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Clinical Trial Results:
A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors

Summary
EudraCT number	2015-003656-40
Trial protocol	ES GB
Global end of trial date	20 Aug 2021

Results information
Results version number	v2(current)
This version publication date	19 Oct 2022
First version publication date	10 Feb 2021
Other versions	v1
Version creation reason	New data added to full data set Completion of additional cohorts

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

PCYC-1128-CA

ISRCTN number

US NCT number

NCT02599324

WHO universal trial number (UTN)

Sponsor organisation name

Pharmacyclics LCC, an AbbVie Company

Sponsor organisation address

1000 Gateway Blvd, South San Francisco, CA, United States, 94080

Public contact

Clinical Trial information, Pharmacyclics LLC, Pharmacyclics LLC, an AbbVie Company, 1 4087740330, info@pcyc.com

Scientific contact

Clinical Trial information, Pharmacyclics LLC , Pharmacyclics LLC, an AbbVie Company, 1 4087740330, info@pcyc.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Aug 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Aug 2021

Global end of trial reached?

Yes

Global end of trial date

20 Aug 2021

Was the trial ended prematurely?

Main objective of the trial

Phase 1b: Primary Objective: • To determine the recommended Phase 2 dose (RP2D) of ibrutinib in combination with everolimus in renal cell carcinoma (RCC) in Cohort 1, paclitaxel in urothelial carcinoma (UC) in Cohort 2, docetaxel in gastric adenocarcinoma (GC) in Cohort 3, cetuximab in colorectal adenocarcinoma (CRC) in Cohort 4, and pembrolizumab in UC in Cohort 6. • To confirm the RP2D of single agent ibrutinib in UC in Cohort 5. Phase 2: Primary Objectives: • To assess progression-free survival (PFS) of ibrutinib in combination with everolimus in RCC (Cohort 1) and ibrutinib in combination with paclitaxel for UC (Cohort 2) • To assess the overall response rate (ORR) of ibrutinib combination therapy in GC (Cohort 3), CRC (Cohort 4), UC (Cohort 6), and ibrutinib as a single agent in UC (Cohort 5).

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.

Background therapy

None

Evidence for comparator

No comparators were used for this Phase 1b/2 cohort study. The combination partners were selected based on whether these were already approved for the different solid tumor indications.

Actual start date of recruitment

01 Dec 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Korea, Republic of: 61

Country: Number of subjects enrolled

Spain: 88

Country: Number of subjects enrolled

United Kingdom: 33

Country: Number of subjects enrolled

United States: 80

Worldwide total number of subjects

262

EEA total number of subjects

121

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

129

From 65 to 84 years

128

85 years and over

Subject disposition

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Recruitment details

This study was conducted in 38 sites in the US (18), South Korea (8), UK (4) and Spain (8). The first subject consented 01 Dec 2015 and the last visit of the last subjects for this analysis was 20 August 2021.

Screening details

Disease-related cohort inclusion criteria included histologically confirmed RCC, GC or gastroesophageal junction adenocarcinoma, and K-RAS or N-RAS wild-type epidermal growth factor receptor-expressing CRC or advanced or metastatic urothelial carcinoma. Patients had to have 1 or more measurable lesions per RECIST 1.1 criteria.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

This was an open-label study; no blinding was performed. Subjects were enrolled into cohorts according to disease type.

Are arms mutually exclusive

Yes

Renal cell carcinoma

Arm description

Subjects were to receive ibrutinib PO qd in combination with everolimus (6 hours after ibrutinib) at a dose of 10 mg PO qd in 21-day cycles until unacceptable toxicity or disease progression occurred. If one component of the regimen was discontinued prior to RECIST 1.1 determined disease progression, the other component was to be continued until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Ibrutinib 840 mg, 560 mg, or 420 mg (6 x, 4 x, or 3 x 140 mg capsules, respectively) was administered PO qd with 8 ounces (approximately 240 mL) of water. The capsules were to be swallowed intact, and subjects were not to attempt to open capsules or dissolve them in water.

Investigational medicinal product name

Everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Everolimus 10 mg tablets were taken PO qd at the same time every day either consistently with food or consistently without food. Four × 2.5 mg tablets or 2 × 5.0 mg tablets could be substituted if 10 mg tablets were not available. Everolimus tablets were to be taken approximately 6 hours after ibrutinib capsules. Everolimus was administered in continual 21-day cycles. The first dose was delivered in the clinic on Day 1, after which subsequent dosing was usually on an outpatient basis. Everolimus was to be dispensed to subjects on Day 1 of each cycle.

Gastric Adenocarcinoma

Arm description

Subjects were to receive ibrutinib administered PO qd in combination with docetaxel at a dose of 60 to 75 mg/sqm administered as a 60-minute IV infusion q3weeks in 21-day cycles until unacceptable toxicity or disease progression occurred. If one component of the regimen was discontinued prior to RECIST 1.1 determined disease progression, the other component was to be continued until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered as a 60-minute infusion (±10 minutes) at a dose of 60 to 75 mg/sqm, given continually in 21-day cycles. Following the first dose of docetaxel combination therapy (on Cycle 1 Day 1), subjects were to remain in the clinic for 2 hours after completion of administration in order to assess any acute toxicity. On days when ibrutinib was to be administered, ibrutinib was to be taken in the clinic approximately 30 minutes prior to commencement of IV drug delivery. If an episode of febrile neutropenia, prolonged neutropenia, or neutropenic infection occurred despite use of granulocyte-colony stimulating factor, the docetaxel dose was to be reduced from 75 to 60 mg/sqm.

