Ibrutinib Combined With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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Gemcitabine and nab-paclitaxel is a standard regimen (NCCN, Category 1) for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). However, further improvement in treatment is needed. Increasingly, the nature of the immune infiltrate in PDAC appears to be tumor promoting. In preclinical studies, ibrutinib treatment, presumably by reprogramming B cells, results in increased CD8+ T cells to assist in tumor control. Preclinical studies of ibrutinib plus gemcitabine show superior antitumor effects compared to gemcitabine alone in both orthotopic murine pancreatic cancer cell line grafts and in genetically engineered mouse models. Thus, the investigators propose a clinical trial of ibrutinib plus the standard gemcitabine based regimen of gemcitabine and nab-paclitaxel, evaluating safety, then efficacy and including correlative studies.

Detailed Description
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Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related mortality in the United States, with an estimated 39,950 deaths attributable to PDAC in 2014 (http://seer.cancer.gov/statfacts/html/pancreas.html). Over 90% of patients have inoperable disease at presentation, at which point systemic therapy becomes the primary form of treatment. Treating PDAC has been challenging and few approved drugs are available. Recently, however, some breakthroughs have occurred, raising hope that this aggressive disease can be better controlled. FOLFIRINOX, a combination of 5FU, oxaliplatin, and irinotecan, has been found to be substantially superior to treatment of gemcitabine alone in patients with metastatic disease and good performance status. Similarly, gemcitabine and nab-paclitaxel, a regimen with less non-hematologic toxicity, demonstrated improved overall survival and progression-free survival compared to gemcitabine alone. Both of these combinations or modifications of these combinations are now front line options for patients with good performance status. Furthermore, these improvements in survival, however incremental, now afford patients with pancreatic cancer time to participate in and possibly benefit from clinical trials of novel therapeutics.

Official Title
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A Study of the Safety, Immunopharmacodynamics and Anti-tumor Activity of Ibrutinib Combined With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Adenocarcinoma

