A Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer
A Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer
This research study is studying a combination of drugs as a possible treatment for Hepatocellular Carcinoma or Biliary Tract Cancer.
The interventions involved in this study are:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drugs work in treating a specific disease. "Investigational" means that the drugs are being studied.
The FDA (the U.S. Food and Drug Administration) has not approved durvalumab for this specific disease but it has been approved for other uses.
The FDA has not approved tremelimumab as a treatment for any disease.
Both durvalumab and tremelimumab are antibodies (proteins that work with the immune system) that target proteins produced by the cancer cells. These cancerous proteins suppress the immune system which allows the cancer cells to grow. The study drugs may target these cancerous proteins and stop the cancer cells from suppressing the immune system.
The investigators hope that the combination of these study drugs with radiation therapy will help stop the cancer cells from growing and spreading.
**After activation of a protocol amendment on July 14, 2022, only participants with biliary tract cancer will be permitted to enroll.**
Inclusion Criteria:
Histologically or cytologically confirmed hepatocellular carcinoma or biliary tract cancer
Locally advanced/unresectable or metastatic disease
Age ≥ 18 years at time of study entry
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-naïve
Progressed on, be intolerant of, or refused sorafenib [for HCC], second line treatment and beyond for cholangiocarcinoma or gemcitabine-based chemotherapy for biliary tract cancer
The benefits of sorafenib have been discussed with the patient and the patient has refused treatment with sorafenib.
Viral status (Hepatitis B and C) must be known. All HBV-positive patients must be on antiviral medication for viral suppression.
Body weight ≥ 30 kg
Child-Pugh Score of A. A score of B7 is allowed without severe ascites or without hepatic encephalopathy.
Adequate organ and marrow function, defined as:
Males:
--Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
Females:
--Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)
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
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 Fredericia'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
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive 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.
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 NCI 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 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 an 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.