Colorectal Adenocarcinoma

Arm description

Subjects were to receive ibrutinib administered PO qd in combination with cetuximab at a dose of 400 mg/sqm administered initially as a 120-minute IV infusion, then weekly 250 mg/sqm IV over 60 minutes in 21-day cycles until unacceptable toxicity or disease progression occurred. If one component of the regimen was discontinued prior to RECIST 1.1 determined disease progression, the other component was to be continued until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

The recommended initial dose of cetuximab was 400 mg/sqm administered as a 120-minute IV infusion. The recommended subsequent weekly dose (all other infusions) was 250 mg/sqm infused over 60 minutes. On days when ibrutinib was to be administered, ibrutinib was to be taken in the clinic approximately 30 minutes prior to commencement of IV drug delivery.

Urothelial carcinoma paclitaxel

Arm description

In Phase 1b, patients in Cohort 2 (UC) were treated first with Ibrutinib 560 mg PO qd and Paclitaxel 80 mg/m^2 IV, once weekly in continual 3 weekly cycles (4 patients) followed by Ibrutinib 840 mg and the same dose of Paclitaxel (10 patients). In Phase 2, 49 additional patients were treated with Ibrutinib 840 mg PO qd and Paclitaxel 80 mg/m^2 IV. Treatment was given until disease progression or unacceptable toxicity. If one component of the regimen was discontinued prior to RECIST 1.1 determined disease progression, the other component was to be continued until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

In Phase 1b, patients in Cohort 2 (UC) were treated first with Ibrutinib 560 mg PO qd and Paxlitaxel 80 mg/m^2 IV (4 patients) followed by Ibrutinib 840 mg and the same dose of Paxlitaxel (10 patients). In Phase 2, 57 additional patients were treated with Ibrutinib 840 mg PO qd and Paxlitaxel 80 mg/m^2 IV

Investigational medicinal product name

paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

In Phase 1b, patients in Cohort 2 (UC) were treated first with Ibrutinib 560 mg PO qd and Paclitaxel 80 mg/m^2 IV (4 patients) followed by Ibrutinib 840 mg and the same dose of Paclitaxel (10 patients). In Phase 2, 57 additional patients were treated with Ibrutinib 840 mg PO qd and Paclitaxel 80 mg/m^2 IV

Urothelial carcinoma ibrutinib mono

Arm description

Monotherapy with ibrutinib 840 mg daily until treatment progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

ibrutinib 840 mg po daily

Urothelial carcinoma pembrolizumab

Arm description

Patients were treated with Ibrutinib 560 mg PO qd and pembrolizumab 200 mg as 30 min intravenous infusion, once weekly in continual 3 weekly cycles Treatment was given until disease progression or unacceptable toxicity. If one component of the regimen was discontinued prior to RECIST 1.1 determined disease progression, the other component was to be continued until disease progression or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

ibrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

ibrutinib 560 mg once daily.

Investigational medicinal product name

pembrolizumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

pembrolizumumab 200 mg as intravenous infusion for 30 minutes weekly in 3-weekly cycles

Number of subjects in period 1	Renal cell carcinoma	Gastric Adenocarcinoma	Colorectal Adenocarcinoma	Urothelial carcinoma paclitaxel	Urothelial carcinoma ibrutinib mono	Urothelial carcinoma pembrolizumab
Started	42	46	58	63	35	18
Completed	27	32	42	43	25	8
Not completed	15	14	16	20	10	10
Consent withdrawn by subject	2	4	5	8	3	4
Physician decision	-	2	1	2	-	-
Adverse event not related to PD	-	-	-	9	5	3
Adverse event, non-fatal	13	8	9	-	-	-
Death	-	-	1	1	2	1
Study terminated by sponsor	-	-	-	-	-	2

Baseline characteristics

Top of page

Reporting group title

Renal cell carcinoma

Reporting group description

Reporting group title

Gastric Adenocarcinoma

Reporting group description

Reporting group title

Colorectal Adenocarcinoma

Reporting group description

Reporting group title

Urothelial carcinoma paclitaxel

Reporting group description

Reporting group title

Urothelial carcinoma ibrutinib mono

Reporting group description

Monotherapy with ibrutinib 840 mg daily until treatment progression or unacceptable toxicity.

Reporting group title

Urothelial carcinoma pembrolizumab

Reporting group description

Reporting group values	Renal cell carcinoma	Gastric Adenocarcinoma	Colorectal Adenocarcinoma	Urothelial carcinoma paclitaxel	Urothelial carcinoma ibrutinib mono	Urothelial carcinoma pembrolizumab	Total
Number of subjects	42	46	58	63	35	18	262
Age categorical
Units: Subjects
Adults (18-64 years)	24	33	31	24	11	6	129
From 65-84 years	18	13	27	36	22	12	128
85 years and over	0	0	0	3	2	0	5
Age continuous
Units: years
median (full range (min-max))	62 (40 to 81)	58 (35 to 77)	62 (32 to 81)	68 (48 to 90)	71 (52 to 88)	70 (52 to 84)	-
Gender categorical
Units: Subjects
Female	9	12	28	8	9	5	71
Male	33	34	30	55	26	13	191

Subject analysis set title

Cohort 1: RCC subjects treated with 560 mg ibr + everolimus

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.

