Clinical Trials /

Nivolumab, Fluorouracil, and Interferon Alpha 2B for the Treatment of Unresectable Fibrolamellar Cancer

NCT04380545

Description:

This phase I/II trial studies the side effects and how well nivolumab, fluorouracil, and interferon alpha 2b work for the treatment of fibrolamellar cancer (liver cell cancer) that cannot be removed by surgery (unresectable). 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. Chemotherapy drugs, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Interferon alpha 2b may help stimulate the immune system to fight cancer. Giving nivolumab, fluorouracil, and interferon alpha 2b may work better in treating unresectable fibrolamellar cancer compared to fluorouracil and interferon alpha 2b alone.

Related Conditions:
  • Fibrolamellar Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab, Fluorouracil, and Interferon Alpha 2B for the Treatment of Unresectable Fibrolamellar Cancer
  • Official Title: A Phase I/II Study of Nivolumab Plus 5-Fluorouracil Plus Interferon-α2b for Unresectable Fibrolamellar Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2019-1135
  • SECONDARY ID: NCI-2020-02614
  • SECONDARY ID: 2019-1135
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04380545

Conditions

  • Stage III Hepatocellular Carcinoma AJCC v8
  • Stage IIIA Hepatocellular Carcinoma AJCC v8
  • Stage IIIB Hepatocellular Carcinoma AJCC v8
  • Stage IV Hepatocellular Carcinoma AJCC v8
  • Stage IVA Hepatocellular Carcinoma AJCC v8
  • Stage IVB Hepatocellular Carcinoma AJCC v8
  • Unresectable Fibrolamellar Carcinoma

Interventions

DrugSynonymsArms
Fluorouracil5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Treatment (fluorouracil, interferon alpha 2b, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (fluorouracil, interferon alpha 2b, nivolumab)
Recombinant Interferon Alpha 2b-like ProteinNovaferon, Recombinant IFN Alfa-2b-like ProteinTreatment (fluorouracil, interferon alpha 2b, nivolumab)

Purpose

This phase I/II trial studies the side effects and how well nivolumab, fluorouracil, and interferon alpha 2b work for the treatment of fibrolamellar cancer (liver cell cancer) that cannot be removed by surgery (unresectable). 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. Chemotherapy drugs, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Interferon alpha 2b may help stimulate the immune system to fight cancer. Giving nivolumab, fluorouracil, and interferon alpha 2b may work better in treating unresectable fibrolamellar cancer compared to fluorouracil and interferon alpha 2b alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the safety and tolerability of therapy with nivolumab + fluorouracil (5-FU) +
      recombinant interferon alpha 2b-like protein (IFN-alpha2b) in patients with unresectable
      fibrolamellar hepatocellular carcinoma (FLHCC) in the context of palliative systemic and
      prebiopsy therapy.

      SECONDARY OBJECTIVE:

      I. To assess the efficacy of nivolumab + 5-FU + IFN-alpha2b therapy in patients with
      unresectable FLHCC by estimating the overall response rate (ORR) and progression-free
      survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, and
      comparing those rates to those from historical controls in the investigator's published data.

      EXPLORATORY OBJECTIVES:

      I. To assess the immunological/biomarker changes in tumor tissues and peripheral blood in
      response to nivolumab + 5-FU + IFN-aplha2b therapy (pre- versus [vs] post-treatment).

      II. To explore any potential association between these biomarker measures and both antitumor
      response and immune-related response criteria (irRC) assessed by the University of Texas MD
      Anderson Cancer Center (MD Anderson) Department of Diagnostic Imaging.

      OUTLINE:

      Patients receive fluorouracil intravenously (IV) continuously on days 1-7 and 15-21 and
      recombinant interferon alpha 2b-like protein subcutaneously (SC) on days 1, 3, 5, 15, 17, and
      19. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or
      unacceptable toxicity. Beginning in cycle 3, patients receive nivolumab IV over 30 minutes on
      day 1, fluorouracil IV continuously on days 1-7 and 15-21, and recombinant interferon alpha
      2b-like protein interferon alpha 2b SC on days 1, 3, 5, 15, 17, and 19. Cycles repeat every
      28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 12
      weeks for 6 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (fluorouracil, interferon alpha 2b, nivolumab)ExperimentalPatients receive fluorouracil IV continuously on days 1-7 and 15-21 and recombinant interferon alpha 2b-like protein SC on days 1, 3, 5, 15, 17, and 19. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 3, patients receive nivolumab IV over 30 minutes on day 1, fluorouracil IV continuously on days 1-7 and 15-21, and recombinant interferon alpha 2b-like protein interferon alpha 2b SC on days 1, 3, 5, 15, 17, and 19. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Fluorouracil
  • Nivolumab
  • Recombinant Interferon Alpha 2b-like Protein

Eligibility Criteria

        Inclusion Criteria:

