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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Participants with an evaluable pharmacokinetic (PK) sample for this analysis

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.

Participants with an evaluable PK sample for this analysis

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.

Participants with an evaluable PK sample for this analysis

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.

Participants with an evaluable PK sample for this analysis

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.

Participants with an evaluable PK sample for this analysis

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).

Participants with an evaluable PK sample for this analysis

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).

Participants with an evaluable PK sample for this analysis

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.

Participants with an evaluable PK sample for this analysis