Subject analysis set title

Cohort 4: CRC subjects treated with 560 mg ibr + cetuximab

Subject analysis set type

Intention-to-treat

Subject analysis set description

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.

Subject analysis set title

Cohort 1: RCC subjects treated with 840 mg ibr + everolimus

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.

Subject analysis set title

Cohort 3: GC subjects treated with 560 mg ibr + docetaxel

Subject analysis set type

Intention-to-treat

Subject analysis set description

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.

Subject analysis set title

Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab

Subject analysis set type

Intention-to-treat

Subject analysis set description

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 1b.

Subject analysis set title

Cohort 2: UC subjects treated with 560 mg ibr + paclitaxel

Subject analysis set type

Intention-to-treat

Subject analysis set description

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.

Subject analysis set title

Cohort 5: UC subjects treated with 840 mg ibrutinib mono

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with UC received monotherapy with ibrutinib 840 mg QD.

Subject analysis set title

Cohort 6: UC subjects treated with 840 mg ibr + pembrolizumab

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks.

Subject analysis set title

Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m^2, once weekly, in continual 3 weekly cycles.

Subject analysis sets values	Cohort 1: RCC subjects treated with 560 mg ibr + everolimus	Cohort 4: CRC subjects treated with 560 mg ibr + cetuximab	Cohort 1: RCC subjects treated with 840 mg ibr + everolimus	Cohort 3: GC subjects treated with 560 mg ibr + docetaxel	Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab	Cohort 2: UC subjects treated with 560 mg ibr + paclitaxel	Cohort 5: UC subjects treated with 840 mg ibrutinib mono	Cohort 6: UC subjects treated with 840 mg ibr + pembrolizumab	Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel
Number of subjects	3	8	39	46	50	4	35	18	59
Age categorical
Units: Subjects
Adults (18-64 years)	1	6	23	33	25	3	11	6	21
From 65-84 years	2	2	16	13	25	1	22	12	35
85 years and over	0	0	0	0	0	0	2	0	3
Age continuous
Units: years
median (full range (min-max))	67 (61 to 72)	54.5 (35 to 77)	62 (40 to 81)	58 (35 to 77)	64 (32 to 81)	56.5 (48 to 69)	71 (52 to 88)	70 (52 to 84)	68.0 (48 to 90)
Gender categorical
Units: Subjects
Female	1	7	8	12	21	0	9	5
Male	2	1	31	34	29	4	26	13

End points

Top of page

Reporting group title

Renal cell carcinoma

Reporting group description

Reporting group title

Gastric Adenocarcinoma

Reporting group description

Reporting group title

Colorectal Adenocarcinoma

Reporting group description

Reporting group title

Urothelial carcinoma paclitaxel

Reporting group description

Reporting group title

Urothelial carcinoma ibrutinib mono

Reporting group description

Monotherapy with ibrutinib 840 mg daily until treatment progression or unacceptable toxicity.

Reporting group title

Urothelial carcinoma pembrolizumab

Reporting group description

Subject analysis set title

Cohort 1: RCC subjects treated with 560 mg ibr + everolimus

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with RCC received ibrutinib 560 mg QD in combination with everolimus 10 mg QD in Phase 1b.

Subject analysis set title

Cohort 4: CRC subjects treated with 560 mg ibr + cetuximab

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 1: RCC subjects treated with 840 mg ibr + everolimus

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with RCC received ibrutinib 840 mg QD in combination with everolimus 10 mg QD in Phase 1b.

Subject analysis set title

Cohort 3: GC subjects treated with 560 mg ibr + docetaxel

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Cohort 2: UC subjects treated with 560 mg ibr + paclitaxel

Subject analysis set type

Intention-to-treat

Subject analysis set description

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.

Subject analysis set title

Cohort 5: UC subjects treated with 840 mg ibrutinib mono

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with UC received monotherapy with ibrutinib 840 mg QD.

Subject analysis set title

Cohort 6: UC subjects treated with 840 mg ibr + pembrolizumab

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with UC received ibrutinib 560 mg QD in combination with pembrolizumab 200 mg IV every 3 weeks.

Subject analysis set title

Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants with UC received ibrutinib 840 mg QD in combination with paclitaxel 80 mg/m^2, once weekly, in continual 3 weekly cycles.

Primary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS) ^[1]

End point description

PFS was defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease or date of death from any cause, whichever occurs first, regardless of the use of subsequent anti-cancer treatment. PFS was primary endpoint for the combined Phase 1b/2 RP2D analyses in the RCC and UC Ibrutinib + paclitaxel arms and secondary endpoint in the GC, CRC, UC ibrutinib monotherapy arm, and the UC ibrutinib + pembrolizumab arms. The evaluations are based on the efficacy evaluable population treated with the RP2D. Due to limitation of the system, data is only provided for treatment arms for which 90% CIs could be calculated.

