Ibrutinib Combined With Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Cancer

Study Overview

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

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.

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.

Metastatic Pancreatic Adenocarcinoma

DRUG: Ibrutinib
DRUG: Paclitaxel
DRUG: Gemcitabine

144525
NCI-2015-01780 (REGISTRY Identifier) (REGISTRY: NCI Clinical Trials Reporting Program (CTRP))

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2015-09-03	Results First Submitted 2020-06-26	Last Update Submitted that met QC Criteria 2021-04-13
First Submitted that Met QC Criteria 2015-09-28	Results First Submitted that Met QC Criteria 2020-06-26	Last Update Posted (ACTUAL) 2021-05-06
First Posted (ACTUAL) 2015-09-29	Results First Posted 2020-07-16	Last Verified 2021-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Dose escalation for safety and toxicity 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	DRUG: Ibrutinib 560, 840, 420, or 280mg, orally once per day - 4 week cycle DRUG: Paclitaxel 125mg/m2 IV Day 1, 8, and 15 - 4 week cycle DRUG: Gemcitabine 1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle
EXPERIMENTAL: Immune Response cohort 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 combin	DRUG: Ibrutinib 560, 840, 420, or 280mg, orally once per day - 4 week cycle DRUG: Paclitaxel 125mg/m2 IV Day 1, 8, and 15 - 4 week cycle DRUG: Gemcitabine 1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Dose escalation for safety and toxicity

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

DRUG: Ibrutinib

560, 840, 420, or 280mg, orally once per day - 4 week cycle

DRUG: Paclitaxel

125mg/m2 IV Day 1, 8, and 15 - 4 week cycle

DRUG: Gemcitabine

1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle

EXPERIMENTAL: Immune Response cohort

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 combin

DRUG: Ibrutinib

560, 840, 420, or 280mg, orally once per day - 4 week cycle

DRUG: Paclitaxel

125mg/m2 IV Day 1, 8, and 15 - 4 week cycle

DRUG: Gemcitabine

1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle

Primary Outcome Measures	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	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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.

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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Stand Up To Cancer
Lustgarten Foundation

Investigators

PRINCIPAL_INVESTIGATOR: Margaret Tempero, MD, University of California, San Francisco

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

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