Durvalumab, Tremelimumab, and Radiation Therapy in Treating Participants with Unresectable, Locally Advanced, or Metastatic Hepatocellular Carcinoma or Biliary Tract Cancer

Status: Active

Description

This phase II trial studies how well durvalumab, tremelimumab, and radiation therapy work in treating participants with hepatocellular carcinoma or biliary tract cancer that can't be removed via surgery or that has spread to other parts of the body. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Giving durvalumab, tremelimumab, and radiation therapy may work better than radiation therapy alone in treating participants with hepatocellular carcinoma or biliary tract cancer.

Eligibility Criteria

Inclusion Criteria

  • Histologically or cytologically confirmed hepatocellular carcinoma or biliary tract cancer.
  • Locally advanced/unresectable or metastatic disease.
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1.
  • One previously unirradiated lesion amenable to 8 Gy x 3 radiotherapy based on dosimetric organ tolerance AND another unirradiated measurable lesion (per irRECIST) outside of the radiation field.
  • Immunotherapy-naive.
  • Progressed on, be intolerant of, or refused: * Sorafenib for hepatocellular carcinoma (HCC) * Gemcitabine-based chemotherapy for biliary tract cancer.
  • For patients that have refused treatment with sorafenib, the benefits of sorafenib have been discussed in detail with the patient.
  • Viral status (hepatitis B and C) must be known. All hepatitis B virus (HBV)-positive patients must be on antiviral medication for viral suppression. Testing should be completed =< 28 days prior to study registration. * Patients with concomitant HBV infection must have a confirmed diagnosis of HBV characterized by the presence of hepatitis B core antibodies, and be sufficiently suppressed with active antiviral treatment (per local institutional practice) prior to enrollment to ensure adequate viral suppression (HBV deoxyribonucleic acid [DNA] < 2000 IU/mL). * Patients with concomitant hepatitis C virus (HCV) infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV ribonucleic acid (RNA or anti-HCV antibody upon enrollment.
  • Body weight >= 30 kg.
  • Child-Pugh score of A. A score of B7 is allowed without severe ascites or without hepatic encephalopathy.
  • Hemoglobin >= 9 g/dL.
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
  • Platelet count >= 75×10^9/L.
  • Serum bilirubin =< 2.0 × the upper limit of normal (ULN) for HCC. Serum bilirubin =< 3.0 x the upper limit of normal (ULN) for biliary tract carcinoma (BTC).
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x institutional ULN, or two down trending values.
  • Albumin > 2.8 g/dL.
  • International normalized ratio (INR) < 2.0.
  • Calculated creatinine clearance > 40 mL/min as determined by Cockcroft-Gault (using actual body weight).
  • Ability to understand and the willingness to sign a written informed consent document.
  • Female subjects must be either of non-reproductive potential (i.e., post-menopausal by history: >= 50 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
  • Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations with follow up.

Exclusion Criteria

  • Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
  • Prior irradiation to the planned radiation target lesion.
  • Prior immunotherapy including but not limited to anti-CTLA4, including tremelimumab anti-PD-1, and anti-PD-L1, including durvalumab. Participants with HCC are permitted to have had prior anti-PD-1 or anti-PD-LI therapy per Food and Drug Administration (FDA) approval and phase II KEYNOTE-224 trial.
  • Concurrent enrollment in another study unless it is an observational (e.g. non-interventional) study.
  • Received live attenuated vaccines within 30 days of first dose.
  • Mean QT interval corrected for heart rate (QTc) >= 470 ms using Fridericia’s correction.
  • History of primary immunodeficiency.
  • History of solid organ transplantation.
  • Active or prior documented autoimmune disease within the past 2 years (NOTE: The following are exceptions to this criterion: Participants with vitiligo or alopecia; Participants with hypothyroidism (e.g. following Hashimoto syndrome) who are stable on hormone replacement; Participants with celiac disease controlled by diet alone: Participants with Grave’s disease, or any chronic skin condition not requiring systemic treatment. Participants without active disease in the last 5 years may be included but only after consultation with the study physician.
  • Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis).
  • Prior other malignancy within 2 years (except for in situ disease, which is permissible).
  • History of hypersensitivity to durvalumab, tremelimumab or any excipient.
  • History of (non-infectious) pneumonitis that required steroids; or evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of treatment on this protocol, with the exceptions of: * Intranasal and inhaled corticosteroids * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent * Premedication for hypersensitivity reactions (e.g. to computed tomography [CT] contrast for scans).
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. TB, HIV, hepatitis B, and hepatitis C testing should be performed =< 28 days (4 weeks) prior to study registration.
  • Subjects with uncontrolled seizures.
  • Female subjects who are pregnant or breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period.
  • Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria * Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician. * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the study physician.
  • Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of investigational product (IP). * Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a magnetic resonance imaging (MRI) (preferred) or CT each preferably with IV contrast of the brain prior to study entry or brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases; and stable and off steroids and anti-convulsants for at least 14-28 days prior to start of study treatment). Following radiotherapy and/or surgery of the brain metastases patients must wait 4 weeks following the intervention to confirm stability.

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Jeffrey A. Meyerhardt
Email: jmeyerhardt@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Jeffrey A. Meyerhardt
Email: jmeyerhardt@partners.org
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Theodore Sunki Hong
Phone: 617-726-6050
Email: tshong1@partners.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) by irRECIST (Immune-Related Response Evaluation Criteria in Solid Tumors) of administering durvalumab and tremelimumab with radiation therapy to patients with hepatocellular carcinoma or biliary tract cancer.

SECONDARY OBJECTIVES:

I. To describe the toxicity profile of administering durvalumab and tremelimumab with radiation therapy to patients with hepatocellular carcinoma or biliary tract cancer.

II. To estimate the overall survival (OS) in patients with hepatocellular carcinoma treated with a combination of durvalumab, tremelimumab, and radiation therapy.

III. To estimate the progression-free survival (PFS) in patients with hepatocellular carcinoma treated with a combination of durvalumab, tremelimumab, and radiation therapy.

IV. To estimate the disease control rate (DCR) in patients with hepatocellular carcinoma tract cancer treated with a combination of durvalumab, tremelimumab, and radiation therapy.

V. To estimate duration of response (DOR) in patients with hepatocellular carcinoma treated with a combination of durvalumab, tremelimumab, and radiation therapy.

VI. To estimate the time to disease progression (TTP) in patients with hepatocellular carcinoma treated with a combination of durvalumab, tremelimumab, and radiation therapy.

EXPLORATORY OBJECTIVES:

I. To explore the efficacy of durvalumab and tremelimumab in combination with radiation therapy in patients with metastatic biliary tract cancer.

OUTLINE:

Participants receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 4 courses the absence of disease progression or unacceptable toxicity. Participants also undergo radiation therapy for 3 fractions within 4 business days or up to 2 weeks during course 2. After completion of course 4, participants may continue receiving durvalumab at the discretion of the treating physician every 28 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 and 60 days, at 3, 6, 9, 12, and 18 months, and then every 6 months until 3 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Theodore Sunki Hong

Trial IDs

Primary ID 17-517
Secondary IDs NCI-2018-01193
Clinicaltrials.gov ID NCT03482102