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Ibrutinib Combined With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer (144525)

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ClinicalTrials.gov Identifier: NCT02562898
Recruitment Status : Active, not recruiting
First Posted : September 29, 2015
Last Update Posted : March 22, 2018
Sponsor:
Information provided by (Responsible Party):
Margaret Tempero, University of California, San Francisco

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Adenocarcinoma Drug: Ibrutinib Drug: Paclitaxel Drug: Gemcitabine Phase 1 Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Study of the Safety, Immunopharmacodynamics and Anti-tumor Activity of Ibrutinib Combined With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Adenocarcinoma
Study Start Date : October 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


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 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
560, 840, 420, or 280mg, orally once per day - 4 week cycle
Other Name: PCI-32765

Drug: Paclitaxel
125mg/m2 IV Day 1, 8, and 15 - 4 week cycle
Other Name: Abraxane, Taxol

Drug: Gemcitabine
1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle
Other Name: Gemzar

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 combination of chemotherapy with ibrutinib. Approximately 20 patients will be enrolled in this arm.
Drug: Ibrutinib
560, 840, 420, or 280mg, orally once per day - 4 week cycle
Other Name: PCI-32765

Drug: Paclitaxel
125mg/m2 IV Day 1, 8, and 15 - 4 week cycle
Other Name: Abraxane, Taxol

Drug: Gemcitabine
1000mg/m2 IV Day 1, 8, and 15 - 4 week cycle
Other Name: Gemzar




Primary Outcome Measures :
  1. Phase Ib: Maximum tolerated dose of ibrutinib in combination with albumin bound paclitaxel and gemcitabine in patients with metastatic pancreatic adenocarcinoma. [ Time Frame: Every Cycle Days 1 ]
  2. Phase Ib: Drug concentration in the blood of ibrutinib at dosing level 560 mg/day [ Time Frame: Every Cycle Days 1, 8 and 15 ]

Secondary Outcome Measures :
  1. Median time-to-progression (TTP) [ Time Frame: 10 months ]
  2. Median overall survival (OS) [ Time Frame: 10 months ]
  3. CA19-9 clinical response rate [ Time Frame: 12 months ]
    Estimate the CA19-9 clinical response rate of patients with metastatic pancreatic adenocarcinoma treated with ibrutinib in combination with nab-Paclitaxel and gemcitabine.

  4. Median progression-free survival (PFS) [ Time Frame: 10 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma
  • Stage IV disease (measurable disease NOT required)
  • Intact primary tumor
  • CA 19-9 greater than 75 units
  • 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/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 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, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02562898


Locations
United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94158
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
Sponsors and Collaborators
Margaret Tempero

Responsible Party: Margaret Tempero, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02562898     History of Changes
Other Study ID Numbers: 144525
First Posted: September 29, 2015    Key Record Dates
Last Update Posted: March 22, 2018
Last Verified: March 2018

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs