Trial Outcomes & Findings for Study of BTK Inhibitor, Ibrutinib in Combination With Carfilzomib in Subjects With Relapsed and Refractory Multiple Myeloma (NCT NCT01962792)

NCT ID: NCT01962792

Last Updated: 2021-12-21

Results Overview

-To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

84 participants

Primary outcome timeframe

up to 4 years

Results posted on

2021-12-21

Participant Flow

A total of 84 participants were enrolled and received at least 1 dose of study treatment (All-treated population); of these participants, a total of 59 received treatment at the recommended Phase 2 dose of study drug (All RP2D population).

Participant milestones

Participant milestones
Measure	Cohort 1 (560 mg) Ibrutinib PO 560mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Overall Study STARTED	3	5	17	59
Overall Study COMPLETED	3	5	17	59
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of BTK Inhibitor, Ibrutinib in Combination With Carfilzomib in Subjects With Relapsed and Refractory Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 (560 mg) n=3 Participants Ibrutinib PO 560mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) n=5 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) n=17 Participants Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) n=59 Participants Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	Total n=84 Participants Total of all reporting groups
Age, Categorical <=18 years	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
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	1 Participants n=7 Participants	12 Participants n=5 Participants	33 Participants n=4 Participants	46 Participants n=21 Participants
Age, Categorical >=65 years	3 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	26 Participants n=4 Participants	38 Participants n=21 Participants
Age, Continuous	69.0 years STANDARD_DEVIATION 1.53 • n=5 Participants	72.0 years STANDARD_DEVIATION 9.21 • n=7 Participants	60.0 years STANDARD_DEVIATION 10.29 • n=5 Participants	63.0 years STANDARD_DEVIATION 9.86 • n=4 Participants	63.5 years STANDARD_DEVIATION 9.88 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	1 Participants n=7 Participants	11 Participants n=5 Participants	28 Participants n=4 Participants	41 Participants n=21 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	31 Participants n=4 Participants	43 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	7 Participants n=4 Participants	10 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants	51 Participants n=4 Participants	73 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment United States	3 participants n=5 Participants	5 participants n=7 Participants	17 participants n=5 Participants	59 participants n=4 Participants	84 participants n=21 Participants

PRIMARY outcome

Timeframe: up to 4 years

Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All-treated population (per protocol).

-To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone.

Outcome measures

Outcome measures
Measure	Cohort 1 (560 mg) n=3 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) n=5 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) n=17 Participants Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) n=59 Participants Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Overall Response Rate (ORR)	2 Participants	2 Participants	12 Participants	42 Participants

SECONDARY outcome

Timeframe: Up to 4 years

Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All-treated population (per protocol).

The time interval between the date of initial documentation of a response (PR or better) and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects who had not progressed/died. The censoring date was the last adequate tumor assessment date.

Outcome measures

Outcome measures
Measure	Cohort 1 (560 mg) n=3 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) n=5 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) n=17 Participants Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) n=59 Participants Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Duration of Response (DOR)	7.1 Months Interval 1.2 to 13.0	15.3 Months Interval 5.4 to 15.3	9.2 Months Interval 3.0 to 14.5	7.2 Months Interval 2.7 to 16.6

SECONDARY outcome

Timeframe: Up to 4 years

Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All RP2D population (per protocol).

Time from date of first dose of study treatment to the date of death from any cause

Outcome measures

Outcome measures
Measure	Cohort 1 (560 mg) n=59 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Overall Survival	35.9 Months Interval 0.9 to 51.8	—	—	—

SECONDARY outcome

Timeframe: Up to 4 years

Population: Please note that the analysis only includes participants who achieved the best response of complete response or partial response from the All RP2D population (per protocol).

Time from date of first dose of study treatment to the date of first documented evidence of progressive disease, death or date of censoring for the subjects not progressed/died. The censoring date was the last adequate tumor assessment date.

Outcome measures

Outcome measures
Measure	Cohort 1 (560 mg) n=59 Participants Ibrutinib PO 560 mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Progression Free Survival (PFS)	7.4 Months Interval 4.6 to 10.2	—	—	—

Adverse Events

Cohort 1 (560 mg)

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Cohort 2a (560 mg)

Serious events: 5 serious events

Other events: 5 other events

Deaths: 4 deaths

Cohort 2b (560 mg)

Serious events: 17 serious events

Other events: 17 other events

Deaths: 9 deaths

All RP2D (840 mg)

Serious events: 59 serious events

Other events: 58 other events

Deaths: 22 deaths

Serious adverse events

Other adverse events

Additional Information

Thorsten Graef, Head of Clinical Development

Pharmacyclics LLC

Phone: +1 (408) 215-3127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Cohort 1 (560 mg) n=3 participants at risk Ibrutinib PO 560mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) n=5 participants at risk Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) n=17 participants at risk Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) n=59 participants at risk Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Infections and infestations Infection	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Necrotising Fasciitis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Osteomyelitis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Pseudomonal sepsis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Investigations Blood creatinine increased	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Metabolism and nutrition disorders Dehydration	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Metabolism and nutrition disorders Tumor Lysis Syndrome	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.1% 3/59 • Number of events 3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasma cell myeloma	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Pneumonia	33.3% 1/3 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	40.0% 2/5 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	10.2% 6/59 • Number of events 6 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Atrial Flutter	33.3% 1/3 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Constipation	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Atrial fibrillation	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Cardiac failure	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Cardiac failure congestive	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Left ventricular dysfunction	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Mitral valve disease	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Sinus bradycardia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Ventricular tachycardia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Toothache	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Incarcerated umbilical hernia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Vomiting	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Pyrexia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	17.6% 3/17 • Number of events 3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • Number of events 2 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Asthenia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Fatigue	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Multiple organ dysfunction syndrome	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Sepsis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	17.6% 3/17 • Number of events 3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Bacteraemia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Bronchopulmonary aspergillosis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Clostridium difficile colitis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Escherichia bacteraemia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Escherichia sepsis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Gastrointestinal infection	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to nervous sytem	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • Number of events 1 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.

Other adverse events
Measure	Cohort 1 (560 mg) n=3 participants at risk Ibrutinib PO 560mg + Carfilzomib IV 20/27 mg/m2 Ibrutinib Carfilzomib	Cohort 2a (560 mg) n=5 participants at risk Ibrutinib PO 560 mg + Carfilzomib IV 20/36 mg/m2 Ibrutinib Carfilzomib	Cohort 2b (560 mg) n=17 participants at risk Ibrutinib PO 560 mg+ Carfilzomib IV 20/36 mg/m2 Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone	All RP2D (840 mg) n=59 participants at risk Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg Ibrutinib Carfilzomib Dexamethasone
Investigations Blood bilirubin increased	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	10.2% 6/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Nervous system disorders Headache	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	40.0% 2/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	47.1% 8/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	22.0% 13/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Haemorrhoids	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Blood and lymphatic system disorders Anaemia	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	60.0% 3/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	35.3% 6/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	40.7% 24/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Blood and lymphatic system disorders Thrombocytopenia	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	17.6% 3/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	50.8% 30/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Atrial fibrillation	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Atrial flutter	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Constipation	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	40.0% 2/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	29.4% 5/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	23.7% 14/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Pyrexia	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	60.0% 3/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	47.1% 8/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.3% 12/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Hepatobiliary disorders Hyperbilirubinaemia	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	6.8% 4/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Influenza	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Upper respiratory tract infection	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	41.2% 7/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	28.8% 17/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Renal and urinary disorders Acute kidney injury	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	6.8% 4/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Respiratory, thoracic and mediastinal disorders cough	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	41.2% 7/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Respiratory, thoracic and mediastinal disorders Haemoptysis	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Vascular disorders Hypertension	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	40.0% 2/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	35.3% 6/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	27.1% 16/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Vascular disorders Hypotension	33.3% 1/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Blood and lymphatic system disorders Neutropenia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	8.5% 5/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Left ventricular dysfunction	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Cardiac disorders Sinus bradycardia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Eye disorders Eye swelling	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.1% 3/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	60.0% 3/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	64.7% 11/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	49.2% 29/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	17.6% 3/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	8.5% 5/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Flatulence	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.1% 3/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Gastrointestinal disorders Vomiting	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	23.5% 4/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	16.9% 10/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Chills	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	60.0% 3/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.9% 7/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Fatigue	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	80.0% 4/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	70.6% 12/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	45.8% 27/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Malaise	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	11.8% 2/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Asthenia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.1% 3/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Non-cardiac chest pain	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	6.8% 4/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Oedema peripheral	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	23.5% 4/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
General disorders Pain	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Immune system disorders Drug hypersensitivity	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Cellulitis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	8.5% 5/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Gastroenteritis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Oral candidiasis	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	1.7% 1/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Pneumonia	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Skin infection	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	5.9% 1/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Infections and infestations Urinary tract infection	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	29.4% 5/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	13.6% 8/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/3 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	20.0% 1/5 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	0.00% 0/17 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.	3.4% 2/59 • 4 years, 2months The Deaths reported are Death during treatment and within 30 Days of Last Study Treatment.