Clinical trial NCT02599324: Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors
Official title: A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal and Genitourinary Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Advanced Urothelial Carcinoma
Advanced Gastric Adenocarcinoma
Metastatic Colorectal Adenocarcinoma
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
First posted: 2015-11-06
Enrollment: 263
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6
timeFrame: 21 days after the initiation of therapy at the start of Cycle 1
measure: Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2
timeFrame: 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.
measure: Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6
timeFrame: 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 outcomes:
measure: Phase 1b: ORR in Cohorts 1 to 6
timeFrame: 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.
measure: Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6
timeFrame: 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.
measure: Phase 1b/2 RP2D: DCR in Cohorts 1 to 6
timeFrame: 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)
measure: Phase 1b/2 RP2D: PFS in Cohorts 3 to 6
timeFrame: 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)
measure: Phase 1b/2 RP2D: ORR in Cohorts 1 and 2
timeFrame: 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)
measure: Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6
timeFrame: 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)
measure: Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6
timeFrame: 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)
measure: Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: 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
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: 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
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
measure: Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4
timeFrame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Clearview Cancer Institute /ID# 1128-0965
state: Alabama
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center /ID# 1128-0802
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center - Tucson /ID# 1128-1546
state: Arizona
city: Berkeley
country: United States
facility: Alta Bates Comprehensive Cancer Center /ID# 1128-0135
state: California
city: Daly City
country: United States
facility: St Marys Medical Center /ID# 1128-0969
state: California
city: La Jolla
country: United States
facility: Duplicate_University of California San Diego/ Moores Cancer Center /ID# 1128-0241
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System /ID# 1128-0480
state: California
city: Los Angeles
country: United States
facility: USC Norris Cancer Center /ID# 1128-0209
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center - Chao Family Comprehensive Cancer Center /ID# 1128-0008
state: California
city: Saint Helena
country: United States
facility: Gregory Smith, MD (Private Practice) /ID# 1128-0419
state: California
city: Salinas
country: United States
facility: Salinas Valley Memorial Hosp /ID# 1128-0482
state: California
city: Santa Monica
country: United States
facility: Premiere Oncology, A Medical Corporation /ID# 1128-1085
state: California
city: Santa Rosa
country: United States
facility: St. Joseph Health /ID# 1128-1462
state: California
city: Norwalk
country: United States
facility: Whittingham Cancer Center at Norwalk Hospital /ID# 1128-0411
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Hospital /ID# 1128-0824
state: District of Columbia
city: Jacksonville
country: United States
facility: Duplicate_Cancer Specialist of North Florida (CSNF) ( R ) /ID# 1128-1093
state: Florida
city: Columbus
country: United States
facility: IACT Health-Columbus /ID# 1128-1389
state: Georgia
city: Evanston
country: United States
facility: Northshore Kellogg Cancer Center /ID# 1128-0484
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis /ID# 1128-1125
state: Indiana
city: Lafayette
country: United States
facility: Horizon Oncology Research Center /ID# 1128-0337
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics /ID# 1128-0766
state: Iowa
city: Fairway
country: United States
facility: The University of Kansas Cancer Center /ID# 1128-0706
state: Kansas
city: Metairie
country: United States
facility: East Jefferson General Hospital /ID# 1128-1084
state: Louisiana
city: Boston
country: United States
facility: Duplicate_Tufts Medical Center /ID# 1128-0016
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer In /ID# 1128-0130
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital /ID# 1128-0195
state: Michigan
city: Bolivar
country: United States
facility: Central Care Cancer Center /ID# 1128-1596
state: Missouri
city: Jefferson City
country: United States
facility: Capital Region Medical Center /ID# 1128-1412
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital /ID# 1128-0229
state: Nebraska
city: Brick
country: United States
facility: New Jersey Center for Cancer Research /ID# 1128-0493
state: New Jersey
city: Albuquerque
country: United States
facility: Duplicate_New Mexico Cancer Care Alliance /ID# 1128-0938
state: New Mexico
city: Farmington
country: United States
facility: San Juan Oncology Associates /ID# 1128-1020
state: New Mexico
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center-Koch Center /ID# 1128-0091
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Univ HS /ID# 1128-0975
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University /ID# 1128-0251
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Ctr /ID# 1128-0220
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the Univ. of Pennsylvania /ID# 1128-0402
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Infectious Disease Clinic /ID# 1128-0024
state: Tennessee
city: Galveston
country: United States
facility: The University of Texas Medical Branch (UTMB) - Cancer Center - Galves /ID# 1128-0974
state: Texas
city: Temple
country: United States
facility: Duplicate_Scott & White Mem Hosp & Clin /ID# 1128-0046
state: Texas
city: Fairfax
country: United States
facility: Duplicate_Virginia Cancer Specialists - Fairfax Office /ID# 1128-0972
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center /ID# 1128-0005
state: Washington
city: Seattle
country: United States
facility: University of Washington /ID# 1128-1382
state: Washington
city: Wenatchee
country: United States
facility: Confluence Health /ID# 1128-0894
state: Washington
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital /ID# 1128-0982
state: Gyeonggido
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System Severance Hospital /ID# 1128-0927
state: Seoul Teugbyeolsi
city: Jeonnam
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital /ID# 1128-0916
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital /ID# 1128-0926
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center /ID# 1128-0963
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center /ID# 1128-0925
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital /ID# 1128-0928
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital /ID# 1128-0924
city: Badalona
country: Spain
facility: Instituto Catalan de Oncologia (ICO) Badalona /ID# 1128-0984
state: Barcelona
city: Santander
country: Spain
facility: Hospital Unversitario Marques de Valdecilla /ID# 1128-0973
state: Cantabria
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron /ID# 1128-0534
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona /ID# 1128-0533
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal /ID# 1128-0874
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre /ID# 1128-0864
city: Madrid
country: Spain
facility: Hospital Universitario La Paz /ID# 1128-0921
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio /ID# 1128-0863
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute /ID# 1128-1079
state: England
city: Glasgow
country: United Kingdom
facility: Duplicate_Beatson west of scotland cancer center /ID# 1128-0652
state: Scotland
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust /ID# 1128-0543
city: Manchester
country: United Kingdom
facility: The Christie Hospital /ID# 1128-0030
city: Oxford
country: United Kingdom
facility: Duplicate_Oxford University Hospitals NHS Trust /ID# 1128-0814
Study officials:
affiliation: Pharmacyclics LLC.
name: Pharmacyclics LLC
role: STUDY_DIRECTOR
References: