Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors

Metastatic Renal Cell Carcinoma Clinical Trial

Official title:

A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal and Genitourinary Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02599324
• Other study ID #: PCYC-1128-CA
• Secondary ID: 2015-003656-40
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 1, 2015
• Est. completion date: August 20, 2021

Study information

• Verified date: September 2022
• Source: Pharmacyclics LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety, tolerability, and efficacy of single agent ibrutinib or the combination treatments of ibrutinib with everolimus, paclitaxel, docetaxel, pembrolizumab or cetuximab in selected advance gastrointestinal and genitourinary tumors.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 263
• Est. completion date: August 20, 2021
• Est. primary completion date: August 20, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

RCC (clear cell), urothelial carcinoma (UC) (transitional cell), gastric or gastro-esophageal junctional (GEJ) adenocarcinoma, or K-RAS or N-RAS wild-type EGFR expressing CRC For cohort 1 RCC: minimum of 1 and maximum of 4 prior regimens, one or more of which must have included a VEGF-TKI For UC cohort 2: minimum of 1 and maximum of 2 prior regimens, one of which must have included a platinum-based regimen For UC cohort 5: Minimum of 1 and maximum of 2 prior regimens, one of which must have included a checkpoint inhibitor.

For UC cohort 6:

Locally advanced or mUC who are not eligible for cisplatin chemo with a PDL-1 score (CPS) of = 10 without prior treatment.

Locally advanced or mUC who have progressed on platinum chemo or within 12 months of neo- or adjuvant therapy with a platinum chemotherapy. A minimum of 1 and maximum of 2 prior therapies.

For cohort 3 gastric or GEJ adenocarcinoma: minimum of 1 and maximum of 3 prior regimens one of which must have included a fluoropyrimidine regimen For cohort 4 CRC: minimum of 2 and maximum of 4 prior regimens, which must have included both an irinotecan and an oxaliplatin based regimen unless unable to tolerate irinotecan chemotherapy

Laboratory:

Adequate hematologic function:

Absolute neutrophil count =1500 cells/mm3 (1.5 x 109/L) Platelet count >80,000 cells/mm3 (80 x 109/L) for cohort 1 (RCC) Platelet counts >100,000 cells/mm3 (100 x 109/L) for all UC cohorts Hemoglobin =8.0 g/dL. for cohort 1 (RCC),all UC cohorts, and cohort 3 (GC) Hemoglobin =9.0 g/dL for cohort 4 (CRC)

Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) and/or alanine transaminase (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) with the exception of subjects in the GC cohort where docetaxel is administered, these subjects must have bilirubin within normal limits (WNL) Estimated Creatinine Clearance =30 mL/min (Cockcroft-Gault)

Exclusion Criteria

Prior treatment with:

Everolimus or temsirolimus (RCC cohort 1) Any taxane (UC cohort of ibrutinib + paclitaxel) (cohort 2) Checkpoint inhibitors (UC cohort 6) Any taxane (GC cohort 3) Cetuximab or panitumumab (CRC cohort 4)

For all Cohorts:

Concomitant use of warfarin or other Vitamin K antagonists History of stroke or intracranial hemorrhage within 6 months prior to enrollment Major surgery within 4 weeks of first dose of study drug Requires treatment with strong CYP3A inhibitors known bleeding disorders or hemophilia

UC cohort 6 only:

Subjects who have an active, known or suspected autoimmune disease. Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.

Non-steroid immunosuppressive medications within 14 days before the first dose of ibrutinib and pembrolizumab.

Subjects in whom prior anti PD-1 / anti-PD-L1 therapy was intolerable and required discontinuation of treatment.

