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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02436668

Enrollment

430

Registered

2015-05-07

Start date

2015-05-31

Completion date

2019-04-25

Last updated

2020-12-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Metastatic Pancreatic Adenocarcinoma

Brief summary

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.

Interventions

DRUGIbrutinib

DRUGGemcitabine

DRUGNab-paclitaxel

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma. 2. Stage IV disease diagnosed within 6 weeks of randomization 3. Adequate hematologic function: * Absolute neutrophil count (ANC) ≥1.5 x 109/L * Platelet count ≥100 x 109/L * Hemoglobin ≥9 g/dL 4. 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 5. PT/INR \<1.5 x ULN and PTT (aPTT) \<1.5 x ULN 6. KPS ≥70. 7. Eastern Cooperative Oncology Group (ECOG) 0-1

Exclusion criteria

1. Prior therapies: BTK inhibitor, radiotherapy, radiotherapy in the adjuvant setting, or cytotoxic chemotherapy for primary disease of pancreatic adenocarcinoma. 2. Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma 3. Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement). 4. Major surgery within 4 weeks of first dose of study drug. 5. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 6. Treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

Design outcomes

Primary

Measure	Time frame	Description
Progression Free Survival (PFS)	Results at an overall median follow-up of 24.87 months	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.
Overall Survival (OS)	Results at an overall median follow-up of 24.87 months	OS, is defined as the time from date of randomization until date of death from any cause.

Secondary

Measure	Time frame	Description
Clinical Benefit Response	Results at an overall median follow-up of 24.87 months	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).
Carbohydrate Antigen 19-9 (CA19-9) Response	Results at an overall median follow-up of 24.87 months	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.
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.	Results at an overall median follow-up of 24.87 months	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.
Rate of Venous Thromboembolic Events (VTE)	Results at an overall median follow-up of 24.87 months	The VTE rate is defined as percentage of subjects with Venous thromboembolic events (SMQ) per investigator assessment.
Patient-reported Outcome (PRO) by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).	Results at an overall median follow-up of 24.87 months	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.
Overall Response Rate	Results at an overall median follow-up of 24.87 months	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.

Countries

Belgium, France, Germany, Italy, South Korea, Spain, United Kingdom, United States

Participant flow

Recruitment details

This study was conducted at 75 centers in the United States (US), European Union, and South Korea. The first subject enrolled 08 May 2015 and the last was enrolled on April 19, 2018.

Pre-assignment details

There was a safety run-in of 6 patients; subsequently, 430 total patients were enrolled. Eligible subjects were required to have a confirmed diagnosis of Stage IV pancreatic adenocarcinoma within 6 weeks of randomization evaluable per RECIST 1.1 criteria with at least 1 measurable metastatic lesion. Key exclusion criteria included any previous cytotoxic chemotherapy for primary disease of pancreatic adenocarcinoma.

Participants by arm

Arm	Count
Pbo+n-P/G Placebo daily in combination with: Nab-paclitaxel and gemcitabine Nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 were administered on Days 1, 8, and 15 of each 28-day cycle, each as a 30- to 40-minute intravenous infusion.	213
Ibr+n-P/G Ibrutinib daily in combination with: Nab-paclitaxel and gemcitabine Ibrutinib- orally once daily at a starting dose of 560 mg. Nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 were administered on Days 1, 8, and 15 of each 28-day cycle, each as a 30- to 40-minute intravenous infusion	211
Total	424

Baseline characteristics

Characteristic	Pbo+n-P/G	Ibr+n-P/G	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	94 Participants	93 Participants	187 Participants
Age, Categorical Between 18 and 65 years	119 Participants	118 Participants	237 Participants
Age, Continuous	64.0 Years	64.0 Years	64.0 Years
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants	7 Participants	18 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	197 Participants	198 Participants	395 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants	6 Participants	11 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	59 Participants	53 Participants	112 Participants
Race (NIH/OMB) Black or African American	7 Participants	5 Participants	12 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	6 Participants	11 Participants
Race (NIH/OMB) White	142 Participants	146 Participants	288 Participants
Sex: Female, Male Female	92 Participants	97 Participants	189 Participants
Sex: Female, Male Male	121 Participants	114 Participants	235 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	188 / 212	189 / 208
other Total, other adverse events	211 / 212	208 / 208
serious Total, serious adverse events	127 / 212	112 / 208