          -  Patients, or their legal guardian, must give written informed consent prior to
             initiation of therapy, and patients under age 18 must give assent in keeping with the
             policies of the institution. Patients with a history of major psychiatric illness must
             be judged able to fully understand the investigational nature of the study and the
             risks associated with the therapy

          -  Patients with histologically confirmed FLHCC (or with documentation of original biopsy
             for diagnosis is acceptable if tumor tissue is unavailable). The determination of
             resectability status will ultimately lie in the clinical judgment of the surgical
             oncologist and medical oncologist involved in the care of the patient. The definition
             of resectability is as follows: hepatectomy can achieve a negative margin while
             preserving more than 30% of the total estimated liver volume, sparing two contiguous
             hepatic segments, and maintaining vascular inflow, vascular outflow, and biliary
             drainage. Patients with extrahepatic disease are defined as having unresectable
             disease

          -  Patient must have measurable disease defined as a lesion that can be accurately
             measured in at least one dimension (longest diameter to be recorded) and measures >=
             15 mm with conventional techniques or >= 10 mm with more sensitive techniques such as
             magnetic resonance imaging (MRI) or spiral computed tomography (CT) scan

          -  Eastern Cooperative Oncology Group performance status (ECOG PS =< 1), or for patients
             under age 18 Karnofsky performance status of >= 70

          -  No advanced cirrhosis, with Child-Pugh A

          -  Absolute neutrophil count (ANC) >= 1,000 /mm^3 (within 14 days of the first dose of
             study drug)

          -  Platelets >= 100,000 /mm^3 (within 14 days of the first dose of study drug)

          -  Hemoglobin > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen] to
             maintain or exceed this level) (within 14 days of the first dose of study drug)

          -  Total bilirubin =< 1.5 mg/dL (within 14 days of the first dose of study drug)

          -  Serum creatinine =< 1.5 times the upper limit of normal (ULN) or estimated creatinine
             clearance (CrCL) > 40 mL/min (within 14 days of the first dose of study drug)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
             and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 5 times institutional ULN (within 14 days of the first dose of study drug)

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin)
             within 24 hours prior to the start of study drug

          -  Women must not be breastfeeding

          -  WOCBP must agree to follow instructions for method(s) of contraception from the time
             of enrollment for the duration of treatment with study drug(s) plus 5 half-lives of
             study drug(s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post
             treatment completion

          -  Men who are sexually active with WOCBP must agree to follow instructions for method(s)
             of contraception for the duration of treatment with study drug(s) plus 5 half-lives of
             study drug(s) plus 90 days (duration of sperm turnover) for a total of 7 months
             post-treatment completion

          -  Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
             from contraceptive requirements. However, WOCBP must still undergo pregnancy testing
             as described in these sections. Investigators shall counsel WOCBP and male subjects
             who are sexually active with WOCBP on the importance of pregnancy prevention and the
             implications of an unexpected pregnancy. Investigators shall advise WOCBP and male
             subjects who are sexually active with WOCBP on the use of highly effective methods of
             contraception, which have a failure rate of < 1% per year when used consistently and
             correctly. At a minimum, subjects must agree to the use of two methods of
             contraception, with one method being highly effective and the other method being
             either highly effective or less effective as listed below:

               -  HIGHLY EFFECTIVE METHODS OF CONTRACEPTION:

                    -  Male condoms with spermicide

                    -  Hormonal methods of contraception including combined oral contraceptive
                       pills, vaginal ring, injectables, implants, and intrauterine devices such as
                       Mirena by WOCBP subject or male subject's WOCBP partner

                    -  Nonhormonal intrauterine devices, such as ParaGard

                    -  Tubal ligation

                    -  Vasectomy

                    -  Complete Abstinence

                         -  Complete abstinence is defined as complete avoidance of heterosexual
                            intercourse and is an acceptable form of contraception for all study
                            drugs. Abstinence is only acceptable when this is in line with the
                            preferred and usual lifestyle of the subject. Periodic abstinence
                            (e.g., calendar, ovulation, symptothermal, profession of abstinence for
                            entry into a clinical trial, post-ovulation methods) and withdrawal are
                            not acceptable methods of contraception. Subjects who choose complete
                            abstinence are not required to use a second method of contraception,
                            but female subjects must continue to have pregnancy tests. Acceptable
                            alternate methods of highly effective contraception must be discussed
                            in the event that the subject chooses to forego complete abstinence

               -  LESS EFFECTIVE METHODS OF CONTRACEPTION:

                    -  Diaphragm with spermicide

                    -  Cervical cap with spermicide

                    -  Vaginal sponge

                    -  Male condom without spermicide

                    -  Progestin-only pills by WOCBP subject or male subject's WOCBP partner

                    -  Female condom

                         -  A male and female condom must not be used together

        Exclusion Criteria:

          -  Any other malignancy from which the patient has been disease-free for less than 2
             years, except for non-melanoma skin cancer, or in situ carcinoma of any site