Conditions
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Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Paclitaxel
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma Stage IV disease (measurable disease NOT required) Intact primary tumor CA19-9 greater than 75 units Eastern Cooperative Oncology Group (ECOG) performance score of 0-1 At least 18 years of age Female patients who are not of child-bearing potential, and fertile female patients of child-bearing potential, who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of randomization. Fertile male patients willing to use adequate contraceptive measures. Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1500/microliter (uL) platelet count ≥ 100,000/uL hemoglobin ≥ 9.0 g/dL Adequate hepatic function: Total bilirubin ≤ 1.5 X ULN (unless bilirubin rise due to Gilbert's syndrome) Aspartate amino transferase (AST) (SGOT) ≤ 3.0 X ULN; ≤5.0X ULN if liver metastases are present. Alanine aminotransferase (ALT) (SGPT) ≤ 3.0 X ULN; ≤0 5.0X ULN if liver metastases are present. Adequate renal function (defined as serum creatinine ≤ 1.5 X ULN) Ability to understand the nature of this study protocol, comply with study and/or follow-up procedures, and give written informed consent Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Exclusion Criteria: Any prior systemic or investigational therapy for metastatic pancreatic cancer. Systemic therapy administered alone or in combination with radiation in the adjuvant or neoadjuvant setting is permissible as long as it was completed > 6 months prior to the time of study registration. History of other diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that, in the opinion of the investigator, renders the subject at high risk from treatment complications or might affect the interpretation of the results of the study. History of previous malignancy (except basal cell) within 5 years. Life expectancy of <3 months. Inability to undergo two sequential Endoscopic Ultrasound (EUS)-directed core biopsies of the primary tumor. Presence of known central nervous system or brain metastases. Known human immunodeficiency virus (HIV) infection. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. Known bleeding disorders (e.g., von Willebrand's disease or hemophilia). Patients receiving warfarin or other Vitamin K antagonists. However, if therapeutic anticoagulation is necessary, low molecular weight heparin (LMWH) is the anticoagulant of choice. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization. Current peripheral sensory neuropathy > Grade 1 Major surgery within 4 weeks of the start of study treatment (defined as those surgeries that require general anesthesia. Insertion of a vascular access device is NOT considered major surgery. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor. Unable to swallow capsules or has malabsorption syndrome, disease significantly affecting gastrointestinal function or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation for safety and toxicity<br>All patients in phase Ib dosing escalation with extended safety and toxicity cohorts will start treatment with daily dosing of ibrutinib concurrently with standard doses of gemcitabine and nab-paclitaxel. Ibrutinib (560 mg/day, 840 mg/day, or 420 and 280 mg/day if de-escalation is necessary) will be started on day 1. Approximately patients 15-30 will be enrolled in escalation and extended safety cohort. | Drug: Ibrutinib<br>* 560, 840, 420, or 280mg, orally once per day - 4 week cycle<br>* Other names: PCI-32765;Drug: Paclitaxel<br>* 125mg/m2 IV Day 1, 8, and 15 - 4 week cycle<br>* Other names: Abraxane, Taxol;Drug: Gemcitabine<br>* 1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle<br>* Other names: Gemzar;|
| Experimental: Immune Response cohort<br>Subjects who are assigned to the Immune Response Cohort will have a biopsy before starting ibrutinib-only therapy. They will then receive ibrutinib for 7 days and have a second biopsy after completing the ibrutinib-only therapy, before starting the combination of chemotherapy with ibrutinib. Approximately 20 patients will be enrolled in this arm. | Drug: Ibrutinib<br>* 560, 840, 420, or 280mg, orally once per day - 4 week cycle<br>* Other names: PCI-32765;Drug: Paclitaxel<br>* 125mg/m2 IV Day 1, 8, and 15 - 4 week cycle<br>* Other names: Abraxane, Taxol;Drug: Gemcitabine<br>* 1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced a Dose-Limiting Toxicity (DLT) | DLTs will be based on the first course of treatment and defined as any unexpected grade 3 non-hematologic toxicity not reversible to grade 2 or less within 96 hours, or any grade 4 toxicity. Grade 4 hematological toxicities will not be considered dose limiting in this trial since a significant fraction of patients who are treated with gemcitabine and nab-paclitaxel are expected to experience these toxicities. Grade 3 peripheral neuropathy, a common and expected toxicity of treatment with nabpaclitaxel, will not be considered a DLT. | Up to 2 years | 
| Maximum Tolerated Dose (MTD) | The dose level at which fewer than 2 of 6 patients experience a dose-limiting toxicity (DLT) will be designated as the Maximum Tolerated Dose (MTD) | Up to 2 years | 
| CA19-9 Clinical Response Rate | The CA19-9 Response Rate is calculated using CA 19-9 treated patients who had a baseline CA19-9 > 75 units who have confirmed CA19-9 reduction of 75% from baseline value. Patients who have missing CA19-9 measurements will be treated as non-responders, i.e., they will be included in the denominator when calculating the percentage. The CA19-9 Response Rate, along with exact 95% confidence intervals, will be reported for the study. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time-to-progression (TTP) | Time to Progression is defined as the time from date of first dose of protocol therapy to time of documented radiographic and/or clinical disease progression or death from any cause. Kaplan-Meier methods will be used to summarize median TTP with 95% confidence intervals. | 10 months | 
| Median Overall Survival (OS) | Median OS for all enrolled patients will be calculated from date of first dose of protocol therapy until date of death, using chart review and/or follow up phone calls to determine date of death in patients after removal from study. The survival of patients still alive after 2 years of follow up post study discontinuation will be censored. Alive patients are censored at the date last known alive. Kaplan-Meier methods will be used to summarize median OS with 95% confidence intervals. | Up to 2 years | 
| Median Progression-free Survival (PFS) | PFS is defined as the duration of time from date of first dose of protocol therapy to time of documented radiographic and/or clinical disease progression or death from any cause. Eligible patients are evaluable for PFS who are response-evaluable and who are removed from study for radiographic or clinical progression and/or who experience death from any cause during study follow up. Patients who have not progressed or died are censored at the date last known to be progression-free. Kaplan-Meier methods will be used to summarize median PFS with 95% confidence intervals. The proportion of patients with PFS equal to or exceeding 6 months will also be calculated and reported along with 95% confidence intervals. | 10 months |