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

Phase 1

Completed

Conditions: Pancreatic Neoplasms
Cancer of Pancreas
Pancreatic Cancer
Pancreas Cancer
Cancer of the Pancreas

Interventions: Biological: Tremelimumab
Biological: Durvalumab
Radiation: Sterostatic body radiation therapy (SBRT)

Registration Number: NCT02311361

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 65

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Tremelimumab + 5 Gy in 5 fractions	Tremelimumab	Cohort 4/Dose Level B2 (was removed with Amendment A) Tremelimumab + 5 Gy in 5 fractions
Tremelimumab + 5 Gy in 5 fractions	Sterostatic body radiation therapy (SBRT)	Cohort 4/Dose Level B2 (was removed with Amendment A) Tremelimumab + 5 Gy in 5 fractions
Durvalumab +Tremelimumab + 8 Gy in 1 fraction	Tremelimumab	Cohort C/ Dose Level C1 Durvalumab +Tremelimumab + 8 Gy in 1 fraction
Durvalumab + 8 Gray (Gy) in 1 fraction	Sterostatic body radiation therapy (SBRT)	Cohort 1/Dose Level A1 Durvalumab + 8 Gray (Gy) in 1 fraction
Durvalumab +5 Gy in 5 fractions	Durvalumab	Cohort 2/Dose Level A2 Durvalumab +5 Gy in 5 fractions
Durvalumab +5 Gy in 5 fractions	Sterostatic body radiation therapy (SBRT)	Cohort 2/Dose Level A2 Durvalumab +5 Gy in 5 fractions
Durvalumab +Tremelimumab +5 Gy in 5 fractions	Tremelimumab	Cohort C/Dose Level C2 Durvalumab +Tremelimumab +5 Gy in 5 fractions
Durvalumab +Tremelimumab +5 Gy in 5 fractions	Sterostatic body radiation therapy (SBRT)	Cohort C/Dose Level C2 Durvalumab +Tremelimumab +5 Gy in 5 fractions
Tremelimumab + 8 Gy in 1 fraction	Tremelimumab	Cohort 3/Dose Level B1 (was removed with Amendment A) Tremelimumab + 8 Gy in 1 fraction
Tremelimumab + 8 Gy in 1 fraction	Sterostatic body radiation therapy (SBRT)	Cohort 3/Dose Level B1 (was removed with Amendment A) Tremelimumab + 8 Gy in 1 fraction
Durvalumab +Tremelimumab + 8 Gy in 1 fraction	Durvalumab	Cohort C/ Dose Level C1 Durvalumab +Tremelimumab + 8 Gy in 1 fraction
Durvalumab +Tremelimumab +5 Gy in 5 fractions	Durvalumab	Cohort C/Dose Level C2 Durvalumab +Tremelimumab +5 Gy in 5 fractions
Durvalumab + 8 Gray (Gy) in 1 fraction	Durvalumab	Cohort 1/Dose Level A1 Durvalumab + 8 Gray (Gy) in 1 fraction
Durvalumab +Tremelimumab + 8 Gy in 1 fraction	Sterostatic body radiation therapy (SBRT)	Cohort C/ Dose Level C1 Durvalumab +Tremelimumab + 8 Gy in 1 fraction

Primary Outcome Measures

Name	Time	Method
Number of Adverse Events in Each Cohort With Grade 1 Through 5 Related to Study Drug	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.	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.

Secondary Outcome Measures

Name	Time	Method
Plasma Pharmacokinetic (PK)	30 days after treatment	Drug level in blood
Percentage of Participants With 6-month Overall Survival	6 month	Participants who survived at least 6 months after therapy.
Overall Survival	From study entry to death or date of last contact, whichever occurs first, up to 2 years of follow-up	Amount of time participants survived after therapy.
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)	At screening then every 8 weeks until disease progression or patient is taken off the trial, whichever comes first, approximately 6 months.	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.
Progression Free Survival (PFS)	From study entry to disease progression, death or date of last contact, whichever occurs first, an average of 6 months	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.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	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	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.