          -  Patients who have organ allografts

          -  Patients who have had a major surgical procedure, open biopsy, or significant
             traumatic injury with poorly healed wound within 6 weeks prior to first dose of study
             drug; or have an anticipated need for major surgical procedure during the course of
             the study (other than defined by protocol). NOTE: Patients will be allowed to start
             cycle 1 day 1 therapy after 24 hours from pre-treatment biopsy

          -  Autoimmune disease: patients with a history of inflammatory bowel disease (including
             Crohn's disease and ulcerative colitis) are excluded from this study as are patients
             with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive
             sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
             Wegener's granulomatosis])

          -  Known history of testing positive for human immunodeficiency virus or known acquired
             immunodeficiency syndrome

          -  Any underlying medical condition, which in the opinion of the investigator will make
             the administration of study drug hazardous or will obscure the interpretation of
             adverse events (AEs), such as a condition associated with frequent diarrhea

          -  Patients who have had a history of acute diverticulitis, abdominal fistula,
             gastrointestinal perforation, intra-abdominal abscess, gastrointestinal obstruction,
             or abdominal carcinomatosis which are known risks factors for bowel perforation

          -  Patients who have a primary brain tumor (excluding meningiomas and other benign
             lesions), any brain metastases, leptomeningeal disease, seizure disorders not
             controlled with standard medical therapy, or history of stroke within the past year

          -  History of serious systemic disease, including myocardial infarction or unstable
             angina within the last 12 months, history of hypertensive crisis or hypertensive
             encephalopathy, uncontrolled hypertension (blood pressure of >140/90 mmHg) at the time
             of enrollment, New York Heart Association grade II or greater congestive heart
             failure, unstable symptomatic arrhythmia requiring medication (patients with chronic
             atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular
             tachycardia are eligible), or significant vascular disease or symptomatic peripheral
             vascular disease

          -  Patients who have history of other diseases, metabolic dysfunction, physical
             examination finding, or clinical laboratory finding giving reasonable suspicion of a
             disease or condition that contraindicates the use of an investigational drug or that
             might affect the interpretation of the results of the study or render the subject at
             high risk from treatment complications

          -  Patients who have received any live or attenuated viral vaccines within a month prior
             to initiation of study drugs

          -  Patients who have active hepatitis B virus (HBV) infection (chronic or acute), defined
             as having a positive hepatitis B surface antigen (HBsAg) test at screening

               -  Patients with a past or resolved HBV infection, defined as having a negative
                  HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and
                  negative HBV deoxyribonucleic acid (DNA) test at screening, are eligible for the
                  study

          -  Patients who have active hepatitis C virus (HCV) infection, defined as having a
             positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at
             screening

               -  The HCV RNA test will be performed only for patients who have a positive HCV
                  antibody test

          -  Patients who have clinical history of coagulopathy, bleeding diathesis, or thrombosis
             within the past year

          -  Patients who have a serious, non-healing wound, ulcer, or bone fracture

          -  Patients who are pregnant (positive pregnancy test) or lactating

          -  Patients with prior orthotropic liver transplantation

          -  Patients with cirrhosis and severe synthetic liver dysfunction (Child Pugh B-C)

          -  Patients must not have received prior anticancer therapy with anti-PD-1 for FLHCC
             treatment. Patients receiving any concomitant systemic therapy for FLHCC are excluded

          -  Patients must not be scheduled to receive another experimental drug while on this
             study

          -  Patients who require ongoing anticoagulation will be excluded. Only aspirin will be
             permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted

          -  Patients must not require total parenteral nutrition

          -  Patients who are on high dose steroid (e.g. > 10 mg prednisone daily or equivalent) or
             other more potent immune suppression medications (e.g. infliximab). Corticosteroid use
             will only be allowed during trial participation for grade 3/4 AEs or hypersensitivity
             reactions

          -  Any patients who cannot be compliant with the appointments required in this protocol
             must not be enrolled in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after last treatment dose
Safety Issue:
Description:Safety will be monitored by addressing and recording all adverse events (AEs), serious adverse events (SAEs) and specific laboratory abnormalities (worst grade). Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:12 weeks after initiation of combined treatment
Safety Issue:
Description:Overall response rate (ORR) is defined as the number of subjects with the best response of complete response (CR) or partial response (PR) (by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) divided by the number of subjects who started treatment.
Measure:Conversion rate to surgery
Time Frame:Up to 6 years
Safety Issue:
Description:Conversion rate to surgery is defined as the proportion of patients that will be able to receive surgery after the initiation of the study treatment divided by the number of subjects who started treatment. The conversion rate to surgery will be estimated along with the 95% confidence interval (CI).
Measure:Progression-free survival (PFS)
Time Frame:From the start of treatment to date of patient death (PD), to date of last follow-up if patient is alive without PD, or to date of death, whichever occurs first, assessed up to 6 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate probability of PFS.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 7, 2020