Trial Outcomes & Findings for Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors (NCT NCT02599324)

Last Updated: 2023-11-18

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

263 participants

Primary outcome timeframe

21 days after the initiation of therapy at the start of Cycle 1

Results posted on

2023-11-18

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus Phase 1b: Participants with RCC received ibrutinib 560 mg once daily (QD) in combination with everolimus 10 mg QD.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus Phase 1b: Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD. Phase 2 (RP2D): Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel Phase 1b: Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel Phase 1b: Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles. Phase 2 (RP2D): Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel Phase 1b: 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. Phase 2 (RP2D): 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.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab Phase 1b: 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.	Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab Phase 1b: 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. Phase 2 (RP2D): 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.	Cohort 5 (UC): Ibrutinib 840 mg Phase 1b: Participants with UC received monotherapy with ibrutinib 840 mg QD. Phase 2 (RP2D): Participants with UC received monotherapy with ibrutinib 840 mg QD.	Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab Phase 1b: Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks. Phase 2 (RP2D): Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks.
Phase 1b STARTED	3	7	4	10	21	8	12	10	17
Phase 1b COMPLETED	3	7	4	10	21	8	12	10	17
Phase 1b NOT COMPLETED	0	0	0	0	0	0	0	0	0
Phase 2 (RP2D) STARTED	0	38	0	55	31	0	44	33	13
Phase 2 (RP2D) Continued From Phase 1b	0	6	0	6	6	0	6	8	12
Phase 2 (RP2D) Enrolled in Phase 2	0	32	0	49	25	0	39	25	1
Phase 2 (RP2D) Enrolled and Treated in Phase 2	0	32	0	49	25	0	38	25	1
Phase 2 (RP2D) COMPLETED	0	38	0	55	31	0	44	33	13
Phase 2 (RP2D) NOT COMPLETED	0	0	0	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=3 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=39 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=4 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=59 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel n=46 Participants 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.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab n=8 Participants 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.	Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab n=50 Participants 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.	Cohort 5 (UC): Ibrutinib 840 mg n=35 Participants Participants with UC received monotherapy with ibrutinib 840 mg QD.	Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab n=18 Participants Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks.	Total n=262 Participants Total of all reporting groups
Age, Customized 18 - 64 years	1 Participants n=5 Participants	23 Participants n=7 Participants	3 Participants n=5 Participants	21 Participants n=4 Participants	33 Participants n=21 Participants	6 Participants n=10 Participants	25 Participants n=115 Participants	11 Participants n=6 Participants	6 Participants n=6 Participants	129 Participants n=64 Participants
Age, Customized 65 - 84 years	2 Participants n=5 Participants	16 Participants n=7 Participants	1 Participants n=5 Participants	35 Participants n=4 Participants	13 Participants n=21 Participants	2 Participants n=10 Participants	25 Participants n=115 Participants	22 Participants n=6 Participants	12 Participants n=6 Participants	128 Participants n=64 Participants
Age, Customized ≥ 85 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	2 Participants n=6 Participants	0 Participants n=6 Participants	5 Participants n=64 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	8 Participants n=7 Participants	0 Participants n=5 Participants	8 Participants n=4 Participants	12 Participants n=21 Participants	7 Participants n=10 Participants	21 Participants n=115 Participants	9 Participants n=6 Participants	5 Participants n=6 Participants	71 Participants n=64 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	31 Participants n=7 Participants	4 Participants n=5 Participants	51 Participants n=4 Participants	34 Participants n=21 Participants	1 Participants n=10 Participants	29 Participants n=115 Participants	26 Participants n=6 Participants	13 Participants n=6 Participants	191 Participants n=64 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	7 Participants n=21 Participants	3 Participants n=10 Participants	0 Participants n=115 Participants	1 Participants n=6 Participants	1 Participants n=6 Participants	18 Participants n=64 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	39 Participants n=7 Participants	2 Participants n=5 Participants	55 Participants n=4 Participants	39 Participants n=21 Participants	4 Participants n=10 Participants	50 Participants n=115 Participants	34 Participants n=6 Participants	17 Participants n=6 Participants	243 Participants n=64 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants	1 Participants n=64 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	1 Participants n=6 Participants	1 Participants n=64 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	7 Participants n=7 Participants	0 Participants n=5 Participants	12 Participants n=4 Participants	12 Participants n=21 Participants	2 Participants n=10 Participants	31 Participants n=115 Participants	5 Participants n=6 Participants	0 Participants n=6 Participants	69 Participants n=64 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants	0 Participants n=64 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	1 Participants n=10 Participants	1 Participants n=115 Participants	0 Participants n=6 Participants	1 Participants n=6 Participants	4 Participants n=64 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	32 Participants n=7 Participants	4 Participants n=5 Participants	47 Participants n=4 Participants	32 Participants n=21 Participants	5 Participants n=10 Participants	18 Participants n=115 Participants	30 Participants n=6 Participants	16 Participants n=6 Participants	187 Participants n=64 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants	0 Participants n=64 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants	1 Participants n=64 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=3 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=6 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=4 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=6 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel n=7 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab n=3 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab n=6 Participants 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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg n=7 Participants Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab n=10 Participants Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks in Phase 1b.
Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6	0 Participants	1 Participants	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Maximum time on study for Cohort 1 (Phase 1b/2 RP2D) was 37.4 months; for Cohort 2 (Phase 1b/2 RP2D) was 44.7 months.

