Part 1 and 2.
• History of upper gastrointestinal (GI) bleeding from esophageal and/or gastric varices within 12 months before enrollment.
• Requirement for systemic corticosteroids unless used for adrenal replacement, acute therapy for asthma or bronchitis exacerbation (=\< 2 weeks), or premedication for contrast allergy.
• a. Topical, intranasal, or inhaled steroids are not excluded.
• Active autoimmune condition requiring systemic immunosuppressive medication.
• Known human immunodeficiency virus (HIV) infection.
• Active coinfection with HBV plus hepatitis delta (D) virus (HDV) or HCV:
• Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV DNA and detectable HCV ribonucleic acid (RNA).
• Hepatitis D infection (HDV antibody positive) in subjects with detectable hepatitis B surface antigen or HBV DNA.

Sponsors & Collaborators

• Robin Kate Kelley: lead
• Bayer: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (2)

University of California, Davis

Sacramento, California, 95817, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Nivolumab; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

The Part 2 Child Pugh B Expansion Cohort was closed to further accrual earlier than expected due to slow accrual resulting from a changing treatment landscape in hepatocellular carcinoma (HCC) with multiple new drug approvals.

Results Point of Contact

• Title: Dr. R. Katie Kelley, MD
• Organization: University of California, San Francisco

katie.kelley@ucsf.edu

(415) 353-9888

Study Officials

• Robin K. Kelley, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 13, 2018
• First Posted: February 20, 2018
• Study Start: April 16, 2018
• Primary Completion: November 30, 2023
• Study Completion: November 30, 2023
• Last Updated: February 11, 2025
• Results First Posted: February 11, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)