End point type

Primary

End point timeframe

Results were collected on an ongoing basis with a median time on study in the RCC arm of 37.4/22.5 mo (P1/P2), in the GC arm of 25.3 /11.1 mo (P1/P2), in the CRC arm of 34.1/22.1 mo (P1/P2) and ranging from 10.4 to 37.6 mo in the 3 UC cohorts.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Phase 1b/2 study not powered to show any statistical significant results. No statistical analyses performed.

End point values	Cohort 1: RCC subjects treated with 840 mg ibr + everolimus	Cohort 3: GC subjects treated with 560 mg ibr + docetaxel	Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab	Cohort 5: UC subjects treated with 840 mg ibrutinib mono	Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel
Number of subjects analysed	36 ^[2]	39 ^[3]	47 ^[4]	29 ^[5]	57 ^[6]
Units: months
number (confidence interval 90%)	5.6 (3.9 to 7.5)	4.0 (2.7 to 4.2)	5.4 (4.1 to 5.8)	1.6 (1.4 to 2.5)	4.1 (2.7 to 4.4)

Notes
[2] - Efficacy evaluable population
[3] - Efficacy evaluable population
[4] - Efficacy evaluable population
[5] - Efficacy evaluable population
[6] - Efficacy evaluable population

No statistical analyses for this end point

Primary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR) ^[7]

End point description

ORR was defined as the proportion of subjects achieving complete response (CR) or partial response (PR) with confirmation based on the best overall response (BOR) per RECIST 1.1 guidelines recorded since date of first dose of study treatment until first documentation of progressive disease or initiation of subsequent anti-cancer treatment, whichever occurs first. Confirmation of CR or PR required two consecutive assessments that are at least 28 days apart. ORR was primary endpoint in the GC, CRC RCC, UC ibrutinib monotherapy arm, and the UC ibrutinib + pembrolizumab arms and secondary endpoint in the UC Ibrutinib + paclitaxel arm . The evaluations are based on the efficacy evaluable population.

End point type

Primary

End point timeframe

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Phase 1b/2 study not powered to show any statistical significant results. No statistical analyses performed.

End point values	Cohort 1: RCC subjects treated with 840 mg ibr + everolimus	Cohort 3: GC subjects treated with 560 mg ibr + docetaxel	Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab	Cohort 5: UC subjects treated with 840 mg ibrutinib mono	Cohort 6: UC subjects treated with 840 mg ibr + pembrolizumab	Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel
Number of subjects analysed	36 ^[8]	39 ^[9]	47 ^[10]	29 ^[11]	14 ^[12]	57 ^[13]
Units: percent
number (confidence interval 90%)	2.8 (0.1 to 12.5)	17.9 (8.7 to 31.1)	14.9 (7.2 to 26.2)	6.9 (1.2 to 20.2)	35.7 (15.3 to 61.0)	26.3 (17.0 to 37.6)

Notes
[8] - Efficacy evaluable population
[9] - Efficacy evaluable population
[10] - Efficacy evaluable population
[11] - Efficacy evaluable population
[12] - Efficacy evaluable population
[13] - Efficacy evaluable population

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title

Disease Control Rate (DCR)

End point description

DCR was defined as the proportion of subjects achieving CR, PR, or stable disease of length ≥ 6 weeks based on the BOR per RECIST 1.1 guidelines recorded since date of first dose of study treatment until first documentation of progressive disease or initiation of subsequent anti-cancer treatment, whichever occurs first. Confirmation of CR or PR was not required. DCR was primary endpoint in the GC, CRC RCC, UC ibrutinib monotherapy arm, and the UC ibrutinib + pembrolizumab arms and secondary endpoint in the UC Ibrutinib + paclitaxel arm . The evaluations are based on the efficacy evaluable population.

End point type

Secondary

End point timeframe

End point values	Cohort 1: RCC subjects treated with 840 mg ibr + everolimus	Cohort 3: GC subjects treated with 560 mg ibr + docetaxel	Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab	Cohort 5: UC subjects treated with 840 mg ibrutinib mono	Cohort 6: UC subjects treated with 840 mg ibr + pembrolizumab	Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel
Number of subjects analysed	36 ^[14]	39 ^[15]	47 ^[16]	29 ^[17]	14 ^[18]	57 ^[19]
Units: percent
number (confidence interval 90%)	80.6 (66.6 to 90.5)	74.4 (60.4 to 85.4)	83.0 (71.4 to 91.2)	48.3 (32.0 to 64.8)	71.4 (46.0 to 89.6)	66.7 (55.0 to 77.0)

Notes
[14] - Efficacy evaluable population
[15] - Efficacy evaluable population
[16] - Efficacy evaluable population
[17] - Efficacy evaluable population
[18] - Efficacy evaluable population
[19] - Efficacy evaluable population

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from the date of first dose of study treatment to the date of death from any cause. The evaluations are based on the efficacy evaluable population treated with the RP2D. Due to limitation of the system, data is only provided for treatment arms for which 90% CIs could be calculated.

End point type

Secondary

End point timeframe

End point values	Cohort 1: RCC subjects treated with 840 mg ibr + everolimus	Cohort 3: GC subjects treated with 560 mg ibr + docetaxel	Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab	Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel
Number of subjects analysed	36 ^[20]	39 ^[21]	47 ^[22]	57 ^[23]
Units: months
number (confidence interval 90%)	21.0 (13.1 to 25.3)	7.3 (5.5 to 9.6)	15.0 (10.5 to 17.2)	8.2 (1.0 to 44.7)

Notes
[20] - Efficacy evaluable population
[21] - Efficacy evaluable population
[22] - Efficacy evaluable population
[23] - Efficacy evaluable population

No statistical analyses for this end point

Secondary: Duration of Response (DOR)

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End point title

Duration of Response (DOR)

End point description

DOR was defined for confirmed responders (PR or better) as the time from the date of initial response (PR or better) to the date of first documentation of progressive disease or death, whichever occurs first, regardless of use of subsequent anti-cancer treatment. Confirmed responders without documentation of progressive disease or death or with unknown status at the data extract were censored at the last adequate post-baseline disease assessment showing no evidence of progressive disease. Due to limitation of the system, data is only provided for treatment arms for which 90% CIs could be calculated.

End point type

Secondary

End point timeframe

End point values	Cohort 1: RCC subjects treated with 840 mg ibr + everolimus	Cohort 3: GC subjects treated with 560 mg ibr + docetaxel	Cohort 4: CRC subjects treated with 840 mg ibr + cetuximab	Cohort 2: UC subjects treated with 840 mg ibr + paclitaxel
Number of subjects analysed	1 ^[24]	7 ^[25]	7 ^[26]	15 ^[27]
Units: months
number (confidence interval 90%)	3.1 (3.1 to 3.1)	5.5 (3.0 to 18.0)	11.1 (4.2 to 12.5)	4.4 (3.1 to 6.8)

Notes
[24] - For patients having a response.
[25] - For patients having a response.
[26] - For patients having a response.
[27] - For patients having a response.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to 30 days after the last dose of study drug or the day before initiation of subsequent anti-cancer treatment, whichever comes first.

Adverse event reporting additional description

Note: for non-serious AEs a cutoff of 5% has been used for each individual safety reporting group below. Frequency and number of events was not available for non-serious AEs for all reporting group, i.e. a frequency of "0" for a non-serious AE thus means that the frequency of this AE was lower than 5%.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Subjects treated with RP2D in Cohorts 1, 3, and 4

Reporting group description

Safety is reported here for all subjects treated with the RP2D regardless of the indication for Cohorts 1, 3 and 4 (RCC, GC, CRC). Safety of subjects treated with lower ibrutinib doses in the Phase I part of the study are not reported due to the low number of subjects.

Reporting group title

Cohort 2: UC Subjects treated with 840 mg ibr + paclitaxel

Reporting group description

Safety is reported here for all UC subjects treated in Cohort 2 with the RP2D of 840 mg ibrutinib. Safety of subjects treated with lower ibrutinib doses in the Phase I part of the study are not reported due to the low number of subjects.

Reporting group title

Cohort 5: UC Subjects treated with 840 mg ibr mono

Reporting group description

Safety is reported here for all UC subjects treated in Cohort 5 with the RP2D of 840 mg ibrutinib as monotherapy. No patients have been treated with a lower dose in this cohort.

Reporting group title

Cohort 6: UC Subjects treated with 560 mg ibr + pembrolizumab

Reporting group description

Safety is reported here for all UC subjects treated in Cohort 6 with the RP2D of 560 mg ibrutinib. No subjects have been treated with a lower dose.

Serious adverse events	Subjects treated with RP2D in Cohorts 1, 3, and 4	Cohort 2: UC Subjects treated with 840 mg ibr + paclitaxel	Cohort 5: UC Subjects treated with 840 mg ibr mono	Cohort 6: UC Subjects treated with 560 mg ibr + pembrolizumab
Total subjects affected by serious adverse events
subjects affected / exposed	62 / 135 (45.93%)	36 / 59 (61.02%)	19 / 35 (54.29%)	10 / 18 (55.56%)
number of deaths (all causes)	88	22	22	7
number of deaths resulting from adverse events	7	7	7	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Colorectal adenocarcinoma
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	0 / 135 (0.00%)	2 / 59 (3.39%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
Tumour pain
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Pleurodesis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	4 / 135 (2.96%)	2 / 59 (3.39%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 135 (0.74%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Sudden death
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	3 / 135 (2.22%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pulmonary oedema
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood urine present
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Gun shot wound
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Urinary tract stoma complication
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 135 (1.48%)	1 / 59 (1.69%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleuropericarditis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Subarachnoid haemorrhage
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	11 / 135 (8.15%)	2 / 59 (3.39%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	8 / 14	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	4 / 135 (2.96%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	3 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	3 / 135 (2.22%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	4 / 5	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 135 (2.96%)	1 / 59 (1.69%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 135 (2.22%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	3 / 135 (2.22%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	3 / 135 (2.22%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 135 (1.48%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	2 / 135 (1.48%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal motility disorder
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 135 (1.48%)	2 / 59 (3.39%)	1 / 35 (2.86%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	3 / 3	1 / 2	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 135 (0.74%)	2 / 59 (3.39%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder pain
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal injury
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neck mass
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	8 / 135 (5.93%)	2 / 59 (3.39%)	1 / 35 (2.86%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	1 / 9	1 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	5 / 135 (3.70%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	4 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 135 (1.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 135 (0.00%)	7 / 59 (11.86%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 13	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Emphysematous cystitis
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii infection
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pneumonia streptococcal
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureteritis
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 135 (0.00%)	1 / 59 (1.69%)	1 / 35 (2.86%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Klebsiella infection
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	1 / 35 (2.86%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 135 (0.74%)	2 / 59 (3.39%)	1 / 35 (2.86%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 135 (0.74%)	1 / 59 (1.69%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperphosphataemia
subjects affected / exposed	1 / 135 (0.74%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Subjects treated with RP2D in Cohorts 1, 3, and 4	Cohort 2: UC Subjects treated with 840 mg ibr + paclitaxel	Cohort 5: UC Subjects treated with 840 mg ibr mono	Cohort 6: UC Subjects treated with 560 mg ibr + pembrolizumab
Total subjects affected by non serious adverse events
subjects affected / exposed	132 / 135 (97.78%)	59 / 59 (100.00%)	34 / 35 (97.14%)	17 / 18 (94.44%)
Vascular disorders
Hypotension
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	2 / 35 (5.71%)	1 / 18 (5.56%)
occurrences all number	0	3	3	1
Jugular vein distension
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Pallor
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Hypertension
subjects affected / exposed	0 / 135 (0.00%)	4 / 59 (6.78%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	8	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	52 / 135 (38.52%)	19 / 59 (32.20%)	10 / 35 (28.57%)	8 / 18 (44.44%)
occurrences all number	120	43	14	15
Asthenia
subjects affected / exposed	35 / 135 (25.93%)	29 / 59 (49.15%)	12 / 35 (34.29%)	0 / 18 (0.00%)
occurrences all number	91	125	19	0
Oedema peripheral
subjects affected / exposed	21 / 135 (15.56%)	15 / 59 (25.42%)	6 / 35 (17.14%)	3 / 18 (16.67%)
occurrences all number	29	21	6	5
Pyrexia
subjects affected / exposed	21 / 135 (15.56%)	16 / 59 (27.12%)	3 / 35 (8.57%)	3 / 18 (16.67%)
occurrences all number	27	26	5	3
Chills
subjects affected / exposed	7 / 135 (5.19%)	4 / 59 (6.78%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	10	4	0	0
Influenza like illness
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	1 / 18 (5.56%)
occurrences all number	0	0	2	1
Non-cardiac chest pain
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Swelling
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Gait disturbance
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	4	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	3	0	1
Reproductive system and breast disorders
Vaginal discharge
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	2
Balanoposthitis
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	4	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	37 / 135 (27.41%)	9 / 59 (15.25%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	54	11	0	2
Cough
subjects affected / exposed	24 / 135 (17.78%)	5 / 59 (8.47%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	37	5	0	0
Dyspnoea
subjects affected / exposed	12 / 135 (8.89%)	9 / 59 (15.25%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	25	13	0	0
Oropharyngeal pain
subjects affected / exposed	11 / 135 (8.15%)	0 / 59 (0.00%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	13	0	0	2
Haemoptysis
subjects affected / exposed	8 / 135 (5.93%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	10	0	0	0
Productive cough
subjects affected / exposed	8 / 135 (5.93%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	10	0	0	0
Pleural effusion
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences all number	0	0	2	0
Sputum discoloured
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	3	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	11 / 135 (8.15%)	6 / 59 (10.17%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	14	6	0	2
Anxiety
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	1 / 18 (5.56%)
occurrences all number	0	0	2	1
Depression
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	2
Depressed mood
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	3	0	0
Investigations
Weight decreased
subjects affected / exposed	17 / 135 (12.59%)	0 / 59 (0.00%)	3 / 35 (8.57%)	1 / 18 (5.56%)
occurrences all number	21	0	4	1
Platelet count decreased
subjects affected / exposed	14 / 135 (10.37%)	7 / 59 (11.86%)	0 / 35 (0.00%)	3 / 18 (16.67%)
occurrences all number	19	11	0	3
Aspartate aminotransferase increased
subjects affected / exposed	11 / 135 (8.15%)	4 / 59 (6.78%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	12	10	0	0
Neutrophil count decreased
subjects affected / exposed	11 / 135 (8.15%)	9 / 59 (15.25%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	24	11	0	0
Blood creatinine increased
subjects affected / exposed	10 / 135 (7.41%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	24	0	0	1
White blood cell count decreased
subjects affected / exposed	9 / 135 (6.67%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	18	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	8 / 135 (5.93%)	4 / 59 (6.78%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	9	15	0	1
Protein urine present
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
C-reactive protein increased
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	2
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	1 / 18 (5.56%)
occurrences all number	0	0	4	1
Blood bilirubin increased
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	3
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	2
Blood urea increased
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	2
Hypoalbuminaemia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences all number	0	0	3	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	3 / 18 (16.67%)
occurrences all number	0	0	2	4
Contusion
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Post procedural haemorrhage
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Sinus bradycardia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	22 / 135 (16.30%)	10 / 59 (16.95%)	9 / 35 (25.71%)	4 / 18 (22.22%)
occurrences all number	28	15	13	4
Headache
subjects affected / exposed	12 / 135 (8.89%)	3 / 59 (5.08%)	3 / 35 (8.57%)	1 / 18 (5.56%)
occurrences all number	16	3	4	1
Peripheral sensory neuropathy
subjects affected / exposed	11 / 135 (8.15%)	15 / 59 (25.42%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	16	31	0	1
Neurotoxicity
subjects affected / exposed	7 / 135 (5.19%)	10 / 59 (16.95%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	21	32	0	0
Head discomfort
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Hypoaesthesia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Neuropathy peripheral
subjects affected / exposed	0 / 135 (0.00%)	5 / 59 (8.47%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	15	0	1
Paraesthesia
subjects affected / exposed	0 / 135 (0.00%)	4 / 59 (6.78%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	4	0	1
Dysgeusia
subjects affected / exposed	0 / 135 (0.00%)	6 / 59 (10.17%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	10	0	0
Peripheral motor neuropathy
subjects affected / exposed	0 / 135 (0.00%)	4 / 59 (6.78%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	6	0	0
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	6	0	0
Somnolence
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	3	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	51 / 135 (37.78%)	24 / 59 (40.68%)	6 / 35 (17.14%)	0 / 18 (0.00%)
occurrences all number	160	64	12	0
Thrombocytopenia
subjects affected / exposed	24 / 135 (17.78%)	5 / 59 (8.47%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	55	10	0	3
Neutropenia
subjects affected / exposed	18 / 135 (13.33%)	10 / 59 (16.95%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	46	13	0	0
Coagulopathy
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Increased tendency to bruise
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Iron deficiency anaemia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Eye disorders
Dry eye
subjects affected / exposed	7 / 135 (5.19%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	10	0	0	0
Cataract
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Vitreous detachment
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	70 / 135 (51.85%)	43 / 59 (72.88%)	10 / 35 (28.57%)	8 / 18 (44.44%)
occurrences all number	148	106	14	8
Stomatitis
subjects affected / exposed	68 / 135 (50.37%)	17 / 59 (28.81%)	3 / 35 (8.57%)	4 / 18 (22.22%)
occurrences all number	154	28	3	8
Nausea
subjects affected / exposed	46 / 135 (34.07%)	23 / 59 (38.98%)	16 / 35 (45.71%)	6 / 18 (33.33%)
occurrences all number	82	37	19	7
Vomiting
subjects affected / exposed	34 / 135 (25.19%)	17 / 59 (28.81%)	10 / 35 (28.57%)	1 / 18 (5.56%)
occurrences all number	55	25	15	1
Constipation
subjects affected / exposed	23 / 135 (17.04%)	19 / 59 (32.20%)	9 / 35 (25.71%)	7 / 18 (38.89%)
occurrences all number	26	21	12	7
Abdominal pain
subjects affected / exposed	18 / 135 (13.33%)	6 / 59 (10.17%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	27	6	0	1
Dyspepsia
subjects affected / exposed	17 / 135 (12.59%)	7 / 59 (11.86%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences all number	20	7	2	0
Abdominal pain upper
subjects affected / exposed	13 / 135 (9.63%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	19	4	0	0
Dry mouth
subjects affected / exposed	10 / 135 (7.41%)	0 / 59 (0.00%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	22	0	0	2
Dysphagia
subjects affected / exposed	7 / 135 (5.19%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	9	0	0	0
Change of bowel habit
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Gastritis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Lip oedema
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Lip pain
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Oral mucosal erythema
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Abdominal distension
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences all number	0	0	2	0
Haemorrhoids
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	3	0	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Hepatic function abnormal
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences all number	0	0	4	0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	48 / 135 (35.56%)	7 / 59 (11.86%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	160	11	0	0
Pruritus
subjects affected / exposed	30 / 135 (22.22%)	4 / 59 (6.78%)	3 / 35 (8.57%)	3 / 18 (16.67%)
occurrences all number	42	5	3	3
Dry skin
subjects affected / exposed	27 / 135 (20.00%)	7 / 59 (11.86%)	2 / 35 (5.71%)	2 / 18 (11.11%)
occurrences all number	45	9	2	2
Rash maculo-papular
subjects affected / exposed	19 / 135 (14.07%)	5 / 59 (8.47%)	2 / 35 (5.71%)	5 / 18 (27.78%)
occurrences all number	71	11	2	12
Alopecia
subjects affected / exposed	17 / 135 (12.59%)	18 / 59 (30.51%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	20	24	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	16 / 135 (11.85%)	6 / 59 (10.17%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	38	6	0	0
Petechiae
subjects affected / exposed	9 / 135 (6.67%)	0 / 59 (0.00%)	5 / 35 (14.29%)	0 / 18 (0.00%)
occurrences all number	17	0	6	0
Rash erythematous
subjects affected / exposed	9 / 135 (6.67%)	4 / 59 (6.78%)	2 / 35 (5.71%)	1 / 18 (5.56%)
occurrences all number	12	6	4	1
Rash
subjects affected / exposed	8 / 135 (5.93%)	6 / 59 (10.17%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	10	7	0	0
Hyperhidrosis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Night sweats
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Purpura
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Seborrhoeic dermatitis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Urticaria
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Renal and urinary disorders
Proteinuria
subjects affected / exposed	9 / 135 (6.67%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	18	0	0	0
Haematuria
subjects affected / exposed	0 / 135 (0.00%)	12 / 59 (20.34%)	0 / 35 (0.00%)	5 / 18 (27.78%)
occurrences all number	0	18	0	8
Acute kidney injury
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	3 / 35 (8.57%)	1 / 18 (5.56%)
occurrences all number	0	0	4	1
Dysuria
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	4	0	1
Pollakiuria
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Urinary tract obstruction
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	2
Renal impairment
subjects affected / exposed	0 / 135 (0.00%)	4 / 59 (6.78%)	2 / 35 (5.71%)	0 / 18 (0.00%)
occurrences all number	0	12	3	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	16 / 135 (11.85%)	12 / 59 (20.34%)	2 / 35 (5.71%)	6 / 18 (33.33%)
occurrences all number	27	20	3	12
Back pain
subjects affected / exposed	13 / 135 (9.63%)	10 / 59 (16.95%)	2 / 35 (5.71%)	2 / 18 (11.11%)
occurrences all number	14	12	2	2
Myalgia
subjects affected / exposed	12 / 135 (8.89%)	8 / 59 (13.56%)	2 / 35 (5.71%)	1 / 18 (5.56%)
occurrences all number	16	9	2	1
Pain in extremity
subjects affected / exposed	9 / 135 (6.67%)	5 / 59 (8.47%)	3 / 35 (8.57%)	2 / 18 (11.11%)
occurrences all number	14	6	4	3
Musculoskeletal pain
subjects affected / exposed	7 / 135 (5.19%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	8	0	0	0
Muscle spasms
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	0	0	4
Muscular weakness
subjects affected / exposed	0 / 135 (0.00%)	4 / 59 (6.78%)	0 / 35 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	4	0	4
Flank pain
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	2
Bone pain
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Infections and infestations
Paronychia
subjects affected / exposed	29 / 135 (21.48%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	54	0	0	0
Urinary tract infection
subjects affected / exposed	11 / 135 (8.15%)	6 / 59 (10.17%)	5 / 35 (14.29%)	1 / 18 (5.56%)
occurrences all number	13	10	5	1
Conjunctivitis
subjects affected / exposed	9 / 135 (6.67%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	13	0	0	0
Bronchitis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Fungal infection
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Herpes virus infection
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Herpes zoster
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Rash pustular
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 135 (0.00%)	3 / 59 (5.08%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	3	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	50 / 135 (37.04%)	25 / 59 (42.37%)	12 / 35 (34.29%)	2 / 18 (11.11%)
occurrences all number	92	50	15	2
Hypokalaemia
subjects affected / exposed	18 / 135 (13.33%)	7 / 59 (11.86%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	33	9	0	2
Hypomagnesaemia
subjects affected / exposed	16 / 135 (11.85%)	6 / 59 (10.17%)	3 / 35 (8.57%)	2 / 18 (11.11%)
occurrences all number	35	10	4	3
Dehydration
subjects affected / exposed	8 / 135 (5.93%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	9	0	0	0
Hypocalcaemia
subjects affected / exposed	8 / 135 (5.93%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	14	0	0	0
Hypophosphataemia
subjects affected / exposed	8 / 135 (5.93%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	12	0	0	2
Hyperglycaemia
subjects affected / exposed	7 / 135 (5.19%)	0 / 59 (0.00%)	0 / 35 (0.00%)	0 / 18 (0.00%)
occurrences all number	21	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	0	2
Gout
subjects affected / exposed	0 / 135 (0.00%)	0 / 59 (0.00%)	0 / 35 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1
Hyponatraemia
subjects affected / exposed	0 / 135 (0.00%)	4 / 59 (6.78%)	4 / 35 (11.43%)	1 / 18 (5.56%)
occurrences all number	0	4	8	1