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.

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=36 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=57 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	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 in Phase 1b.	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 in Phase 1b.	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 Phase 1b.	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 Phase 1b.	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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	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 in Phase 1b.
Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2	5.6 months Interval 3.9 to 7.5	4.1 months Interval 2.7 to 4.4	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Maximum time on study (Phase 1b/2 RP2D) for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.

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.

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=39 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=47 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=29 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=14 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	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 Phase 1b.	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 Phase 1b.	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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	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 in Phase 1b.
Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6	17.9 percentage of participants Interval 8.7 to 31.1	14.9 percentage of participants Interval 7.2 to 26.2	6.9 percentage of participants Interval 1.2 to 20.2	35.7 percentage of participants Interval 15.3 to 61.0	—	—	—	—	—

SECONDARY outcome

Timeframe: Maximum time on study (Phase 1b only) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 34.2 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=3 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=7 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=4 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=10 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel n=18 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab n=8 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab n=10 Participants 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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg n=8 Participants Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab n=13 Participants Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks in Phase 1b.
Phase 1b: ORR in Cohorts 1 to 6	0 percentage of participants Interval 0.0 to 63.2	0 percentage of participants Interval 0.0 to 34.8	50.0 percentage of participants Interval 9.8 to 90.2	20.0 percentage of participants Interval 3.7 to 50.7	11.1 percentage of participants Interval 2.0 to 31.0	12.5 percentage of participants Interval 0.6 to 47.1	0 percentage of participants Interval 0.0 to 25.9	12.5 percentage of participants Interval 0.6 to 47.1	38.5 percentage of participants Interval 16.6 to 64.5

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=3 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=7 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=4 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=10 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel n=18 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab n=8 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 840 mg + Cetuximab n=10 Participants 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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg n=8 Participants Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	Cohort 6 (UC): Ibrutinib 560 mg + Pembrolizumab n=13 Participants Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks in Phase 1b.
Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6	66.7 percentage of participants Interval 13.5 to 98.3	71.4 percentage of participants Interval 34.1 to 94.7	75.0 percentage of participants Interval 24.9 to 98.7	50.0 percentage of participants Interval 22.2 to 77.8	77.8 percentage of participants Interval 56.1 to 92.0	75.0 percentage of participants Interval 40.0 to 95.4	80.0 percentage of participants Interval 49.3 to 96.3	37.5 percentage of participants Interval 11.1 to 71.1	76.9 percentage of participants Interval 50.5 to 93.4

SECONDARY outcome

Timeframe: Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates)

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=36 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=57 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=39 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=47 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel n=29 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab n=14 Participants 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 Phase 1b.	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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	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 in Phase 1b.
Phase 1b/2 RP2D: DCR in Cohorts 1 to 6	80.6 percentage of participants Interval 66.6 to 90.5	66.7 percentage of participants Interval 55.0 to 77.0	74.4 percentage of participants Interval 60.4 to 85.4	83.0 percentage of participants Interval 71.4 to 91.2	48.3 percentage of participants Interval 32.0 to 64.8	71.4 percentage of participants Interval 46.0 to 89.6	—	—	—

SECONDARY outcome

Timeframe: Maximum time on study (Phase 1b/2 RP2D) for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates)

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=39 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=47 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=29 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=14 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	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 Phase 1b.	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 Phase 1b.	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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	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 in Phase 1b.
Phase 1b/2 RP2D: PFS in Cohorts 3 to 6	4.0 months Interval 2.7 to 4.2	5.4 months Interval 4.1 to 5.8	1.6 months Interval 1.4 to 2.5	2.9 months Interval 1.7 to Not estimable because of the small number of events.	—	—	—	—	—

SECONDARY outcome

Timeframe: Maximum time on study for Cohort 1 (Phase 1b/2 RP2D) was 37.4 months; for Cohort 2 (Phase 1b/2 RP2D) was 44.7 months. (Reverse Kaplan-Meier estimates)

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=36 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=57 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	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 in Phase 1b.	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 in Phase 1b.	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 Phase 1b.	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 Phase 1b.	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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	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 in Phase 1b.
Phase 1b/2 RP2D: ORR in Cohorts 1 and 2	2.8 percentage of participants Interval 0.1 to 12.5	26.3 percentage of participants Interval 17.0 to 37.6	—	—	—	—	—	—	—

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus n=36 Participants Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus n=57 Participants Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.	Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel n=39 Participants Participants with UC received ibrutinib 560 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel n=47 Participants Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m\^2, once weekly, in continual 3 weekly cycles in Phase 1b.	Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel n=29 Participants 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 Phase 1b.	Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab n=14 Participants 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 Phase 1b.	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 in Phase 1b.	Cohort 5 (UC): Ibrutinib 840 mg Participants with UC received monotherapy with ibrutinib 840 mg QD in Phase 1b.	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 in Phase 1b.
Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6	21.0 months Interval 13.1 to 25.3	8.2 months Interval 6.2 to 10.3	7.3 months Interval 5.5 to 9.6	15.0 months Interval 10.5 to 17.2	8.2 months Interval 4.4 to Not estimable because of the small number of events.	15.7 months Interval 7.7 to Not estimable because of the small number of events.	—	—	—

SECONDARY outcome

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.

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.