Ipilimumab and Gemcitabine Hydrochloride in Treating Patients With Stage III-IV or Recurrent Pancreatic Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of ipilimumab when given together with gemcitabine hydrochloride in treating patients with stage III-IV or recurrent pancreatic cancer that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or tumor-killing substances to them. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to kill tumor cells or stop them from growing. Giving monoclonal antibody therapy together with chemotherapy may kill more tumor cells.

Detailed Description
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OUTLINE: This is a dose-escalation study of ipilimumab. INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes in weeks 1, 4, 7, and 10, and gemcitabine hydrochloride IV over 30 minutes in weeks 1-7 and 9-11. MAINTENANCE: Beginning in week 22, patients receive ipilimumab IV over 90 minutes once every 12 weeks and gemcitabine hydrochloride IV over 30 minutes once weekly for 3 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response. After completion of study treatment, patients are followed up monthly for 6 months and then every 3 months.

Official Title
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Ipilimumab and Gemcitabine for Advanced Pancreas Cancer: A Phase Ib Study

Conditions
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Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
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* Biological: ipilimumab
* Drug: gemcitabine hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent Histologic or cytologic diagnosis of pancreas adenocarcinoma advanced or recurrent (stage III or IV) that is unresectable; histologic or cytologic pathology from any prior surgery is sufficient for diagnosis Must have measurable disease by modified WHO criteria White blood cells (WBC) >= 2000/uL Absolute neutrophil count (ANC) >= 1500/uL Platelets >= 100 x 10^3/uL Hemoglobin >= 9 g/dL (>= 80 g/L; may be transfused) Creatinine =< 2.0 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN Bilirubin =< 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL) No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C Performance status: Eastern Cooperative Oncology Group (ECOG) 0-1 Prior systemic therapy for advanced pancreas cancer with gemcitabine is prohibited; prior gemcitabine with radiotherapy for localized pancreas cancer is allowed provided disease is present outside of the radiated field; prior gemcitabine as adjuvant therapy to surgical resection is allowed provided 3 months or greater has elapsed between the last dose of gemcitabine and the detection of recurrent disease Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal; post-menopause is defined as: amenorrhea >= 12 consecutive months without another cause, or for women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >= 35 mIU/mL; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotrophin [HCG]) within 72 hours before the start of ipilimumab Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized Patients on stable anticoagulation are eligible for enrollment; for patients on warfarin, prothrombin time (PT)/international normalized ratio (INR) should be monitored every 2 weeks during induction therapy, monthly thereafter, or more frequent as clinically indicated Exclusion Criteria: Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis) Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab) A history of prior treatment with ipilimumab or prior tumor necrosis factor receptor superfamily, member 9 (CD137) agonist or cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitor or agonist Concomitant therapy with any of the following: interleukin (IL)2, interferon, or other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids WOCBP who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness Patients with symptoms of partial or complete bowel obstruction and recent (within 6 month) history of fistula, intra-abdominal abscess or bowel perforation Patients with a history or evidence of central nervous system (CNS) disease, including brain tumor, seizures not controlled with standard medical therapy or any brain metastases Patients currently receiving radiation therapy or those having received radiation within 4 weeks of study entry Patients with any known active infection or known history of tuberculosis

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (monoclonal antibody, chemotherapy)<br>INDUCTION: Patients receive ipilimumab IV over 90 minutes in weeks 1, 4, 7, and 10 and gemcitabine hydrochloride IV over 30 minutes in weeks 1-7 and 9-11. MAINTENANCE: Beginning in week 22, patients receive ipilimumab IV over 90 minutes once every 12 weeks and gemcitabine hydrochloride IV over 30 minutes once weekly for 3 weeks. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response. | Biological: ipilimumab<br>* Given IV<br>* Other names: monoclonal antibody CTLA-4;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicities (DLTs) Seen in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination in Order to Define the Maximum Tolerated Dose (MTD) | Dose limiting toxicity (DLT) will be monitored by calculating the Bayesian predictive probability of a DLT given the data to date. All toxicities will be summarized in a descriptive manner as to type, frequency, attribution and timing by dose level. Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 where grading is as follows: Mild (grade 1) Moderate (grade 2) Severe (grade 3) Life-threatening (grade 4) Fatal (grade 5) In general a DLT will be defined as any any of the following drug-related toxicities: Febrile neutropenia with grade 3/4 neutropenia Asymptomatic grade 4 neutropenia more than 7 days Grade 3 thrombocytopenia with grade 3-4 hemorrhage or grade 4 thrombocytopenia Non-hematologic toxicity grade 3 or 4 (with some protocol specified exceptions) DLTs will be used to determine the MTD for the expansion cohort of the study. *AST = Aspartate transamina | During the 12 weeks of Induction Therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate Using Immune-related Response Criteria (irRC) in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination | Response will be assessed using CT of MRI scans immune-related response criteria (irRC). The sum of all the products of diameters (SPD) at tumor assessment using the irRC for progressive disease incorporates the contribution of new measurable lesions. Each net percentage change in tumor burden per assessment using irRC accounts for the size and growth kinetics of both old and new lesions as they appear. irComplete Response (irCR)-Complete disappearance of all index lesions. irPartial Response (irPR)-Decrease of 50% or greater in the sum of products of the two largest perpendicular diameters of all index and all new measurable lesions (i.e., percentage change in tumor burden) irStable Disease (irSD)-does not meet criteria for irCR or ir PR, in the absence of progressive disease. irProgressive Disease (irPD)-At least 25% increase in the percentage change in tumor burden (i.e., taking sum of all the products of all the index lesions and any new lesions) when compared to SPD at nadir. | Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10 | 
| Time to Progression Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination Who Progress While on Treatment | Time to Progression will be defined as the time from treatment initiation until the first documentation of progression as calculated by irRC in patients who show progression. Progression will be defined as at least a 25% increase percentage change in tumor burden (i.e., taking the sum of all the products of all index lesions and any new lesions) when compared to sum of all the products of diameters (SPD) at nadir. | Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10 | 
| Progression Free Survival (PFS) in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination | Median Progression Free Survival (mPFS) was estimated using a Kaplan-Meier curve with 0 censored patients. PFS is defined from the time of treatment initiation until the first documentation of progressive disease. Any patient without the event at the time of analysis will be censored from the last documented contact. | Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10 | 
| Overall Survival (OS) in Patients With Pancreas Adenocarcinoma Treated With Ipilimumab and Gemcitabine Combination | Overall Survival (OS) was estimated using a kaplan-meier curve with 0 patients censored. OS is defined from the time of treatment initiation until the time of death from any cause. Any patient without the event at the time of analysis will be censored from the last documented contact. | Every 12 weeks during treatment with a 12 week induction and then 28 day maintenance cycles. Range of cycles completed (including induction cycle) 0-10 | 
| Recovery of Tumor Immune Surveillance: T-cell Response to Defined Pancreatic Cancer Tumor Antigens | Optional blood draws to analyze the inflammatory T cell function before, during and after treatment. | Prior to ipilimumab infusion at weeks 1, 4, 7, and 10, and then every 12 weeks starting at week 13 where range of cycles including induction cycle was 0-10 (Induction cycle = 12 weeks, maintenance cycle = 28 days) |