Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Atezolizumab

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Tremelimumab

Antineoplastic Agents, Immunological

Cohort 1/Dose Level A1 Durvalumab + 8 Gray (Gy) in 1 fraction

Cohort 2/Dose Level A2 Durvalumab +5 Gy in 5 fractions

Cohort 3/Dose Level B1 (was removed with Amendment A) Tremelimumab + 8 Gy in 1 fraction

Cohort 4/Dose Level B2 (was removed with Amendment A) Tremelimumab + 5 Gy in 5 fractions

Cohort C/ Dose Level C1 Durvalumab +Tremelimumab + 8 Gy in 1 fraction

Cohort C/Dose Level C2 Durvalumab +Tremelimumab +5 Gy in 5 fractions

10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Sterostatic body radiation therapy (SBRT)

Tim F Greten, M.D.

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.

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).

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

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

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 who survived at least 6 months after therapy.

Amount of time participants survived after therapy.

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.

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.

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.

National Cancer Institute (NCI)

Principal Investigator

One patient did not get treated in Cohort 2/Dose Level A2 and Cohort C/Dose Level C2.

Cohort 1/Dose Level A1 Durvalumab + 8 Gray (Gy) in 1 fraction

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Durvalumab + 8 Gray (Gy) in 1 Fraction

Cohort 2/Dose Level A2 Durvalumab +5 Gy in 5 fractions

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Durvalumab +5 Gy in 5 Fractions

Cohort C/ Dose Level C1 Durvalumab +Tremelimumab + 8 Gy in 1 fraction

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Tremelimumab: 75 mg IV, every 4 weeks for 16 weeks

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Durvalumab +Tremelimumab + 8 Gy in 1 Fraction

Cohort C/Dose Level C2 Durvalumab +Tremelimumab +5 Gy in 5 fractions

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Tremelimumab: 75 mg IV, every 4 weeks for 16 weeks

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Durvalumab +Tremelimumab +5 Gy in 5 Fractions

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Tim Greten

Grade 1 Abdominal pain

Grade 1 Alanine aminotransferase increased

Grade 1 Alkaline Phosphatase increased

Grade 1 Anemia

Grade 1 Anorexia

Grade 1 Atrial fibrillation

Grade 1 Aspartate aminotransferase increased

Grade 1 Back pain

Grade 1 Blood bilirubin increased

Grade 1 Cough

Grade 1 Creatinine increased

Grade 1 Diarrhea

Grade 1 Dizziness

Grade 1 Dry mouth

Grade 1 Dysgeusia

Grade 1 Endocrine disorders,Other, Elevated T3, T4

Grade 1 Eye disorders - decr. in near vision,bilat

Grade 1 - Fatigue

Grade 1 Fever

Grade 1 Headache

Grade 1 Hemorrhoidal hemorrhage

Grade 1 Hoarseness

Grade 1 Hyperglycemia

Grade 1 - Hyperkalemia

Grade 1 Hyperuricemia

Grade 1 Hypoalbuminemia

Grade 1 Hypocalcemia

Grade 1 - Hyponatremia

Grade 1 Hypothyroidism

Grade 1 Infusion related reaction

Grade 1 Lymphocyte count decreased

Grade 1 Mucositis

Grade 1 Musculoskeletal & connective tissue

Grade 1 Nausea

Grade 1 Neutrophil count decreased

Grade 1 Pain

Grade 1 Platelet count decreased

Grade 1 Pruritis

Grade 1 Rash maculo-papular

Grade 1 Serum amylase increased

Grade 1 - Skin/subc tissue disorder - Night sweats

Grade 1 Skin/subc tissue disorder - Rash

Grade 1 Skin/subc tissue - Psoriasis

Grade 1 Skin/subc tissue disorder - Itching

Grade 1 Skin/subc tissue disorder-Skinpeeling hand

Grade 1 Vertigo

Grade 1 Vomiting

Grade 1 Weight loss

Grade 1 White blood cell decreased

Grade 2 Abdominal pain

Grade 2 Anemia

Grade 2 Anorexia

Grade 2 Autoimmune disorder

Grade 2 Diarrhea

Grade 2 Dysgeusia

Grade 2 Endocrine disorders - TSH elev-Hypothyroid

Grade 2 Fatigue

Grade 2 Fecal incontinence

Grade 2 Fever

Grade 2 Gastroesophageal reflux disease

Grade 2 Hyperglycemia

Grade 2 Hypoalbuminemia

Grade 2 Hypothyroidism

Grade 2 Hypophosphatemia

Grade 2 Infusion related reaction

Grade 2 Lymphocyte count decreased

Grade 2 Malaise

Grade 2 Nausea

Grade 2 Neutrophil count decreased

Grade 2 Platelet count decreased

Grade 2 Rash maculo-papular

Grade 2 Weight loss

Grade 2 White blood cell count

Grade 3 Anemia

Grade 3 Anorexia

Grade 3 Colitis

Grade 3 Dehydration

Grade 3 Diarrhea

Grade 3 Fatigue

Grade 3 Hyperthyroidism

Grade 3 Lymphocyte count decreased

Grade 3 Nausea

Grade 3 Serum amylase increased

Grade 3 Vomiting

Grade 4 Lymphocyte count decreased

Durvalumab + 8 Gray (Gy) in 1 fraction

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Cohort A Dose Level A1

Durvalumab +5 Gy in 5 fractions

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Cohort A Dose Level A2

Durvalumab +Tremelimumab + 8 Gy in 1 fraction

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Tremelimumab: 75 mg IV, every 4 weeks for 16 weeks

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Cohort C Dose Level C1

Durvalumab +Tremelimumab +5 Gy in 5 fractions

Durvalumab: 10 mg/kg, mg intravenous (IV), every two weeks, or 1500 mg, IV, every four weeks.

Tremelimumab: 75 mg IV, every 4 weeks for 16 weeks

Sterostatic body radiation therapy (SBRT): 8 Gray (Gy) x 1; 5Gy x 5

Cohort C Dose Level C2

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

The pharmacokinetic studies were not done since the company were not interested in this after the samples were collected

Plasma Pharmacokinetic (PK)

Percentage of Participants With 6-month Overall Survival

Overall Survival

Complete Response

Partial Response

Stable Disease

Progressive Disease

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)

Progression Free Survival (PFS)

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer	NCT02311361	Pancreatic Neop... Pancreatic Canc... Cancer of Pancr... Cancer of the P... Pancreas Cancer	Durvalumab Tremelimumab Sterostatic bod...	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer	NCT02311361	Pancreatic Neop... Pancreatic Canc... Cancer of Pancr... Cancer of the P... Pancreas Cancer	Durvalumab Tremelimumab Sterostatic bod...	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for sterostatic body radiation therapy (sbrt)