Trial Outcomes & Findings for NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Naïve, KRAS Mutant, Colorectal Cancer (NCT NCT00856375)

Last Updated: 2021-07-12

Results Overview

PFS was defined as the time from the date of randomisation to the date of disease progression (assessed by central radiological review according to Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) or death due to any cause, whichever comes first. PFS was determined using the intention-to-treat (ITT) population which included all randomized patients who underwent baseline evaluation, with treatment assigned according to randomized arm. For patients whose disease did not progress or who did not die, the PFS time was censored at the time of the last tumor assessment that demonstrated lack of disease progression. For patients who received new anti-cancer therapy, the PFS time was censored at the time of last tumor assessment prior to the new anti-cancer therapy starts.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

83 participants

Primary outcome timeframe

Every 6 weeks (± 5 days) from Cycle 1, Day 1 until documented disease progression, start of new therapy for cancer, death, or end of study, approximately 42 months.

Results posted on

2021-07-12

Participant Flow

Participant milestones

Participant milestones
Measure	NKTR-102 NKTR-102 was administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle at a dose level of 145 mg/m\^2.	Irinotecan Irinotecan was administered as an IV infusion on Day 1 of a 21-day treatment cycle at a dose level of 350 mg/m\^2. Patients aged 65 or older, or those with prior abdominal or pelvic irradiation, were given a lower dose of 300 mg/m\^2.
Overall Study STARTED	42	41
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	42	41

Reasons for withdrawal

Reasons for withdrawal
Measure	NKTR-102 NKTR-102 was administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle at a dose level of 145 mg/m\^2.	Irinotecan Irinotecan was administered as an IV infusion on Day 1 of a 21-day treatment cycle at a dose level of 350 mg/m\^2. Patients aged 65 or older, or those with prior abdominal or pelvic irradiation, were given a lower dose of 300 mg/m\^2.
Overall Study Other	0	1
Overall Study Death	32	30
Overall Study Sponsor Terminated Study	7	7
Overall Study Withdrawal by Subject	2	1
Overall Study Lost to Follow-up	1	2

Baseline Characteristics

NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Naïve, KRAS Mutant, Colorectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	NKTR-102 n=42 Participants NKTR-102 NKTR-102: IV every 3 weeks	Irinotecan n=41 Participants IV every 3 weeks irinotecan: IV every 3 weeks	Total n=83 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
Age, Categorical Between 18 and 65 years	30 Participants n=5 Participants	30 Participants n=7 Participants	60 Participants n=5 Participants
Age, Categorical >=65 years	12 Participants n=5 Participants	11 Participants n=7 Participants	23 Participants n=5 Participants
Age, Continuous	58.5 years STANDARD_DEVIATION 10.65 • n=5 Participants	57.8 years STANDARD_DEVIATION 11.4 • n=7 Participants	58.2 years STANDARD_DEVIATION 10.97 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	16 Participants n=7 Participants	34 Participants n=5 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	25 Participants n=7 Participants	49 Participants n=5 Participants

PRIMARY outcome

Timeframe: Every 6 weeks (± 5 days) from Cycle 1, Day 1 until documented disease progression, start of new therapy for cancer, death, or end of study, approximately 42 months.

Outcome measures

Outcome measures
Measure	NKTR-102 n=42 Participants NKTR-102 IV every 3 weeks	Irinotecan n=41 Participants irinotecan IV every 3 weeks
Kaplan-Meier Estimate of PFS by Central Radiological Review: ITT Population	4.0 months Interval 2.7 to 5.9	2.8 months Interval 1.4 to 4.1

SECONDARY outcome

Timeframe: From randomization to death, loss to follow-up, withdrawal of consent for further follow-up for survival, or end of study, approximately 42 months.

Duration of OS was defined as the time from the date of randomization to the date of death due to any cause. Patients were followed until their date of death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final database closure. Patients who were lost-to-follow-up or were not known to have died were censored at last date they were shown to be alive. Patients who did not have any follow-up since the date of randomization were censored at the date of randomization.