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Were there any global substantial amendments to the protocol? Yes

16 Feb 2016

• New starting dose of 560 mg for ibrutinib • Dose escalation clinical trial design for Phase 1b • Revised inclusion criteria for CRC cohort • Revised eligibility criteria for subjects with platelet counts above 100 × 109/L to match relevant labelling • Revise eligibility criteria for hemoglobin • Revised DLT criteria • Refined DLT evaluable population • Updated Pharmacodynamics Collection Schedule • Updated protocol template language to align with most current Investigator’s Brochure

25 Jan 2019

• Cohort 5 (single agent ibrutinib) was added to the study • Summary of Clinical Safety section was updated to align with the current ibrutinib Investigator’s Brochure (version 12.0) • Summary of Clinical Data section was updated to provide safety data from the interim analysis of Study 1128 • Rationale in Specific Solid Tumors section was updated to include information on UC and GC solid tumors • Dosing Rationale section was updated to include the rationale for the 560 mg and 840 mg starting doses (for UC and Cohorts 2 and 5) • The study objectives were updated to include the primary objectives in Phase 1b and Phase 2 and the secondary objectives in Phase 2 for Cohort 5 • Background information on safety and efficacy of ibrutinib monotherapy in previously treated UC and combination therapy in previously treated UC and GC was added to the Overview of Study Design • Updates were made to the permitted concomitant medications • Updates were made to minor surgical procedures to include information pertinent to UC Cohort 5

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results:
A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors

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Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Primary: Overall Response Rate (ORR)

Primary: Overall Response Rate (ORR)

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Clinical trials

Clinical Trial Results: A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Primary: Overall Response Rate (ORR)

Primary: Overall Response Rate (ORR)

Secondary: Disease Control Rate (DCR)

Secondary: Disease Control Rate (DCR)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Duration of Response (DOR)

Secondary: Duration of Response (DOR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors