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

NCT ID: NCT02562898

Last Updated: 2021-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-12
• Study Completion Date: 2020-09-01

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.

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.

Conditions

Metastatic Pancreatic Adenocarcinoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: DRUG

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

Paclitaxel

Intervention Type: DRUG

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

Gemcitabine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: DRUG

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

Paclitaxel

Intervention Type: DRUG

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

Gemcitabine

Intervention Type: DRUG

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

Interventions

Ibrutinib

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

Intervention Type: DRUG

Paclitaxel

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

Intervention Type: DRUG

Gemcitabine

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

Intervention Type: DRUG

Other Intervention Names

PCI-32765; Abraxane, Taxol; Gemzar

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stand Up To Cancer

OTHER

Sponsor Role: collaborator

Lustgarten Foundation

OTHER

Sponsor Role: collaborator

Margaret Tempero

OTHER

Sponsor Role: lead

Responsible Party

Margaret Tempero

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Margaret Tempero, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California, San Francisco

San Francisco, California, United States

Oregon Health and Science University

Portland, Oregon, United States

Countries

United States

References

Sinha M, Betts C, Zhang L, Griffith MJ, Solman I, Chen B, Liu E, Tamaki W, Stultz J, Marquez J, Sivagnanam S, Cheung A, Pener D, Fahlman A, Taber E, Lerner K, Crocker M, Todd K, Rajagopalan B, Ware C, Bridge M, Vo J, Dragomanovich H, Sudduth-Klinger J, Vaccaro G, Lopez CD, Tempero M, Coussens LM, Fong L. Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. J Immunother Cancer. 2023 Jan;11(1):e005425. doi: 10.1136/jitc-2022-005425.

Reference Type: DERIVED

PMID: 36593070 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

NCI-2015-01780

Identifier Type: REGISTRY

Identifier Source: secondary_id

144525

Identifier Type: -

Identifier Source: org_study_id