Advanced Gastric Adenocarcinoma, Advanced Urothelial Carcinoma, Metastatic Colorectal Adenocarcinoma, Metastatic Renal Cell Carcinoma
Conditions
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.
Interventions
DRUGibrutinib
Ibrutinib administered orally once daily with 8 ounces (approximately 240 mL) of water.
DRUGeverolimus
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.
DRUGpaclitaxel
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.
DRUGdocetaxel
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.
DRUGcetuximab
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.
DRUGpembrolizumab
Pembrolizumab 200 mg intravenous (IV) every 3 weeks.
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 21 days after the initiation of therapy at the start of Cycle 1 | 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). |
| Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2 | 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. | 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. |
| Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6 | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b/2 RP2D: PFS in Cohorts 3 to 6 | 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) | 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. |
| Phase 1b/2 RP2D: ORR in Cohorts 1 and 2 | 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) | 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. |
| Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 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) | 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. |
| Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | 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) | 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. |
| Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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. |
| Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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. |
| Phase 1b: ORR in Cohorts 1 to 6 | 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. | 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. |
| 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 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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. |
| 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 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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. |
| Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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)/λz, where λz 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). |
| Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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 λz 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). |
| Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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. |
| Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose | 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. |
| Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 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. | 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. |
| Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 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) | 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. |
Countries
South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
In Phase 1b, participants were enrolled into 6 separate cohorts according to clinical indication: renal cell carcinoma (RCC; Cohort 1), urothelial carcinoma (UC; Cohort 2), gastric adenocarcinoma (GA; Cohort 3), colorectal adenocarcinoma (CRC; Cohort 4), urothelial carcinoma (UC; Cohorts 5 and 6). A dose level review committee (DLRC) evaluated the safety data at the completion of Phase 1b in each cohort to determine the recommended Phase 2 dose (RP2D), with the exception of Cohort 5.
Pre-assignment details
For Cohorts 1 to 4 and 6, participants enrolled into 5 distinct disease specific cohorts to receive ibrutinib at the RP2D determined in Phase 1b for that cohort in combination with the relative cancer agent. Treatment was to follow the same dosing schedule used in Phase 1b, and all cohorts were to continue on ibrutinib RP2D and respective anticancer agents until disease progression or unacceptable toxicity. For Cohort 5, single agent ibrutinib was given at the RP2D PO daily in 21-day cycles.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD. | 3 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD. | 39 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles. | 4 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles. | 59 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel Participants with GA received ibrutinib 560 mg QD in combination with docetaxel administered as a 60 minute infusion (±10 minutes) at a dose level of 60 - 75 mg/m\^2, given continually in 21 day cycles. | 46 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab Participants with CRC received ibrutinib 560 mg QD in combination with cetuximab 400 mg/m\^2 administered as a 120-minute IV infusion. Subsequent weekly dose (all other infusions) was 250 mg/m\^2 infused over 60 minutes. | 8 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab Participants with CRC received ibrutinib 840 mg QD in combination with cetuximab 400 mg/m\^2 administered as a 120-minute IV infusion. Subsequent weekly dose (all other infusions) was 250 mg/m\^2 infused over 60 minutes. | 50 |
| Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD. | 35 |
| Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks. | 18 |
| Total | 262 |
Baseline characteristics
| Characteristic | Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Cohort 5 (UC): Ibrutinib 840 mg | Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized 18 - 64 years | 23 Participants | 3 Participants | 21 Participants | 33 Participants | 6 Participants | 1 Participants | 25 Participants | 11 Participants | 6 Participants | 129 Participants |
| Age, Customized 65 - 84 years | 16 Participants | 1 Participants | 35 Participants | 13 Participants | 2 Participants | 2 Participants | 25 Participants | 22 Participants | 12 Participants | 128 Participants |
| Age, Customized ≥ 85 years | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 4 Participants | 7 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 2 Participants | 55 Participants | 39 Participants | 4 Participants | 3 Participants | 50 Participants | 34 Participants | 17 Participants | 243 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 0 Participants | 12 Participants | 12 Participants | 2 Participants | 0 Participants | 31 Participants | 5 Participants | 0 Participants | 69 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 32 Participants | 4 Participants | 47 Participants | 32 Participants | 5 Participants | 3 Participants | 18 Participants | 30 Participants | 16 Participants | 187 Participants |
| Sex: Female, Male Female | 8 Participants | 0 Participants | 8 Participants | 12 Participants | 7 Participants | 1 Participants | 21 Participants | 9 Participants | 5 Participants | 71 Participants |
| Sex: Female, Male Male | 31 Participants | 4 Participants | 51 Participants | 34 Participants | 1 Participants | 2 Participants | 29 Participants | 26 Participants | 13 Participants | 191 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 1 / 7 | 22 / 38 | 3 / 4 | 4 / 10 | 51 / 55 | 13 / 21 | 17 / 31 | 6 / 8 | 4 / 12 | 31 / 44 | 2 / 10 | 20 / 33 | 4 / 17 | 3 / 13 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 34 / 38 | 4 / 4 | 10 / 10 | 51 / 55 | 20 / 21 | 26 / 31 | 8 / 8 | 12 / 12 | 40 / 44 | 9 / 10 | 29 / 33 | 16 / 17 | 7 / 13 |
| serious Total, serious adverse events | 2 / 3 | 2 / 7 | 18 / 38 | 2 / 4 | 5 / 10 | 32 / 55 | 15 / 21 | 12 / 31 | 5 / 8 | 2 / 12 | 14 / 44 | 3 / 10 | 16 / 33 | 7 / 17 | 3 / 13 |
Outcome results
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.
Time frame: 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.
Population: Efficacy Evaluable Population (Phase 1b/2 RP2D): participants who received ≥ 1 dose of ibrutinib (at RP2D) in combination with ≥ 1 dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had ≥ 1 adequate post-baseline overall disease assessment per RECIST 1.1 guidelines. Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6 | 17.9 percentage of participants |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6 | 14.9 percentage of participants |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6 | 6.9 percentage of participants |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6 | 35.7 percentage of participants |
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.
Time frame: 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.
Population: Efficacy Evaluable Population: Participants who received at least one dose of ibrutinib (at RP2D) in combination with at least one dose of the relevant companion drug and had at least one adequate post-baseline overall disease assessment per RECIST 1.1 guidelines or died prior to the first adequate post-baseline overall disease assessment. Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2 | 5.6 months |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2 | 4.1 months |
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).
Time frame: 21 days after the initiation of therapy at the start of Cycle 1
Population: DLT Evaluable Population: participants from Phase 1b who completed at least 21 days of treatment with ibrutinib in combination with the relevant anticancer agent after the initiation of study treatment at the start of Cycle 1, or those who discontinued from study treatment due to a DLT event prior to completion of DLT observation period. For UC Cohorts 5 and 6, a DLT-evaluable participant had ≥ 90% compliance with ibrutinib during Cycle 1 (the first 21 days).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 1 Participants |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 2 Participants |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
| Cohort 5 (UC): Ibrutinib 840 mg | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
| Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab | Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6 | 0 Participants |
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.
Time frame: 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)
Population: Efficacy Evaluable Population (Phase 1b/2 RP2D): participants who received ≥ 1 dose of ibrutinib (at RP2D) in combination with ≥ 1 dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had ≥ 1 adequate post-baseline overall disease assessment per RECIST 1.1 guidelines. Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 80.6 percentage of participants |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 66.7 percentage of participants |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 74.4 percentage of participants |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 83.0 percentage of participants |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 48.3 percentage of participants |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b/2 RP2D: DCR in Cohorts 1 to 6 | 71.4 percentage of participants |
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.
Time frame: 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)
Population: Confirmed responders in Efficacy Evaluable Population (Phase 1b/2 RP2D): participants who received ≥ 1 dose of ibrutinib (at RP2D) in combination with ≥ 1 dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had ≥ 1 adequate post-baseline overall disease assessment per RECIST 1.1 guidelines.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | 3.1 months |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | 4.4 months |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | 5.5 months |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | 11.1 months |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | 3.5 months |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6 | NA months |
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.
Time frame: 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)
Population: Efficacy Evaluable Population (Phase 1b/2 RP2D): participants who received ≥ 1 dose of ibrutinib (at RP2D) in combination with ≥ 1 dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had ≥ 1 adequate post-baseline overall disease assessment per RECIST 1.1 guidelines. Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: ORR in Cohorts 1 and 2 | 2.8 percentage of participants |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: ORR in Cohorts 1 and 2 | 26.3 percentage of participants |
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.
Time frame: 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)
Population: Efficacy Evaluable Population (Phase 1b/2 RP2D): participants who received ≥ 1 dose of ibrutinib (at RP2D) in combination with ≥ 1 dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had ≥ 1 adequate post-baseline overall disease assessment per RECIST 1.1 guidelines. Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 21.0 months |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 8.2 months |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 7.3 months |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 15.0 months |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 8.2 months |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6 | 15.7 months |
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.
Time frame: 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)
Population: Efficacy Evaluable Population (Phase 1b/2 RP2D): participants who received ≥ 1 dose of ibrutinib (at RP2D) in combination with ≥ 1 dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had ≥ 1 adequate post-baseline overall disease assessment per RECIST 1.1 guidelines. Per protocol, participants in Phase 1b receiving the Phase 2 RP2D and participants in Phase 2 RP2D were analyzed together.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b/2 RP2D: PFS in Cohorts 3 to 6 | 4.0 months |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b/2 RP2D: PFS in Cohorts 3 to 6 | 5.4 months |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b/2 RP2D: PFS in Cohorts 3 to 6 | 1.6 months |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b/2 RP2D: PFS in Cohorts 3 to 6 | 2.9 months |
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.
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 1103 L/h | Standard Deviation 1370 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 622 L/h | Standard Deviation 647 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 994 L/h | Standard Deviation 1217 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 1067 L/h | Standard Deviation 2742 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 1102 L/h | Standard Deviation 1412 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 645 L/h | Standard Deviation 248 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4 | 595 L/h | Standard Deviation 726 |
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.
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | 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 | Ibrutininb | 1467 ng∙h/mL | Standard Deviation 1793 |
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | 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 | PCI-45227 | 646 ng∙h/mL | Standard Deviation 698 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | 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 | Ibrutininb | 2568 ng∙h/mL | Standard Deviation 1968 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | 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 | PCI-45227 | 1810 ng∙h/mL | Standard Deviation 945 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | 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 | Ibrutininb | 2194 ng∙h/mL | Standard Deviation 3023 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | 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 | PCI-45227 | 1146 ng∙h/mL | Standard Deviation 786 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | 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 | Ibrutininb | 3503 ng∙h/mL | Standard Deviation 2613 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | 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 | PCI-45227 | 2604 ng∙h/mL | Standard Deviation 1435 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | 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 | Ibrutininb | 1253 ng∙h/mL | Standard Deviation 1232 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | 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 | PCI-45227 | 1254 ng∙h/mL | Standard Deviation 777 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | 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 | Ibrutininb | 980 ng∙h/mL | Standard Deviation 371 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | 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 | PCI-45227 | 1527 ng∙h/mL | Standard Deviation 717 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | 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 | Ibrutininb | 2807 ng∙h/mL | Standard Deviation 1955 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | 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 | PCI-45227 | 2178 ng∙h/mL | Standard Deviation 1278 |
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.
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | 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 | Ibrutininb | 1316 ng∙h/mL | Standard Deviation 1850 |
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | 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 | PCI-45227 | 548 ng∙h/mL | Standard Deviation 741 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | 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 | Ibrutininb | 2568 ng∙h/mL | Standard Deviation 1968 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | 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 | PCI-45227 | 1810 ng∙h/mL | Standard Deviation 945 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | 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 | Ibrutininb | 1180 ng∙h/mL | Standard Deviation 925 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | 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 | PCI-45227 | 859 ng∙h/mL | Standard Deviation 744 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | 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 | Ibrutininb | 3227 ng∙h/mL | Standard Deviation 2452 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | 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 | PCI-45227 | 2380 ng∙h/mL | Standard Deviation 1561 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | 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 | Ibrutininb | 1107 ng∙h/mL | Standard Deviation 1178 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | 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 | PCI-45227 | 1165 ng∙h/mL | Standard Deviation 803 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | 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 | Ibrutininb | 847 ng∙h/mL | Standard Deviation 310 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | 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 | PCI-45227 | 1527 ng∙h/mL | Standard Deviation 717 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | 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 | Ibrutininb | 2647 ng∙h/mL | Standard Deviation 1967 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | 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 | PCI-45227 | 2178 ng∙h/mL | Standard Deviation 1278 |
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.
Time frame: 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.
Population: Efficacy Evaluable Population (Phase 1b): participants who received at least one dose of ibrutinib (at RP2D) in combination with at least one dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had at least one adequate post-baseline overall disease assessment per RECIST 1.1 guidelines.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 66.7 percentage of participants |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 71.4 percentage of participants |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 75.0 percentage of participants |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 50.0 percentage of participants |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 77.8 percentage of participants |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 75.0 percentage of participants |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 80.0 percentage of participants |
| Cohort 5 (UC): Ibrutinib 840 mg | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 37.5 percentage of participants |
| Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab | Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6 | 76.9 percentage of participants |
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.
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable pharmacokinetic (PK) sample for this analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 172 ng/mL | Standard Deviation 188 |
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 51.2 ng/mL | Standard Deviation 50 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 351 ng/mL | Standard Deviation 247 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 147 ng/mL | Standard Deviation 77.6 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 260 ng/mL | Standard Deviation 287 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 127 ng/mL | Standard Deviation 74 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 424 ng/mL | Standard Deviation 319 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 198 ng/mL | Standard Deviation 106 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 164 ng/mL | Standard Deviation 193 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 106 ng/mL | Standard Deviation 64.6 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 172 ng/mL | Standard Deviation 116 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 154 ng/mL | Standard Deviation 76.1 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 371 ng/mL | Standard Deviation 270 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 177 ng/mL | Standard Deviation 98.9 |
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.
Time frame: 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.
Population: Efficacy Evaluable Population (Phase 1b): participants who received at least one dose of ibrutinib (at RP2D) in combination with at least one dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent therapy and: 1) Had measurable disease per RECIST 1.1 guidelines at baseline. 2) Had at least one adequate post-baseline overall disease assessment per RECIST 1.1 guidelines.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: ORR in Cohorts 1 to 6 | 0 percentage of participants |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: ORR in Cohorts 1 to 6 | 0 percentage of participants |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: ORR in Cohorts 1 to 6 | 50.0 percentage of participants |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: ORR in Cohorts 1 to 6 | 20.0 percentage of participants |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: ORR in Cohorts 1 to 6 | 11.1 percentage of participants |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: ORR in Cohorts 1 to 6 | 12.5 percentage of participants |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: ORR in Cohorts 1 to 6 | 0 percentage of participants |
| Cohort 5 (UC): Ibrutinib 840 mg | Phase 1b: ORR in Cohorts 1 to 6 | 12.5 percentage of participants |
| Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab | Phase 1b: ORR in Cohorts 1 to 6 | 38.5 percentage of participants |
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)/λz, where λz 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).
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | NA hours | — |
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | NA hours | — |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 6.28 hours | Standard Deviation 2.35 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 8.00 hours | Standard Deviation 0.489 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 7.24 hours | Standard Deviation 2.36 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 5.08 hours | Standard Deviation 0.304 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 4.31 hours | Standard Deviation 1.95 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 6.79 hours | Standard Deviation 4.38 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 5.54 hours | Standard Deviation 1.75 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 6.48 hours | Standard Deviation 2.11 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | NA hours | — |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 8.10 hours | — |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 5.52 hours | Standard Deviation 1.26 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 8.02 hours | Standard Deviation 2.17 |
Secondary
Phase 1b: Terminal Elimination Rate Constant (λz) 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 λz 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).
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | NA 1/h | — |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 0.125 1/h | Standard Deviation 0.0477 |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 0.0870 1/h | Standard Deviation 0.00535 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 0.101 1/h | Standard Deviation 0.0327 |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 0.137 1/h | Standard Deviation 0.00849 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 0.149 1/h | Standard Deviation 0.103 |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 0.195 1/h | Standard Deviation 0.0902 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 0.135 1/h | Standard Deviation 0.0349 |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 0.118 1/h | Standard Deviation 0.0399 |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | NA 1/h | — |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 0.0897 1/h | — |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 0.0942 1/h | Standard Deviation 0.0336 |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 0.132 1/h | Standard Deviation 0.0296 |
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.
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 15.0 hours |
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 15.0 hours |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 24.0 hours |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 24.0 hours |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 24.0 hours |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 24.0 hours |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 24.0 hours |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 24.0 hours |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 24.0 hours |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 24.0 hours |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 24.0 hours |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 24.0 hours |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 24.0 hours |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 24.0 hours |
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.
Time frame: Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose
Population: Participants with an evaluable PK sample for this analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 3.01 hours |
| Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 3.03 hours |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 2.00 hours |
| Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 3.93 hours |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 3.71 hours |
| Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 4.00 hours |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 4.00 hours |
| Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 4.00 hours |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 3.89 hours |
| Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 4.00 hours |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 2.89 hours |
| Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 2.99 hours |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | Ibrutininb | 2.03 hours |
| Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab | Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4 | PCI-45227 | 4.00 hours |