A Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer

By CCF Clinical Trials | June 13, 2018

Study Name
	A Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer
ClinicalTrials.gov Identifier (if applicable)
	NCT03482102
Clinical Trial Category (check all that apply)
	Beyond First Line Therapy Immunotherapy Radiation Therapy
Study Center
Institution Name
	Massachusetts General Hospital
Institution Address
	55 Fruit Street
City
	Boston
State
	Massachusetts
Zip Code
	02114
List additional Institutions (include address, phone number, and website)
	This study is also being conducted at Dana Farber Cancer Institute (DFCI)/Brigham & Women’s Hospital (BWH).
Study Contacts
Principal Investigator
	Theodore S. Hong, MD
P.I. Phone
	(617) 726-6050
P.I. Email
	TSHONG1@mgh.harvard.edu
List additional Principal Investigators (include phone number and email)
	This study is also being conducted at Dana Farber Cancer Institute/Brigham & Women’s Hospital. Site Principal Investigator: Jeffrey A. Meyerhardt, MD, MPH Phone: 617-632-6855 Email: Jeffrey_Meyerhardt@dfci.harvard.edu
Study Coordinator
	Leilana Ly
Study Coordinator Phone
	(617) 726-8114
Study Coordinator Email
	LLY2@mgh.harvard.edu
List additional Study Coordinators (include phone number and email)
	Tarin (Grillo) Norkum Phone: 617-724-3661 Email: TGRILLO@partners.org
OVERVIEW – in layman’s terms (150 words max)
	This is a phase II study of the combination of 2 immunotherapy drugs (durvalumab and tremelimumab) with radiation therapy in patients with hepatocellular carcinoma (HCC) with an exploratory cohort of patients with metastatic biliary tract cancer (BTC).
Enrollment
	55 patients with Hepatocellular Carcinoma (HCC) and 15 patients with Biliary Tract Cancer (BTC)
Study Start Date
	05/09/2018
Estimated Completion Date
	10/1/2026
Purpose of the Study – in Layman’s Terms (use the “+” to add more list items)
	The primary objective is to evaluate the overall response rate (ORR) by irRECIST (Response Evaluation Criteria in Solid Tumors) of administering durvalumab and tremelimumab with radiation therapy to patients with hepatocellular carcinoma or biliary tract cancer. The exploratory objective is to explore the efficacy of durvalumab and tremelimumab in combination with radiation therapy in patients with metastatic biliary tract cancer.
Inclusion Criteria – Patients Must:
	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: (1) sorafenib for HCC patients, (2) second line treatment and beyond for cholangiocarcinoma patients, or (3) gemcitabine-based chemotherapy for biliary tract cancer patients 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. 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 <2000 IU/mL). Patients with concomitant 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 ANC >/= 1.5 x 10^9/L Platelet count >/= 75 x 10^9/L Serum bilirubin </=2.0 x the upper limit of normal (ULN). ALT and AST </= 3 x institutional ULN Albumin > 2.8 g/dL 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 – Patients Must NOT:
	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: (1) intranasal and inhaled corticosteroids; (2) systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; and (3) premedication for hypersensitivity reactions (e.g. to CT contrast for scans) 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 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.
REQUIRED TESTS PRIOR TO BEGINNING STUDY TREATMENT – in layman’s terms
	A medical history, which includes questions about your health, demographics, current medications, and any allergies. Physical exam, which includes measurements of your vital signs, height, and weight. Performance status, which evaluates how you are able to carry on with your usual activities. Blood tests, 6 teaspoons of blood will be taken for clinical purposes. Urine test, for clinical purposes Electrocardiogram (ECG), which measures your heart’s electrical activity An assessment of your tumor by one or more of the following standard assessment tools: CT (Computerized Tomography) scan or MRI (Magnetic Resonance Imaging).
POTENTIAL SIDE-EFFECTS – in layman’s terms
	Fatigue, which may be serious Nausea, which may be serious requiring medical intervention Diarrhea, which may be serious requiring medical intervention Decreased/loss of appetite Itchiness Rash Vomiting, which may be serious requiring medical intervention Low thyroid function, which can be serious or life threatening. This may cause fatigue, weight gain, fluid retention, sensitivity to cold, and mental apathy. Joint pain, which may be serious Abnormally high levels of enzymes produced by the liver, meaning that your liver is not functioning properly. This may cause faigue and jaundice (yellowing of the skin and eyes). Although this is usually mild and reversible, this can be serious or life threatening. Muscle pain Difficulty breathing or shortness of breath, which may be serious requiring medical intervention Fever, which may be serious requiring medical intervention Cough Low red blood