Study of Ibrutinib vs Placebo, in Combination With Nab-paclitaxel and Gemcitabine, in the First Line Treatment of Patients With Metastatic Pancreatic Adenocarcinoma (RESOLVE)

Study Overview
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Brief Summary
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This is a phase 3 study to evaluate the efficacy of ibrutinib in combination with nab-paclitaxel and gemcitabine for the first line treatment of patients with metastatic pancreatic adenocarcinoma.

Official Title
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A Randomized, Multicenter, Double-blind, Placebo-controlled, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib in Combination With Nab-paclitaxel and Gemcitabine Versus Placebo in Combination With Nab-paclitaxel and Gemcitabine, in the First Line Treatment of Patients With Metastatic Pancreatic Adenocarcinoma

Conditions
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Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Gemcitabine
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma. Stage IV disease diagnosed within 6 weeks of randomization Adequate hematologic function: Absolute neutrophil count (ANC) ≥1.5 x 109/L Platelet count ≥100 x 109/L Hemoglobin ≥9 g/dL Adequate hepatic and renal function defined as: AST and/or ALT ≤5.0 x upper limit of normal (ULN) if liver metastases, or ≤3 x ULN without liver metastases Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or bone metastases present Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, such as hemolysis) Estimated Creatinine Clearance ≥30 mL/min PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN KPS ≥70. Eastern Cooperative Oncology Group (ECOG) 0-1 Exclusion Criteria: Prior therapies: BTK inhibitor, radiotherapy, radiotherapy in the adjuvant setting, or cytotoxic chemotherapy for primary disease of pancreatic adenocarcinoma. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement). Major surgery within 4 weeks of first dose of study drug. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ibrutinib<br>Ibrutinib daily in combination with: Nab-paclitaxel and gemcitabine | Drug: Ibrutinib<br> <br> * Other names: IMBRUVICA®;Drug: Gemcitabine<br> <br> Drug: Nab-paclitaxel<br> <br> |
| Placebo Comparator: Placebo<br>Placebo daily in combination with: Nab-paclitaxel and gemcitabine | Drug: Gemcitabine<br> <br> Drug: Nab-paclitaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization until disease progression per RECIST 1.1 criteria assessed by investigator, or death from any cause, whichever occurs first. | Results at an overall median follow-up of 24.87 months | 
| Overall Survival (OS) | OS, is defined as the time from date of randomization until date of death from any cause. | Results at an overall median follow-up of 24.87 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib and Nab-paclitaxel and Gemcitabine Versus Placebo in Combination With Nab-paclitaxel and Gemcitabine. | This is a measure of percentage of subjects with Treatment Emergent Adverse Events Grade 3 or above collected Up to 30 days after the last participating subject discontinues study drug. | Results at an overall median follow-up of 24.87 months | 
| Overall Response Rate | ORR is defined as the percentage of subjects who achieve a complete response or partial response, based on investigator assessment according to RECIST 1.1. | Results at an overall median follow-up of 24.87 months | 
| Clinical Benefit Response | Subject achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card [MPAC]) or analgesic consumption, or a 20-point or greater improvement in KPS for a period of at least 4 consecutive weeks, without showing any sustained worsening in other parameters. OR Subject was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation (Burris 1997). | Results at an overall median follow-up of 24.87 months | 
| Carbohydrate Antigen 19-9 (CA19-9) Response | The CA19-9 response rate is defined as the percentage of subjects with a decline of 20%, 90%, and other thresholds considered clinically meaningful, from baseline. This is a percentage of patients with > or = 60% reduction from baseline. | Results at an overall median follow-up of 24.87 months | 
| Patient-reported Outcome (PRO) by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30). | Unit is the month: TUDD1 - the time between random & 1st occurrence of a decrease in QLQ-C30 score ≥10 pts w/o improvement in QoL score of ≥10 points or any further QoL data due to deterioration. The proportion of subjects who met the responder criteria prior to subsequent anticancer therapy initiation. Response defined as achievement of a ≥50% reduction in MPAC visual analog scale which measures pain intensity or analgesic consumption, or a ≥20-point improvement from baseline in KPS sustained for a period of ≥ 4 consecutive weeks without showing any sustained worsening from baseline in any of the other parameters OR Subject stable on all parameters (pain and KPS), & showed a marked, sustained weight gain (≥7% increase from baseline maintained for ≥4 weeks) not due to fluid accumulation. | Results at an overall median follow-up of 24.87 months | 
| Rate of Venous Thromboembolic Events (VTE) | The VTE rate is defined as percentage of subjects with Venous thromboembolic events (SMQ) per investigator assessment. | Results at an overall median follow-up of 24.87 months |