Related Conditions & MeSH terms

• Adenocarcinoma
• Advanced Gastric Adenocarcinoma
• Advanced Urothelial Carcinoma
• Carcinoma
• Carcinoma, Renal Cell
• Metastatic Colorectal Adenocarcinoma
• Metastatic Renal Cell Carcinoma

Intervention

Drug:
• ibrutinib
Ibrutinib administered orally once daily with 8 ounces (approximately 240 mL) of water.
• everolimus
Everolimus 10 mg tablets should be taken orally once daily at the same time every day, either consistently with food or consistently without food. Four (4) x 2.5 mg tablets or two (2) x 5.0 mg tablets may be substituted if 10 mg tablet strength is not available.
• paclitaxel
Paclitaxel should be administered as a 60-minute (±10 minutes) infusion. Paclitaxel should be given at a dose level of 80 mg/m^2, once weekly, in continual 3 weekly cycles.
• docetaxel
Docetaxel administered as a 60 minute infusion (±10 minutes) at a dose level of 60 - 75 mg/m^2 (according to local institutional standard of care), given continually in 21-day cycles.
• cetuximab
Cetuximab 400 mg/m^2 administered as a 120-minute IV infusion. The recommended subsequent weekly dose (all other infusions) is 250 mg/m^2 infused over 60 minutes.
• pembrolizumab
Pembrolizumab 200 mg intravenous (IV) every 3 weeks.