cell count, which can cause tiredness and shortness of breath. This may require a blood transfusion. High thyroid function, which may require medical intervention to resolve symptoms. This may cause weight loss, rapid heartbeat, sweating, trouble with heat, and nervousness. Weakness Fluid in the space surrounding the lung, which can cause shortness of breath. If severe, it may require hospitalization and treatment. Inflammation of the lung (pneumonitis), which can cause shortness of breath and difficulty breathing. Lung infection, which can be life threatening Inflammation of the large intestine (colitis) and the tube leading to the large intestine, which can lead to abdominal pain, diarrhea, and digestive problems. It can be life threatening or fatal. Blockage in the small intestine, which can lead to abdominal pain, constipation, and digestive problems. Failure to produce hormones (hypopituitarism), which can affect body functions such as metabolism, bone and tissue growth, and urine production. Low white blood cell count, which leads to an increased risk of infection. Lack of muscle control during walking or picking up objects Dehydration, which may be serious requiring medical intervention Sudden decrease in kidney function, which may cause swelling in your ankles, vomiting, weakness, poor sleep, and shortness of breath. Elevated level of glucose (sugar) in your blood, which can require hospitalization and urgent treatment (such as with diabetes). Central nervous system inflammation, which can cause irritation and swelling of brain tissue or blood vessels and result in confusion, hallucinations, difficulty walking or using arms. Abnormal heart beat (arrhythmia) which can cause dizziness, fainting, shortness of breath, chest discomfort, weakness, and fatigue. Swelling of the tumor which can cause worsening of tumor related problems and symptoms. Bleeding in the upper portion of the gastrointestinal tract, which may cause abdominal cramps, dizziness, and shortness of breath. Constipation Abdominal pain or cramps, which may be serious requiring medical intervention Weight loss Headache Anemia is a condition in which your body does not have enough healthy red blood cells. Symptoms can include fatigue, lightheadedness, dizziness, and may require a transfusion. Fluid retention in the legs which may cause swelling Insomnia Back pain Pain in the extremities (arms, legs, wrists, ankles, shoulders, or neck) Dizziness Muscular pain in the chest Upper stomach pain Low levels of potassium in the blood, which can cause an abnormal heart rate. This could cause an irregular heartbeat, which can be serious and life threatening. Lung infection Clot/blockage of blood vessel in the lungs which may cause shortness of breath, chest pain, and cough. Confusion Sudden death caused by symptoms that might be consistent with decreased blood flow to the heart. Lack of oxygen to the brain due to suden and unexpected loss of heart function which may cause brain injury. Imbalance of essential minerals necessary for body function Respiratory failure, which may cause difficulty breathing, coughing up mucous, wheezing, rapid breathing, and fatigue. Irritation, redness, and discoloration of the skin in the radiation area Decreased blood counts, which may cause shortness of breath, dizziness, and fatigue. Low platelet count, which may cause an increase in your chance of bleeding (nosebleeds, bruising, stroke, and/or digestive system bleeding). You may need a platelet transfusion. Slow wound healing Indigestion, which may cause abdominal pain, bloating, nausea, and vomiting. Gastritis, which may cause heartburn, indigestion, nausea, and vomiting. Radiation esophagitis, which may cause inflammation, irritation, or swelling of the esophagus (the tube that leads from the back of the mouth to the stomach). Rib microfracture due to radiation, which may cause chest or back pain, and pain when coughing, sneezing, and moving. Damage to the liver which could result in inflammation and scarring oft he liver. This could lead to jaundice and possibly cirrhosis (a chronic condition where the liver functions poorly leading to fatigue, weakness, fluid retention in the abdomen, and other complications). Efforts to prevent extensive liver irradiation will be taken to minimize the chance of these side effects. Mucosal ulceration is an ulcer in the mucous membrane that lines various internal organs. Tissue damage due to radiation, which may require surgery and may be life-threatening. The stomach, kidneys, and bowel are well-protected from excessive radiation. Therefore injury to these organs is unlikely. However, overdosing the stomach or bowel can lead to ulceration or perforation. Pain, inflammation, or scarring of the kidneys, stomach, or bowel may rarely occur. Nerve damage which may cause numbness Spinal cord injury due to radiation, which may cause numbness. Rare development of second tumors due to radiation

Posted in Beyond First Line Therapy, Clinical Trial, Immunotherapy, Radiation