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

NCT02562898 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 144525NCI-2015-01780
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

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.

Conditions

Metastatic Pancreatic Adenocarcinoma

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Median Time-to-progression (TTP)

  10 months

• Median Overall Survival (OS)

  Up to 2 years

• Median Progression-free Survival (PFS)

  10 months

Study Arms (2)

Dose escalation for safety and toxicity

EXPERIMENTAL

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; Drug: Paclitaxel; Drug: Gemcitabine

Immune Response cohort

EXPERIMENTAL

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; Drug: Paclitaxel; Drug: Gemcitabine

Interventions

Ibrutinib DRUG

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

Also known as: PCI-32765

Dose escalation for safety and toxicity; Immune Response cohort

Paclitaxel DRUG

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

Also known as: Abraxane, Taxol

Dose escalation for safety and toxicity; Immune Response cohort

Gemcitabine DRUG

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

Also known as: Gemzar

Dose escalation for safety and toxicity; Immune Response cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Margaret Tempero: lead
• Stand Up To Cancer: collaborator
• Lustgarten Foundation: collaborator

Study Sites (2)

University of California, San Francisco

San Francisco, California, 94158, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Related Publications (1)

• 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.

  PMID: 36593070 DERIVED

MeSH Terms

Interventions

ibrutinib; Paclitaxel; Albumin-Bound Paclitaxel; Gemcitabine

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

Treatment was determined to be ineffective and study was closed to accrual earlier than anticipated.

Results Point of Contact

• Title: Dr. Margaret Tempero
• Organization: University of California, San Francisco

Margaret.Tempero@ucsf.edu

415-353-7528

Study Officials

• Margaret Tempero, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 3, 2015
• First Posted: September 29, 2015
• Study Start: October 12, 2015
• Primary Completion: November 15, 2019
• Study Completion: September 1, 2020
• Last Updated: May 6, 2021
• Results First Posted: July 16, 2020

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: ICF

Locations

US (2)