Locations

Country	Name	City	State
Korea, Republic of	Chonnam National University Hwasun Hospital /ID# 1128-0916	Jeonnam
Korea, Republic of	Seoul National University Bundang Hospital /ID# 1128-0982	Seongnam	Gyeonggido
Korea, Republic of	Asan Medical Center /ID# 1128-0963	Seoul
Korea, Republic of	Korea University Guro Hospital /ID# 1128-0924	Seoul
Korea, Republic of	Samsung Medical Center /ID# 1128-0925	Seoul
Korea, Republic of	Seoul National University Hospital /ID# 1128-0926	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital /ID# 1128-0928	Seoul
Korea, Republic of	Yonsei University Health System Severance Hospital /ID# 1128-0927	Seoul	Seoul Teugbyeolsi
Spain	Instituto Catalan de Oncologia (ICO) Badalona /ID# 1128-0984	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona /ID# 1128-0533	Barcelona
Spain	Hospital Universitario Vall d'Hebron /ID# 1128-0534	Barcelona
Spain	Hospital Universitario 12 de Octubre /ID# 1128-0864	Madrid
Spain	Hospital Universitario La Paz /ID# 1128-0921	Madrid
Spain	Hospital Universitario Ramon y Cajal /ID# 1128-0874	Madrid
Spain	Hospital Unversitario Marques de Valdecilla /ID# 1128-0973	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocio /ID# 1128-0863	Sevilla
United Kingdom	Duplicate_Beatson west of scotland cancer center /ID# 1128-0652	Glasgow	Scotland
United Kingdom	Sarah Cannon Research Institute /ID# 1128-1079	London	England
United Kingdom	The Royal Marsden NHS Foundation Trust /ID# 1128-0543	London
United Kingdom	The Christie Hospital /ID# 1128-0030	Manchester
United Kingdom	Duplicate_Oxford University Hospitals NHS Trust /ID# 1128-0814	Oxford
United States	Duplicate_New Mexico Cancer Care Alliance /ID# 1128-0938	Albuquerque	New Mexico
United States	Alta Bates Comprehensive Cancer Center /ID# 1128-0135	Berkeley	California
United States	Central Care Cancer Center /ID# 1128-1596	Bolivar	Missouri
United States	Duplicate_Tufts Medical Center /ID# 1128-0016	Boston	Massachusetts
United States	New Jersey Center for Cancer Research /ID# 1128-0493	Brick	New Jersey
United States	IACT Health-Columbus /ID# 1128-1389	Columbus	Georgia
United States	St Marys Medical Center /ID# 1128-0969	Daly City	California
United States	Barbara Ann Karmanos Cancer In /ID# 1128-0130	Detroit	Michigan
United States	Henry Ford Hospital /ID# 1128-0195	Detroit	Michigan
United States	Northshore Kellogg Cancer Center /ID# 1128-0484	Evanston	Illinois
United States	Duplicate_Virginia Cancer Specialists - Fairfax Office /ID# 1128-0972	Fairfax	Virginia
United States	The University of Kansas Cancer Center /ID# 1128-0706	Fairway	Kansas
United States	San Juan Oncology Associates /ID# 1128-1020	Farmington	New Mexico
United States	The University of Texas Medical Branch (UTMB) - Cancer Center - Galves /ID# 1128-0974	Galveston	Texas
United States	Banner MD Anderson Cancer Center /ID# 1128-0802	Gilbert	Arizona
United States	Penn State Hershey Medical Ctr /ID# 1128-0220	Hershey	Pennsylvania
United States	Clearview Cancer Institute /ID# 1128-0965	Huntsville	Alabama
United States	Franciscan Health Indianapolis /ID# 1128-1125	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics /ID# 1128-0766	Iowa City	Iowa
United States	Duplicate_Cancer Specialist of North Florida (CSNF) ( R ) /ID# 1128-1093	Jacksonville	Florida
United States	Capital Region Medical Center /ID# 1128-1412	Jefferson City	Missouri
United States	Duplicate_University of California San Diego/ Moores Cancer Center /ID# 1128-0241	La Jolla	California
United States	Horizon Oncology Research Center /ID# 1128-0337	Lafayette	Indiana
United States	VA Long Beach Healthcare System /ID# 1128-0480	Long Beach	California
United States	USC Norris Cancer Center /ID# 1128-0209	Los Angeles	California
United States	East Jefferson General Hospital /ID# 1128-1084	Metairie	Louisiana
United States	Vanderbilt Infectious Disease Clinic /ID# 1128-0024	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center-Koch Center /ID# 1128-0091	New York	New York
United States	Whittingham Cancer Center at Norwalk Hospital /ID# 1128-0411	Norwalk	Connecticut
United States	Nebraska Methodist Hospital /ID# 1128-0229	Omaha	Nebraska
United States	UC Irvine Medical Center - Chao Family Comprehensive Cancer Center /ID# 1128-0008	Orange	California
United States	Abramson Cancer Center of the Univ. of Pennsylvania /ID# 1128-0402	Philadelphia	Pennsylvania
United States	Oregon Health & Science University /ID# 1128-0251	Portland	Oregon
United States	Gregory Smith, MD (Private Practice) /ID# 1128-0419	Saint Helena	California
United States	Salinas Valley Memorial Hosp /ID# 1128-0482	Salinas	California
United States	Premiere Oncology, A Medical Corporation /ID# 1128-1085	Santa Monica	California
United States	St. Joseph Health /ID# 1128-1462	Santa Rosa	California
United States	University of Washington /ID# 1128-1382	Seattle	Washington
United States	Virginia Mason Medical Center /ID# 1128-0005	Seattle	Washington
United States	Duplicate_Scott & White Mem Hosp & Clin /ID# 1128-0046	Temple	Texas
United States	University of Arizona Cancer Center - Tucson /ID# 1128-1546	Tucson	Arizona
United States	Georgetown University Hospital /ID# 1128-0824	Washington	District of Columbia
United States	Confluence Health /ID# 1128-0894	Wenatchee	Washington
United States	Wake Forest Univ HS /ID# 1128-0975	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Pharmacyclics LLC.

Countries where clinical trial is conducted

United States,  Korea, Republic of,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6	A DLT was defined as any Grade 3 (severe) or higher non-hematologic or Grade 4 (life-threatening) hematologic adverse event (AE) occurring during the DLT observation period that was considered to be at least possibly related to the study treatment (ibrutinib or drug combination).	21 days after the initiation of therapy at the start of Cycle 1
Primary	Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2	PFS is defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease (PD) or date of death from any cause, whichever occurs first, regardless of the use of subsequent anti-cancer treatment. PD was defined in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), and an absolute increase of = 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.	Maximum time on study for Cohort 1 (Phase 1b/2 RP2D) was 37.4 months; for Cohort 2 (Phase 1b/2 RP2D) was 44.7 months.
Primary	Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6	ORR is defined as the percentage of participants who have a best response of partial response (PR) or complete response (CR) to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Maximum time on study (Phase 1b/2 RP2D) for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.
Secondary	Phase 1b: ORR in Cohorts 1 to 6	ORR is defined as the percentage of participants who have a best response of partial response (PR) or complete response (CR) to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Maximum time on study (Phase 1b only) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 34.2 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.
Secondary	Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6	DCR is is defined as the percentage of participants who have a best response of PR, CR, or stable disease (SD) to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD since the treatment started (baseline or after). For SD, tthere was no need for confirmation by a subsequent imaging assessment.	Maximum time on study (Phase 1b only) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 34.2 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.
Secondary	Phase 1b/2 RP2D: DCR in Cohorts 1 to 6	DCR is is defined as the percentage of participants who have a best response of PR, CR, or SD to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SOD since the treatment started (baseline or after). For SD, tthere was no need for confirmation by a subsequent imaging assessment.	Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates)
Secondary	Phase 1b/2 RP2D: PFS in Cohorts 3 to 6	PFS is defined as the time from the date of first dose of study treatment to the date of first documentation of PD or date of death from any cause, whichever occurs first, regardless of the use of subsequent anti-cancer treatment. PD was defined in accordance with RECIST 1.1 criteria.	Maximum time on study (Phase 1b/2 RP2D) for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates)
Secondary	Phase 1b/2 RP2D: ORR in Cohorts 1 and 2	ORR is defined as the percentage of participants who have a best response to therapy of PR or CR in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Maximum time on study for Cohort 1 (Phase 1b/2 RP2D) was 37.4 months; for Cohort 2 (Phase 1b/2 RP2D) was 44.7 months. (Reverse Kaplan-Meier estimates)
Secondary	Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6	OS is defined as the time from the date of first dose of study treatment to the date of death from any cause. Subjects who were not known to have died at the data extraction will be censored at date last known alive.	Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates)
Secondary	Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6	DOR is defined for confirmed responders (PR or better) as time from the date of initial response (PR or better) to the date of first documentation of PD (according to RECIST 1.1) or death, whichever occurs first, regardless of use of subsequent anti-cancer treatment. Confirmed responders without documentation of PD or death or with unknown status at the data extraction were censored at the last adequate post-baseline disease assessment showing no evidence of PD. PD was defined as at least a 20% increase in the size of target lesions with an absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.; Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.	Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates)
Secondary	Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The Cmax was noted as observed.	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The tmax was noted as observed.	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The tlast was noted as observed.	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Area Under the Concentration-Time Curve From Time 0 to Hour 24 (AUC0-24h) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The AUC0-24h was calculated by the linear trapezoidal method.	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Area Under the Concentration-Time Curve to Last Observed Time Point (AUClast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The AUClast was calculated by the linear trapezoidal method.	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The apparent t1/2term was calculated by ln(2)/?z, where ?z is the apparent elimination rate constant obtained by linear regression of three or more log-transformed data points in the terminal phase (not including Cmax).	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Terminal Elimination Rate Constant (?z) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. The ?z is the apparent elimination rate constant obtained by linear regression of three or more log-transformed data points in the terminal phase (not including Cmax).	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Secondary	Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4	Actual collection times relative to ibrutinib administration were used for the calculation of pharmacokinetic parameters of ibrutinib and PCI-45227. For actual predose collection times that were < 0, these values were set equal to 0. Predose concentrations were applied as 24 hour concentrations in order to calculate steady-state (Cycle 2 Day 1) pharmacokinetic parameters for ibrutinib and PCI-45227. Apparent total CLss/F (Cycle 2 Day 1) was calculated as dose/AUC0-24h.	Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose