Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Study Overview
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Brief Summary
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Background: - Stereotactic body radiation therapy (SBRT) is used to treat cancer. It is a way of giving very focused beams of radiation to tumors. Researchers think that the drugs being used in this study might work better when combined with SBRT in people with pancreatic cancer. Objective: - To study the safety and effectiveness of Durvalumab (MEDI4736) and/or tremelimumab with SBRT. Eligibility: - People 18 and older who have pancreatic cancer that has not responded or to chemotherapy. They must be candidates for radiation but not resection. Design: Participants will be screened with medical history and physical exam. They will have blood tests. Their tumor will be measured using computerized tomography (CT) or magnetic resonance imaging (MRI). Participants will have their tumor biopsied with a needle. They will have also have a biopsy after cycle 1. Participants will get 1 or 2 drugs in combination with the SBRT. For MEDI4736, the duration of each cycle will be 28-days. Participants will get the drug through an intravenous (IV) infusion twice in each cycle (Days 1 and 15). For tremelimumab, the duration of the first 6 cycles will each last 28 days. Then the duration of the last 3 cycles will change to 12 weeks. Participants will get the drug through an IV once in each cycle. All participants will have SBRT. Some will get 1 dose of radiation and some will get 5. CT scans will map their tumor. Participants will have medical history, physical exam, and blood tests in each cycle. They will have a CT scan or MRI every 8 weeks. Cycles will continue for up to 12 months. Participants will be contacted yearly for follow-up.

Detailed Description
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Background: Tremelimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Anti-CTLA4 therapy has been shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T cells. Durvalumab is a human monoclonal antibody directed against Programmed death-ligand 1 (PD-L1). Blockage of ligation between PD-L1 and Programmed cell death protein 1 (PD1) induces local immune activation and prevent anergy and exhaustion of effectors T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of Immune Checkpoint inhibitor (Durvalumab with or without Tremelimumab) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Objective: To determine the safety, tolerability and feasibility of immune checkpoint inhibition [comprising either Durvalumab alone, or combined Durvalumab and Tremelimumab] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Eligibility: Histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) with at least 1 measurable metastatic lesion by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and accessible for biopsy. There is no limit to the number of prior chemotherapy regimens received. Patients must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG)) less than or equal to 1 Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery within the last 2 weeks prior to entering the study. For recent experimental therapies a 28 day period of time must have elapsed before commencing protocol treatment. No active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years prior to the start of treatment. No active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. No active or history of systemic lupus erythematosus, Wegeners granulomatosis. Design: Subjects will be assigned to 4 arms Anti-PDL1 (Durvalumab) in combination with radiation (8 Gray (Gy) in fraction) - Anti-PDL1 (Durvalumab) in combination with radiation (5 Gy in 5 fractions) Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (8 Gy in 1 fractions) - Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (5 Gy in 5 fractions).

Official Title
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A Pilot Study of Immune Checkpoint Inhibition (Durvalumab With or Without Tremelimumab) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Conditions
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Pancreatic Neoplasms, Pancreatic Cancer, Cancer of Pancreas, Cancer of the Pancreas, Pancreas Cancer

Intervention / Treatment
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* Biological: Durvalumab
* Biological: Tremelimumab
* Radiation: Sterostatic body radiation therapy (SBRT)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histopathological confirmation of pancreatic adenocarcinoma prior to entering this study by the Laboratory of Pathology of the National Cancer Institute (NCI) to entering this study by the Laboratory of Pathology of the NCI prior to entering this study Patients must have disease that is not amenable to potentially curative resection. Primary in-situ (or locally-recurrent) tumor must be present and, in the opinion of radiation oncology, be amenable to radiation therapy as planned in the protocol. Each case will be discussed at GI tumor board with multidisciplinary team. Patients must have at least 1 measurable metastatic lesion by Response Evaluation in Solid Tumors (RECIST) 1.1 criteria. There is no limit to the number of prior chemotherapy regimens received. Patients must have received at least one line of prior systemic chemotherapy for advanced unresectable and/or metastatic disease. Age greater than or equal to 18 years Life expectancy of greater than 3 months. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Patients must have normal organ and marrow function as defined below: absolute neutrophil count - > 1,000/mcL Platelets - greater than or equal to 100,000/mcL total bilirubin - Bili should be less than or equal to 2 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin less than 3.0 mg/dL) serum albumin - greater than or equal 2.5 g/dL Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransaminase (AST) up to 3 x ULN. (up to 5 x ULN if liver metastases present) --Creatinine - < 2X institution upper limit of normal OR --creatinine clearance - >45 mL/min/1.73 m(2), for patients with creatinine levels above institutional normal Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline. Patient must be able to understand and willing to sign a written informed consent document. EXCLUSION CRITERIA: Malignant ascites that is clinically detectable by physical examination or is symptomatic. Evidence of radiographic ascites that is not clinically significant will not be an exclusion criterion. Any prior Grade greater than or equal to 3 imAE while receiving immunotherapy, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment, or any unresolved imAE > Grade 1. Note: Active or history of vitiligo will not be a basis for exclusion. Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery within the last 2 weeks prior to entering the study. Note: Local surgeries for isolated lesions for palliative intent are acceptable. For recent experimental therapies a 28 day period of time must have elapsed before commencing protocol treatment. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events from Durvalumab (MEDI4736) or tremelimumab, or compromise the ability of the subject to give written informed consent. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: Subjects with vitiligo or alopecia Requirement for intermittent use of bronchodilators or local steroid injections Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, or psoriasis not requiring systemic treatment History of primary immunodeficiency or history of active tuberculosis. Note: Latent tuberculosis will not be a basis for exclusion. Diverticulitis (either active or history of) within the past 2 years. Note that diverticulosis is permitted. Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol. True positive test results for hepatitis A (Immunoglobulin M (IgM) positive). Subjects with a history of hepatitis A with Immunoglobulin G (IgG) blood test are not excluded. True positive test results hepatitis B, or C infection. Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegeners granulomatosis. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 and tremelimumab. The following are exceptions to this criterion: Intranasal, inhaled, and topical steroids Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent Steroids as premedication for hypersensitivity reactions (eg, computed tomography (CT) scan premedication) History of sarcoidosis syndrome. Patients should not be vaccinated with live attenuated vaccines within 1 month of starting Tremelimumab and MEDI4736 treatment. Subjects, if enrolled, should not receive live vaccine during the study and 180 days after the last dose of both drugs. Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and Tremelimumab or MEDI4736. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that Tremelimumab or MEDI4736 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events. History of hypersensitivity reaction to human or mouse antibody products. Pregnancy and breast feeding are exclusion factors. The effects of Tremelimumab and MEDI4736 on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 180 days (female patients) or 90 days (male patients) after the end of the treatment. In addition male patients must refrain from sperm donation for 90 days after the final dose of investigational product. Female patients must refrain from egg cell donation for 180 days after the final dose of investigational product. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab + 8 Gray (Gy) in 1 fraction<br>Cohort 1/Dose Level A1 Durvalumab + 8 Gray (Gy) in 1 fraction | Biological: Durvalumab<br>* 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.<br>* Other names: MEDI4736;Radiation: Sterostatic body radiation therapy (SBRT)<br>* 8 Gray (Gy) x 1; 5Gy x 5<br>* Other names: Sterostatic ablative radiotherapy;|
| Experimental: Durvalumab +5 Gy in 5 fractions<br>Cohort 2/Dose Level A2 Durvalumab +5 Gy in 5 fractions | Biological: Durvalumab<br>* 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.<br>* Other names: MEDI4736;Radiation: Sterostatic body radiation therapy (SBRT)<br>* 8 Gray (Gy) x 1; 5Gy x 5<br>* Other names: Sterostatic ablative radiotherapy;|
| Experimental: Tremelimumab + 8 Gy in 1 fraction<br>Cohort 3/Dose Level B1 (was removed with Amendment A) Tremelimumab + 8 Gy in 1 fraction | Biological: Tremelimumab<br>* 75 mg IV, every 4 weeks for 16 weeks<br>* Other names: Ticilmumab;Radiation: Sterostatic body radiation therapy (SBRT)<br>* 8 Gray (Gy) x 1; 5Gy x 5<br>* Other names: Sterostatic ablative radiotherapy;|
| Experimental: Tremelimumab + 5 Gy in 5 fractions<br>Cohort 4/Dose Level B2 (was removed with Amendment A) Tremelimumab + 5 Gy in 5 fractions | Biological: Tremelimumab<br>* 75 mg IV, every 4 weeks for 16 weeks<br>* Other names: Ticilmumab;Radiation: Sterostatic body radiation therapy (SBRT)<br>* 8 Gray (Gy) x 1; 5Gy x 5<br>* Other names: Sterostatic ablative radiotherapy;|
| Experimental: Durvalumab +Tremelimumab + 8 Gy in 1 fraction<br>Cohort C/ Dose Level C1 Durvalumab +Tremelimumab + 8 Gy in 1 fraction | Biological: Durvalumab<br>* 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.<br>* Other names: MEDI4736;Biological: Tremelimumab<br>* 75 mg IV, every 4 weeks for 16 weeks<br>* Other names: Ticilmumab;Radiation: Sterostatic body radiation therapy (SBRT)<br>* 8 Gray (Gy) x 1; 5Gy x 5<br>* Other names: Sterostatic ablative radiotherapy;|
| Experimental: Durvalumab +Tremelimumab +5 Gy in 5 fractions<br>Cohort C/Dose Level C2 Durvalumab +Tremelimumab +5 Gy in 5 fractions | Biological: Durvalumab<br>* 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.<br>* Other names: MEDI4736;Biological: Tremelimumab<br>* 75 mg IV, every 4 weeks for 16 weeks<br>* Other names: Ticilmumab;Radiation: Sterostatic body radiation therapy (SBRT)<br>* 8 Gray (Gy) x 1; 5Gy x 5<br>* Other names: Sterostatic ablative radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events in Each Cohort With Grade 1 Through 5 Related to Study Drug | Adverse Events (AEs) are reported by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1=Mild, Grade 2= Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Fatal. | Participants were assessed from the start of study treatment at Cycle 1 then after every cycle (1 cycle = 28 days) of protocol treatment until 30 days after they were taken off treatment, approximately 4.0 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetic (PK) | Drug level in blood | 30 days after treatment | 
| Percentage of Participants With 6-month Overall Survival | Participants who survived at least 6 months after therapy. | 6 month | 
| Overall Survival | Amount of time participants survived after therapy. | From study entry to death or date of last contact, whichever occurs first, up to 2 years of follow-up | 
| Tumor Response Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Measured by Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) | Progressive disease (PD): >=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): >=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. | At screening then every 8 weeks until disease progression or patient is taken off the trial, whichever comes first, approximately 6 months. | 
| Progression Free Survival (PFS) | PFS is the defined as the median amount of time subject survives without disease progression after treatment. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). NOTE: While RECIST Progressive Disease (PD) will be noted and recorded the immune-related (IR) RECIST criteria will be applied to determine discontinuation of study treatment. For modified Immune-Related Response Criteria (irRC), only target and measurable lesions are taken into account. | From study entry to disease progression, death or date of last contact, whichever occurs first, an average of 6 months | 
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 18 months and 4 days for Cohort 1/Dose Level A1, 23 months and 29 days for Cohort 2/Dose Level A2, 32 months and 19 days for Cohort C/Dose Level C1, and 44 months and 18 days for Cohort C/Dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-PDL1, Anti-CTLA4, Streostatic Body Radiation Therapy (SBRT), Monoclonal Antibody, Antitumor Immunity