Outcome measures

Outcome measures
Measure	NKTR-102 n=42 Participants NKTR-102 IV every 3 weeks	Irinotecan n=41 Participants irinotecan IV every 3 weeks
Kaplan-Meier Estimate of OS: ITT Population	9.6 months Interval 7.3 to 13.2	8.4 months Interval 4.4 to 13.3

SECONDARY outcome

Timeframe: From randomization of the first subject until documented disease progression, start of new therapy for cancer, death, or end of study approximately 42 months

ORR was defined as the proportion of patients with a complete response (CR) or a partial response (PR) per RECIST 1.1 based upon the best response as assessed by central radiological review; confirmation of response was not required. The analyses were performed for patients in the ITT population who had measurable disease as determined by the central imaging facility at baseline.

Outcome measures

Outcome measures
Measure	NKTR-102 n=42 Participants NKTR-102 IV every 3 weeks	Irinotecan n=41 Participants irinotecan IV every 3 weeks
ORR by Central Radiological Review: ITT Population	9.8 percentage of patients Interval 2.7 to 23.1	5.0 percentage of patients Interval 0.6 to 16.9

SECONDARY outcome

Timeframe: From the time measurement criteria for CR/PR (whichever was first recorded) were first met until the first date that recurrent disease or PD or death was objectively documented, assessed until the end of study approximately 42 months

Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that was the smallest on study); in addition to a relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. CR is defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters

Outcome measures

Outcome measures
Measure	NKTR-102 n=42 Participants NKTR-102 IV every 3 weeks	Irinotecan n=41 Participants irinotecan IV every 3 weeks
DoR by Central Radiological Review: ITT Population	7.9 months Interval 1.5 to 11.6	1.4 months Interval 1.4 to 1.4

SECONDARY outcome

Timeframe: From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months

An adverse event (AE) was any untoward medical occurrence in a patient administered a pharmaceutical product which did not necessarily have a causal relationship with the treatment. An AE could have been any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Pre-existing events, which increased in frequency or severity or changed in nature during or as a consequence of use of the study medication were also considered as AEs. All AEs were assessed for severity using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0. If a particular AE was not listed in the NCI CTCAE Version 3.0, the following criteria were used: Grade 3 = severe; Grade 4 = life threatening or disabling; Grade 5 = death.

Outcome measures

Outcome measures
Measure	NKTR-102 n=42 Participants NKTR-102 IV every 3 weeks	Irinotecan n=41 Participants irinotecan IV every 3 weeks
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Hypokalemia	7.1 % of participants	7.3 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with ≥1 TEAE	61.9 % of participants	63.9 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Diarrhea	21.4 % of participants	19.5 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Neutropenia	7.1 % of participants	14.6 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Abdominal Pain	14.3 % of participants	4.9 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Dehydration	9.5 % of participants	9.8 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Vomiting	11.9 % of participants	7.3 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Nausea	14.3 % of participants	2.4 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Fatigue	9.5 % of participants	2.4 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Intestinal Obstruction	2.4 % of participants	9.8 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Leukopenia	7.1 % of participants	4.9 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Febrile Neutropenia	2.4 % of participants	7.3 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Alopecia	2.4 % of participants	4.9 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Disease Progression	4.8 % of participants	2.4 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Hyponatremia	2.4 % of participants	4.9 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Acute Prerenal Failure	2.4 % of participants	2.4 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Asthenia	2.4 % of participants	2.4 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Hyperbilirubinemia	2.4 % of participants	2.4 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Performance Status Decreased	4.8 % of participants	0 % of participants
Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher Percentage of participants with Sepsis	0 % of participants	4.9 % of participants

SECONDARY outcome

Timeframe: Days 1, 2, 3, 4, 8 and 15 of Cycles 1 and 3 and Day 1 of Cycles 2, 4 and all subsequent cycles, until End of Study, approximately 42 months.

Population: There are no data available for this outcome, due to the very small number of PK samples that were collected from these patients.

Blood samples for PK analysis were collected from 4 patients only, 3 from the irinotecan treatment arm and 1 from the NKTR-102 treatment arm. NKTR-102, irinotecan, SN38, SN38-G, 7-ethyl-10-\[4-N-(5-aminopentanoic acid)-1-piperidino\]carbonyloxycamptothecin, and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin concentration levels were determined. However, due to the limited number of patients with PK samples, no further PK analysis was conducted.

Outcome measures

Outcome data not reported

Adverse Events

NKTR-102

Serious events: 19 serious events

Other events: 42 other events

Deaths: 32 deaths

Irinotecan

Serious events: 24 serious events

Other events: 38 other events

Deaths: 30 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Nektar Therapeutics

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee There are restrictions to the PI's rights to discuss or publish trial results.
Publication restrictions are in place

Restriction type: OTHER

Measure	NKTR-102 n=42 participants at risk NKTR-102 IV every 3 weeks	Irinotecan n=41 participants at risk irinotecan IV every 3 weeks
Investigations Haemoglobin decreased	4.8% 2/42 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	14.6% 6/41 • Number of events 8 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Investigations Weight decreased	31.0% 13/42 • Number of events 14 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	14.6% 6/41 • Number of events 6 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Investigations Neutrophil count decreased	11.9% 5/42 • Number of events 8 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	4.9% 2/41 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Respiratory, thoracic and mediastinal disorders Cough	4.8% 2/42 • Number of events 2 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	7.3% 3/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.1% 3/42 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	4.9% 2/41 • Number of events 2 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Blood and lymphatic system disorders Anaemia	14.3% 6/42 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	14.6% 6/41 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Blood and lymphatic system disorders Leukopenia	11.9% 5/42 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	2.4% 1/41 • Number of events 1 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Blood and lymphatic system disorders Neutropenia	16.7% 7/42 • Number of events 14 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	12.2% 5/41 • Number of events 8 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Blood and lymphatic system disorders Thrombocytopenia	9.5% 4/42 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	9.8% 4/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Nervous system disorders Lethargy	7.1% 3/42 • Number of events 10 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	12.2% 5/41 • Number of events 19 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Nervous system disorders Headache	11.9% 5/42 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	2.4% 1/41 • Number of events 1 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Nervous system disorders Dizziness	16.7% 7/42 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	14.6% 6/41 • Number of events 10 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Eye disorders Vision blurred	11.9% 5/42 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	2.4% 1/41 • Number of events 1 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
General disorders Fatigue	47.6% 20/42 • Number of events 25 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	43.9% 18/41 • Number of events 34 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
General disorders Pyrexia	9.5% 4/42 • Number of events 8 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	17.1% 7/41 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
General disorders Asthenia	14.3% 6/42 • Number of events 9 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	7.3% 3/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
General disorders Oedema peripheral	2.4% 1/42 • Number of events 1 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	9.8% 4/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Psychiatric disorders Anxiety	11.9% 5/42 • Number of events 7 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	0.00% 0/41 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Psychiatric disorders Insomnia	7.1% 3/42 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	4.9% 2/41 • Number of events 2 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Diarrhoea	61.9% 26/42 • Number of events 62 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	68.3% 28/41 • Number of events 66 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Nausea	54.8% 23/42 • Number of events 41 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	58.5% 24/41 • Number of events 45 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Vomiting	40.5% 17/42 • Number of events 27 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	48.8% 20/41 • Number of events 33 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Abdominal pain	40.5% 17/42 • Number of events 25 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	31.7% 13/41 • Number of events 21 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Constipation	28.6% 12/42 • Number of events 18 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	24.4% 10/41 • Number of events 16 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Abdominal pain upper	11.9% 5/42 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	9.8% 4/41 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Dyspepsia	7.1% 3/42 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	9.8% 4/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Abdominal distension	2.4% 1/42 • Number of events 1 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	12.2% 5/41 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Gastrointestinal disorders Proctalgia	4.8% 2/42 • Number of events 2 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	7.3% 3/41 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Skin and subcutaneous tissue disorders Alopecia	16.7% 7/42 • Number of events 8 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	58.5% 24/41 • Number of events 27 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Musculoskeletal and connective tissue disorders Back pain	7.1% 3/42 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	7.3% 3/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Musculoskeletal and connective tissue disorders Pain in extremity	7.1% 3/42 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	7.3% 3/41 • Number of events 3 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Metabolism and nutrition disorders Anorexia	31.0% 13/42 • Number of events 15 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	24.4% 10/41 • Number of events 11 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Metabolism and nutrition disorders Dehydration	11.9% 5/42 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	12.2% 5/41 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Metabolism and nutrition disorders Hypokalaemia	21.4% 9/42 • Number of events 17 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	7.3% 3/41 • Number of events 9 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months
Metabolism and nutrition disorders Hyponatraemia	11.9% 5/42 • Number of events 5 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months	4.9% 2/41 • Number of events 4 • From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug), assessed until the end of study approximately 42 months