Trial Outcomes & Findings for A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL (NCT NCT01203930)

NCT ID: NCT01203930

Last Updated: 2018-11-16

Results Overview

ORR was assessed based on standardized International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria as specifically modified for this study to reflect current recommendations which consider the mechanism of action of idelalisib and similar drugs, and was defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as assessed by the investigator. Based on the CLL response definition in the protocol (modified Hallek 2008), the parameters of lymphadenopathy, liver and/or spleen size, constitutional symptoms, polymorphonuclear leukocytes, circulating clonal B-lymphocytes, platelet count, hemoglobin, and marrow were assessed. * CR: meeting all defined criteria * PR: meeting at least 2 of the criteria of circulating lymphocytes, lymphadenopathy, liver, spleen, or bone marrow (or only lymphadenopathy if liver and spleen normal at baseline) and at least 1 of the criteria for polymorphonuclear leukocytes, platelet count, or hemoglobin.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

105 participants

Primary outcome timeframe

Up to 28 Months

Results posted on

2018-11-16

Participant Flow

Participants were enrolled at study sites in the United States. The first participant was screened on 28 September 2010. The last study visit occurred on 07 June 2016.

113 participants were screened.

Participant milestones

Participant milestones
Measure	Idelalisib+Rituximab (Cohort 1) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Overall Study STARTED	64	41
Overall Study COMPLETED	43	0
Overall Study NOT COMPLETED	21	41

Reasons for withdrawal

Reasons for withdrawal
Measure	Idelalisib+Rituximab (Cohort 1) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Overall Study Disease Progression	0	4
Overall Study Death	3	1
Overall Study Withdrew Consent	1	10
Overall Study Investigator Request	0	8
Overall Study Study Terminated by Sponsor	0	12
Overall Study Poor tolerance of study drug	0	1
Overall Study Adverse Event	17	5

Baseline Characteristics

A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Idelalisib+Rituximab (Cohort 1) n=64 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses. Participants who completed 12 cycles of idelalisib were eligible to continue treatment on an extension study (101-99).	Idelalisib (Cohort 2) n=41 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity	Total n=105 Participants Total of all reporting groups
Age, Customized < 70 Years	29 participants n=5 Participants	14 participants n=7 Participants	43 participants n=5 Participants
Age, Customized ≥ 70 Years	35 participants n=5 Participants	27 participants n=7 Participants	62 participants n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	9 Participants n=7 Participants	33 Participants n=5 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	32 Participants n=7 Participants	72 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	64 Participants n=5 Participants	40 Participants n=7 Participants	104 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White/Caucasian	61 participants n=5 Participants	40 participants n=7 Participants	101 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 28 Months

Population: Intent-to-treat (ITT) Analysis Set: participants who received at least 1 dose of idelalisib.

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=64 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=41 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Overall Response Rate (ORR)	96.9 percentage of participants Interval 89.2 to 99.6	87.8 percentage of participants Interval 73.8 to 95.9

SECONDARY outcome

Timeframe: Up to 28 Months

Population: ITT Analysis Set

The overall safety of idelalisib was assessed as the percentage of participants experiencing treatment-emergent adverse events (AEs; Serious AEs, Grade ≥ 3 AEs, AEs related to idelalisib, and AEs leading to discontinuation of idelalisib).

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=64 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=41 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Overall Safety of Idelalisib Any AE	100.0 percentage of participants	100.0 percentage of participants
Overall Safety of Idelalisib Serious AE	48.4 percentage of participants	68.3 percentage of participants
Overall Safety of Idelalisib Grade ≥ 3 AE	76.6 percentage of participants	85.4 percentage of participants
Overall Safety of Idelalisib AE related to idelalisib	81.3 percentage of participants	97.6 percentage of participants
Overall Safety of Idelalisib AE leading to permanent drug discontinuation	28.1 percentage of participants	56.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline and up to 28 Months

Population: Participants in the ITT Analysis Set with baseline measurable lymph nodes were analyzed.

Lymphadenopathy response rate was defined as the percentage of participants with a ≥ 50% reduction from baseline in the sum of the perpendicular diameters of all measurable lesions while receiving study therapy.

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=50 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=38 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Lymphadenopathy Response Rate	98.0 percentage of participants Interval 89.4 to 99.9	86.8 percentage of participants Interval 71.9 to 95.6

SECONDARY outcome

Timeframe: Baseline; Weeks 8, 16, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Population: Participants in the ITT Analysis Set with available data were analyzed.

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=50 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=38 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 72	—	-78.0 percent change Interval -85.5 to -68.8
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 84	—	-80.0 percent change Interval -91.2 to -68.1
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 96	—	-81.3 percent change Interval -100.0 to -62.5
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 108	—	-78.1 percent change Interval -78.1 to -78.1
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 120	—	-71.9 percent change Interval -71.9 to -71.9
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions Best % Change	-100.0 percent change Interval -100.0 to -40.0	-81.1 percent change Interval -100.0 to 0.0
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 8	-100.0 percent change Interval -100.0 to -8.3	-69.8 percent change Interval -100.0 to 0.0
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 16	-100.0 percent change Interval -100.0 to -69.2	-74.5 percent change Interval -100.0 to 0.0
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 24	-100.0 percent change Interval -100.0 to -50.0	-76.0 percent change Interval -100.0 to 0.0
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 36	-100.0 percent change Interval -100.0 to -66.7	-77.5 percent change Interval -100.0 to 0.0
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 48	-100.0 percent change Interval -100.0 to -50.0	-73.9 percent change Interval -98.3 to 44.4
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions % Change at Wk 60	—	-69.7 percent change Interval -93.3 to -56.7

SECONDARY outcome

Timeframe: Up to 28 Months

Population: Participants in the ITT Analysis Set who achieved complete or partial response.

Duration of response (DOR) was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of disease progression or death from any cause.

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=62 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=35 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Duration of Response	NA months NA: Not reached	14.8 months Interval 10.0 to NA: Not reached

SECONDARY outcome

Timeframe: Up to 28 Months

Population: ITT Analysis Set

Progression-free survival (PFS) was defined as the interval from the first dose date of drug to the earlier of the first documentation of definitive disease progression or death from any cause. Progression was defined using the Standardized IWCLL criteria as specifically modified for this study to consider the mechanism of action of idelalisib and similar drugs. The occurrence of any of the following events indicated progression: 1. Evidence of any new disease 2. Evidence of worsening of index lesions, spleen or liver, or non-index disease 3. Decrease in platelet count or hemoglobin that is attributable to CLL and is confirmed by bone marrow biopsy

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=64 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=41 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Progression-Free Survival	NA months Not reached	26.2 months Interval 14.0 to Not reached

SECONDARY outcome

Timeframe: Predose and 1.5 hours postdose at Weeks 0, 4, and 24

Population: Pharmacokinetic (PK) Analysis Set: participants in the ITT Analysis Set from Cohort 1 who had the necessary baseline and on-study measurements to provide interpretable results for the specific parameters of interest.

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=64 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Idelalisib Plasma Concentrations (Cohort 1) Week 0 predose	0.0 ng/mL Interval 0.0 to 0.0	—
Idelalisib Plasma Concentrations (Cohort 1) Week 0 postdose	1710.0 ng/mL Interval 1060.0 to 2660.0	—
Idelalisib Plasma Concentrations (Cohort 1) Week 4 predose	305.0 ng/mL Interval 189.0 to 606.0	—
Idelalisib Plasma Concentrations (Cohort 1) Week 4 postdose	1720.0 ng/mL Interval 1090.0 to 2500.0	—
Idelalisib Plasma Concentrations (Cohort 1) Week 24 predose	256.5 ng/mL Interval 173.5 to 625.5	—
Idelalisib Plasma Concentrations (Cohort 1) Week 24 postdose	1460.0 ng/mL Interval 925.0 to 2010.0	—

SECONDARY outcome

Timeframe: Predose and 1.5 hours postdose at Weeks 0 and 4 and predose at Weeks 8 and 20

Population: PK Analysis Set: participants in the ITT Analysis Set from Cohort 2 who had the necessary baseline and on-study measurements to provide interpretable results for the specific parameters of interest.

Outcome measures

Outcome measures
Measure	Idelalisib+Rituximab (Cohort 1) n=40 Participants Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Idelalisib Plasma Concentrations (Cohort 2) Week 0 predose	0.0 ng/mL Interval 0.0 to 0.0	—
Idelalisib Plasma Concentrations (Cohort 2) Week 0 postdose	2190.0 ng/mL Interval 1575.0 to 2920.0	—
Idelalisib Plasma Concentrations (Cohort 2) Week 4 predose	293.0 ng/mL Interval 228.0 to 549.0	—
Idelalisib Plasma Concentrations (Cohort 2) Week 4 postdose	2120.0 ng/mL Interval 1850.0 to 2590.0	—
Idelalisib Plasma Concentrations (Cohort 2) Week 8 predose	453.0 ng/mL Interval 207.0 to 904.0	—
Idelalisib Plasma Concentrations (Cohort 2) Week 20 predose	590.0 ng/mL Interval 317.0 to 971.5	—

SECONDARY outcome

Timeframe: Up to 169 days

Population: The collection of plasma samples for pharmacodynamic (PD) analysis in this study was planned prior to the availability of results from an identical PD analysis in another idelalisib study with a larger sample size (n = 176 unique subjects with 2085 longitudinal plasma samples). Therefore, PD analysis was not performed in this study (n = 41).

Changes in potential pharmacodynamic markers of drug activity will include assessments of chemokine and cytokine concentrations, effects on the activity of PI3K and related pathways, and effect on cell migration and other functional outcomes. This endpoint will be assessed at the following time points: * Idelalisib+Rituximab (Cohort 1): Predose and 1.5 hour postdose on Day 1 and predose on Days 15, 29, 57, 113, and 169 * Idelalisib (Cohort 2): Predose on Days 1, 29, 57, 141

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 28 Months

Population: Overall survival analysis was not performed because the follow-up period was insufficient to capture enough events.

Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause.

Outcome measures

Outcome data not reported

Adverse Events

Idelalisib+Rituximab (Cohort 1)

Serious events: 31 serious events

Other events: 63 other events

Deaths: 0 deaths

Idelalisib (Cohort 2)

Serious events: 28 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosures

Gilead Sciences

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
Publication restrictions are in place

Restriction type: OTHER

Measure	Idelalisib+Rituximab (Cohort 1) n=64 participants at risk Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses	Idelalisib (Cohort 2) n=41 participants at risk Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity
Infections and infestations Oesophageal candidiasis	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Blood and lymphatic system disorders Anaemia	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Blood and lymphatic system disorders Aplasia pure red cell	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Blood and lymphatic system disorders Febrile neutropenia	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	4.9% 2/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Blood and lymphatic system disorders Neutropenia	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Cardiac disorders Sinus node dysfunction	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Gastrointestinal disorders Abdominal distension	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Gastrointestinal disorders Colitis	9.4% 6/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	9.8% 4/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Gastrointestinal disorders Diarrhoea	9.4% 6/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	17.1% 7/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Gastrointestinal disorders Intestinal obstruction	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Gastrointestinal disorders Small intestinal obstruction	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
General disorders Asthenia	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
General disorders Chest pain	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
General disorders Face oedema	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
General disorders Fatigue	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
General disorders Impaired healing	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
General disorders Pyrexia	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	7.3% 3/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Cellulitis	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	4.9% 2/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Clostridial infection	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Cytomegalovirus oesophagitis	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Oral candidiasis	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Pneumocystis jiroveci pneumonia	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Pneumocystis jirovecii pneumonia	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Pneumonia	12.5% 8/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	12.2% 5/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Sepsis	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Urinary tract infection	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Infections and infestations Urosepsis	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Injury, poisoning and procedural complications Arterial injury	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Injury, poisoning and procedural complications Infusion related reaction	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Metabolism and nutrition disorders Dehydration	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	4.9% 2/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Metabolism and nutrition disorders Hypercalcaemia	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic malignant melanoma	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Nervous system disorders Balance disorder	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Nervous system disorders Syncope	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Psychiatric disorders Confusional state	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Renal and urinary disorders Acute kidney injury	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Renal and urinary disorders Renal failure acute	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Renal and urinary disorders Urinary retention	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Reproductive system and breast disorders Testicular pain	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	4.9% 2/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Hypoxia	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Organising pneumonia	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Pneumonitis	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	4.9% 2/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Respiratory, thoracic and mediastinal disorders Respiratory failure	3.1% 2/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Vascular disorders Embolism	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Vascular disorders Hypertension	1.6% 1/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	0.00% 0/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.
Vascular disorders Hypotension	0.00% 0/64 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.	2.4% 1/41 • Up to 28 Months Adverse events were coded according to MedDRA Version 15.1 for Cohort 1 and MedDRA Version 19.0 for Cohort 2.