Metastatic renal cell carcinoma (RCC), advanced urothelial carcinoma, advanced gastric (including gastro-esophageal [GEJ]) adenocarcinoma, and metastatic colorectal adenocarcinoma (CRC) MedDRA version: 18.1 Level: PT Classification code 10052360 Term: Colorectal adenocarcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.1 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 10029104 - Ne
Conditions
Interventions
Trade Name: Ibrutinib (PCI-32765)
Product Name: Ibrutinib
Pharmaceutical Form: Capsule
INN or Proposed INN: IBRUTINIB
CAS Number: 936563-96-1
Current Sponsor code: PCI-32765
Other descriptive name: IB
Sponsors
Pharmacyclics LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed: RCC (clear cell) Urothelial carcinoma (transitional cell) Gastric or GEJ adenocarcinoma K-RAS wild-type EGFR expressing CRC 2. One or more measurable lesions per RECIST 1.1 criteria. 3. The following prior criteria should be followed: Metastatic RCC: minimum of 1 and maximum of 4 prior regimens, one or more of which must have included a VEGF-TKI Advanced (locally recurrent and/or metastatic) urothelial carcinoma: minimum of 1 and maximum of 2 prior regimens, one of which must be a cisplatin based regimen Advanced (locally recurrent and or metastatic) gastric or GEJ adenocarcinoma: minimum of 1 and maximum of 3 prior regimens one of which must be a fluoropyrimidine based regimen Metastatic CRC: minimum of 2 and maximum of 4 prior regimens, which must have included both an irinotecan and an oxaliplatin based regimen or unable to tolerate irinotecan chemotherapy 4. Each subject must be assessed by the investigator to be a suitable candidate for treatment with everolimus, docetaxel, paclitaxel or cetuximab, as appropriate according to their type of cancer. 5. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose of study drug and agree to use dual methods of contraception during the study and for 1 month following the last dose with study drug. Post-menopausal females (>45 years old and without menses for >1 year) and surgically sterilized females are exempt from this criterion. 6. Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential. Laboratory 7. Adequate hematologic function (independent of transfusion and growth factor support for at least 7 days prior to enrollment, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to enrollment defined as: Absolute neutrophil count more than 1500 cells/mm3 (1.5 x 109/L) Platelet count >80,000 cells/mm3 (80 x 109/L) Hemoglobin >8.0 g/dL 8. Adequate hepatic and renal function defined as: Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) smaller or equal than 5.0 x upper limit of normal (ULN) if liver metastases, or less than 3 x ULN without liver metastases Alkaline phosphatase less than 3.0 x ULN or ?5.0 x ULN if liver or bone metastases present Bilirubin smaler or equal 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 patients in the gastric adenocarcinoma cohort where docetaxel is administered, these patients must have bilirubin within normal limits (WNL). Estimated Creatinine Clearance greater than or equal 30 mL/min (Cockcroft-Gault) Demographic 9. Men and women greater than or equal 18 years of age 10. Eastern Cooperative Oncology Group (ECOG) performance status 0 1. For subjects with RCC or CRC, an ECOG score of 2, may be acceptable if approved by the medical monitor. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 189 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 189
Exclusion criteria
Exclusion criteria: 1. Anticancer therapy (chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 28 days of the first dose of study drug (6 weeks for nitrosureas, mitomycin C, or antibody based therapies) 2. Prior treatment with: Everolimus or temsirolimus (RCC cohort) Any taxane (urothelial carcinoma cohort) Any taxane (gastric adenocarcinoma cohort) Cetuximab or panitumumab (CRC cohort) 3. Prior radiotherapy to measurable lesion, unless documented progression has occurred post-irradiation 4. Lack of recovery from previous therapeutic radiation (persistence of Grade greater than or equal than 2 radiation-related toxicity), or planned radiation therapy during the study period Concurrent Conditions 5. Any uncontrolled active systemic infection including any infection requiring systemic IV treatment which was completed minor or equal than 7 days before Cycle 1 Day 1. 6. History of other malignancies, except: Malignancy treated with curative intent and with no known active disease present for mayor than or equal 3 years before the first dose of study drug and felt to be at low risk for recurrence by investigator Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without current evidence of disease 7. Prior treatment with ibrutinib or other BTK inhibitor 8. ALT and/or AST more than 1.5 x ULN and alkaline phosphatase more than 2.5 x ULN (gastric adenocarcinoma cohort only) 9. Known allergy or hypersensitivity to ibrutinib or any other component of combination therapy, including polysorbate 80 or Cremophor® EL (polyoxyethylated castor oil) 10. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade 0 or 1 11. Known bleeding disorders (eg, von Willebrand?s disease) or hemophilia 12. Grade mayor than or equal 3 sensory peripheral neuropathy 13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 14. Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement) 15. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV) Patients who are positive for hepatitis B core antibody, hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. 16. Major surgery within 4 weeks of first dose of study drug 17. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator s opinion, could compromise the subject s safety or put the study outcomes at undue risk 18. 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 enrollment 19. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction 20. Unable to swallow capsules and/or tablets 21. Concomitant use of warfarin or other Vitamin K antagonists 22. Requires t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Phase 1b: Primary Objective: To determine the recommended Phase 2 dose (RP2D) of ibrutinib in combination with everolimus in RCC, paclitaxel in urothelial carcinoma, docetaxel in gastric adenocarcinoma and cetuximab in CRC. Phase 2: Primary Objectives: To assess progression-free survival (PFS) of ibrutinib combination therapy in RCC and urothelial carcinoma To assess the ORR of ibrutinib combination therapy in gastric adenocarcinoma and CRC;Timepoint(s) of evaluation of this end point: A dose level review committee (DLRC) will evaluate the safety data at the completion of the initial Phase 1b portion in each cohort to determine the RP2D, prior to continuing with enrollment into the Phase 2 portion. The DLT observation period will encompass 21 days after the initiation of combination therapy. Phase 1b of the study will follow a 6+3 dose de-escalation design. In any given cohort if 2 subjects within the initial group of 6 subjects experience a DLT, an additional 3 subjects will be enrolled at the same dose level. If 3 or more of 9 subjects in total experience a DLT, dose de escalation will occur and an additional 6 subjects will be treated at a lower dose level;Main Objective: Phase 1b: Primary Objective: To determine the recommended Phase 2 dose (RP2D) of ibrutinib in combination with everolimus in RCC, paclitaxel in urothelial carcinoma, docetaxel in gastric adenocarcinoma and cetuximab in CRC. Phase 2: Primary Objectives: To assess progression-free survival (PFS) of ibrutinib combination therapy in RCC and urothelial carcinoma To assess the ORR of ibrutinib combination therapy in gastric adenocarcinoma and CRC;Secondary Objective: Phase 1b: Assess the overall response rate of ibrutinib combination therapy in each cohort Assess the safety and tolerability of ibrutinib combination therapy in each cohort Assess the disease control rate of ibrutinib combination therapy in each cohort Evaluate the pharmacokinetics of ibrutinib combination t | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b: Secondary objectives: To assess the overall response rate (ORR) of ibrutinib combination therapy in each cohort To assess the safety and tolerability of ibrutinib combination therapy in each cohort To assess the disease control rate (DCR) of ibrutinib combination therapy in each cohort To evaluate the pharmacokinetics (PK) of ibrutinib combination therapy in each cohort Phase 2: Secondary Objectives: To assess the PFS of ibrutinib combination therapy in gastric adenocarcinoma and CRC To assess the ORR of ibrutinib combination therapy in RCC and urothelial carcinoma To assess the DCR of ibrutinib combination therapy in each cohort To assess the median overall survival (OS) of ibrutinib combination therapy in each cohort To assess the safety and tolerability of ibrutinib combination therapy in each cohort Exploratory Objectives: Biomarker analysis for response and resistance to ibrutinib based therapy To assess ITK occupancy during ibrutinib treatment in each cohort To evaluate the pharmacokinetics (PK) of ibrutinib combination therapy in each cohort;Timepoint(s) of evaluation of this end point: RCC: A single interim analysis for futility will take place when the 25th subject has completed 6 months of follow-up. The proportion of subjects that are PFS event-free at 6 months will be assessed along with other safety and efficacy data in making the determination if the study should continue. Urothelial carcinoma: A single interim analysis for futility will take place when the 25th subject has completed 4 months of follow-up. The proportion of subjects PFS event-free at 4 months will be assessed along with other safety and efficacy data in making the determination if the study should continue. Gastric adenocarcinoma and CRC:The gastric adenocarcinoma and CRC cohorts employ a Simon two stage Minimax design involving the ORR endpoint. | — |
Countries
Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial Manager
Pharmacyclics LLC
Outcome results
None listed