Trial Outcomes & Findings for A Study of Palifermin for the Reduction of Oral Mucositis in Subjects With Multiple Myeloma (NCT NCT00434161)

Last Updated: 2015-03-30

Results Overview

For the primary efficacy endpoint maximum severity of Oral Mucositis (OM) was assessed, the number of participants who had the different severity. To assess severity of OM, a 5-grade WHO scale (0, 1, 2, 3, or 4) was used. 0 = no findings or erythema only, 1= soreness present with or without erythema, 2=ulcers present but able to take solid food, 3 =ulcers present and only able to take liquids, 4 =ulcers present/not able to take anything orally.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

281 participants

Primary outcome timeframe

at Day 32

Results posted on

2015-03-30

Participant Flow

Participant milestones

Participant milestones
Measure	Palifermin Before Only Subjects to receive palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses). Daily dose of intravenous (IV) 60 µg/kg/day of palifermin as 1 bolus IV injection on Days -6, 5 and -4 before high dose chemotherapy and placebo on Days 0, 1 and 2 after high dose chemotherapy.	Placebo Subjects to receive matched placebo before- and after-high dose chemotherapy (total of 6 doses). Daily dose of intravenous (IV) 60 µg/kg/day of placebo as 1 bolus IV injection on Days -6, 5 and -4 before high dose chemotherapy and on Days 0, 1 and 2 after high dose chemotherapy.	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy (total of 6 doses). Daily dose of intravenous (IV) 60 µg/kg/day of palifermin as 1 bolus IV injection on Days -6, 5 and -4 before high dose chemotherapy and on Days 0, 1 and 2 after high dose chemotherapy
Overall Study STARTED	109	57	115
Overall Study COMPLETED	99	54	104
Overall Study NOT COMPLETED	10	3	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Palifermin Before Only Subjects to receive palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses). Daily dose of intravenous (IV) 60 µg/kg/day of palifermin as 1 bolus IV injection on Days -6, 5 and -4 before high dose chemotherapy and placebo on Days 0, 1 and 2 after high dose chemotherapy.	Placebo Subjects to receive matched placebo before- and after-high dose chemotherapy (total of 6 doses). Daily dose of intravenous (IV) 60 µg/kg/day of placebo as 1 bolus IV injection on Days -6, 5 and -4 before high dose chemotherapy and on Days 0, 1 and 2 after high dose chemotherapy.	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy (total of 6 doses). Daily dose of intravenous (IV) 60 µg/kg/day of palifermin as 1 bolus IV injection on Days -6, 5 and -4 before high dose chemotherapy and on Days 0, 1 and 2 after high dose chemotherapy
Overall Study Adverse Event	5	1	4
Overall Study Lost to Follow-up	0	1	0
Overall Study Death	1	0	1
Overall Study Non-Compliance	1	1	0
Overall Study Withdrawal by Subject	2	0	3
Overall Study Logistical error study assessments	1	0	3

Baseline Characteristics

A Study of Palifermin for the Reduction of Oral Mucositis in Subjects With Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Palifermin Before Only n=109 Participants Subjects to receive palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses)	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=115 Participants Subjects to receive palifermin before- and after-high dose chemotherapy (total of 6 doses)	Total n=281 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
Age, Categorical Between 18 and 65 years	90 Participants n=5 Participants	49 Participants n=7 Participants	100 Participants n=5 Participants	239 Participants n=4 Participants
Age, Categorical >=65 years	19 Participants n=5 Participants	8 Participants n=7 Participants	15 Participants n=5 Participants	42 Participants n=4 Participants
Age, Continuous	55.3 years STANDARD_DEVIATION 8.4 • n=5 Participants	57.1 years STANDARD_DEVIATION 7.0 • n=7 Participants	56.1 years STANDARD_DEVIATION 7.5 • n=5 Participants	56 years STANDARD_DEVIATION 7.7 • n=4 Participants
Sex: Female, Male Female	50 Participants n=5 Participants	24 Participants n=7 Participants	52 Participants n=5 Participants	126 Participants n=4 Participants
Sex: Female, Male Male	59 Participants n=5 Participants	33 Participants n=7 Participants	63 Participants n=5 Participants	155 Participants n=4 Participants
Region of Enrollment Germany	16 participants n=5 Participants	9 participants n=7 Participants	23 participants n=5 Participants	48 participants n=4 Participants
Region of Enrollment Hungary	22 participants n=5 Participants	9 participants n=7 Participants	16 participants n=5 Participants	47 participants n=4 Participants
Region of Enrollment France	15 participants n=5 Participants	10 participants n=7 Participants	16 participants n=5 Participants	41 participants n=4 Participants
Region of Enrollment Austria	16 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants	30 participants n=4 Participants
Region of Enrollment Belgium	8 participants n=5 Participants	1 participants n=7 Participants	11 participants n=5 Participants	20 participants n=4 Participants
Region of Enrollment Czech Republic	7 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants	18 participants n=4 Participants
Region of Enrollment Italy	4 participants n=5 Participants	4 participants n=7 Participants	9 participants n=5 Participants	17 participants n=4 Participants
Region of Enrollment Switzerland	4 participants n=5 Participants	5 participants n=7 Participants	6 participants n=5 Participants	15 participants n=4 Participants
Region of Enrollment United Kingdom	4 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants	11 participants n=4 Participants
Region of Enrollment Finland	3 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants	10 participants n=4 Participants
Region of Enrollment Netherlands	4 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants	10 participants n=4 Participants
Region of Enrollment Ireland	2 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants	7 participants n=4 Participants
Region of Enrollment Sweden	2 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	4 participants n=4 Participants
Region of Enrollment Denmark	2 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants

PRIMARY outcome

Timeframe: at Day 32

Population: Full analysis set that includes all randomized subjects, and was used to compare treatment effects for all efficacy endpoints. This set of subjects was analyzed according to their randomized treatment assignment.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=109 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=115 Participants Subjects to receive palifermin before- and after-high dose chemotherapy
Maximum Severity of Oral Mucositis (World Health Organization (WHO) Grades 0/1, 2, 3, or 4) WHO grade 0/1 or 2	79 Participants	36 Participants	68 Participants
Maximum Severity of Oral Mucositis (World Health Organization (WHO) Grades 0/1, 2, 3, or 4) WHO grade 3 or 4	26 Participants	21 Participants	44 Participants
Maximum Severity of Oral Mucositis (World Health Organization (WHO) Grades 0/1, 2, 3, or 4) Unknown	4 Participants	0 Participants	3 Participants

PRIMARY outcome

Timeframe: 12 months

Number of participants from the primary cataract subset showing an increase from baseline of \>= 0.3 in the Lens Opacities Classification System III (LOCS III score). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist trained in LOCS III uses a slit lamp for examining the lens of the eye. The classification evaluates four features: posterior subcapsular cataract(P),cortical cataract(C),nuclear opalescence(NO) and nuclear color(NC). NO and NC are graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. In the current study, cataract development or progression was defined as an increase from baseline of ≥ 0.3 on any of the three features P, C or NO (NC is of less importance and has not been analysed further in this study).

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of Cataract Development or Progression at Month 12. Yes	4 Participants	25 Participants	—
Incidence of Cataract Development or Progression at Month 12. No	10 Participants	27 Participants	—
Incidence of Cataract Development or Progression at Month 12. Missing	8 Participants	27 Participants	—

SECONDARY outcome

Timeframe: at Day 32

Population: Full analysis set that includes all randomized subjects (total 281 subjects), and was used to compare treatment effects for all efficacy endpoints. This set of subjects was analyzed according to their randomized treatment assignment.

The incidence of ulcerative mucositis WHO grades 2, 3, and 4. Measured the number of participants who had WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=109 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=115 Participants Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence Ulcerative Mucositis (WHO Grades 2, 3, and 4) Incidence (n): No	49 participants	24 participants	33 participants
Incidence Ulcerative Mucositis (WHO Grades 2, 3, and 4) Incidence (n): yes	56 participants	33 participants	79 participants
Incidence Ulcerative Mucositis (WHO Grades 2, 3, and 4) Incidence (n): unknown	4 participants	0 participants	3 participants

SECONDARY outcome

Timeframe: at Day 32

The duration of ulcerative mucositis measured the number of days the participants had different WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3 =ulcers present and only able to take liquids, 4 =ulcers present/not able to take anything orally. Patients that did not have any ulcerative mucositis were given a value of 0 days.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=109 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=115 Participants Subjects to receive palifermin before- and after-high dose chemotherapy
Duration of Ulcerative Mucositis (WHO Grades 2, 3, and 4)	4.78 Days Full Range 6.13 • Interval 0.0 to 32.0	4.98 Days Full Range 5.95 • Interval 0.0 to 25.0	7.38 Days Full Range 6.82 • Interval 0.0 to 27.0

SECONDARY outcome

Timeframe: at Day 32

The mean daily scores were calculated using the subject daily assessment of Patient-reported mouth and throat soreness (MTS) on the 5 point scale with higher values in MTS indicating a worse self assessed MTS. A 5-grade WHO scale (0, 1, 2, 3, or 4). 0=no findings or erythema only, 1=soreness present with or without erythema, 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. The incidence of ulcerative mucositis WHO grades 2, 3, and 4. Measured the number of participants who had WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. The area under the curve were calculated at the time points; Day(D)-2, up to Day 32.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=109 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=115 Participants Subjects to receive palifermin before- and after-high dose chemotherapy
The Area Under the Curve (AUC) Was Calculated From the Patient-reported Outcome Mouth and Throat Soreness (MTS) Score.	29.82 units on a scale * days Standard Deviation 45.04	24.55 units on a scale * days Standard Deviation 32.35	39.97 units on a scale * days Standard Deviation 52.90

SECONDARY outcome

Timeframe: 6 Months

Population: Of the 281 subjects who participated in the acute phase of the study a total of 101 subjects study were eligible for participation in the cataract assessment procedures, 22 in the placebo group and 79 in the palifermin group. Number of patients with non-missing values at Months 6; were 17 in the placebo group and 53 in the palifermin group.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of Cataract Development or Progression (Change of ≥0.3 in Lens Opacities Classification System III (LOCS III Score)) at Month 6. Yes	6 participants	23 participants	—
Incidence of Cataract Development or Progression (Change of ≥0.3 in Lens Opacities Classification System III (LOCS III Score)) at Month 6. No	11 participants	30 participants	—
Incidence of Cataract Development or Progression (Change of ≥0.3 in Lens Opacities Classification System III (LOCS III Score)) at Month 6. Missing	5 participants	26 participants	—

SECONDARY outcome

Timeframe: at Month 6 and Month 12

Population: 281 subjects participated in the acute phase study of those 101 subjects were eligible for the cataract assessment study, 22 placebo and 79 palifermin. Month 6: 69 completed (17/22 \[77.3%\] in the placebo, 52/79 \[65.8%\] in the palifermin. Month 12: 66 completed (14/22 \[63.6%\] in the placebo, 52/79 \[65.8%\] in the palifermin group.

To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior (P), Cortical Cataract (C) and Nuclear Opalescence (NO). For Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO): at month 6 and 12 adjusted difference of rate of cataract, Palifermin - Placebo were used and the confidence interval were calculated on the adjusted difference.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 P month 6 - Yes	0 participants	5 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 P, month 6 - No	17 participants	47 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 P, month 12 - Yes	1 participants	13 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 P, month 12 - No	13 participants	39 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 C month 6 - Yes	3 participants	9 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 C, month 6 - No	14 participants	43 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 C, month 12 - Yes	2 participants	13 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 C, month 12 - No	12 participants	39 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 NO month 6 - Yes	3 participants	19 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 NO month 6 - No	14 participants	33 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 NO month 12 - Yes	4 participants	20 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 NO month 12 - No	10 participants	32 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 P, C and NO, month 6 - Subjects who discontinued	5 participants	27 participants	—
Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 P, C and NO, month 12 - Subjects who discontinued	8 participants	27 participants	—

SECONDARY outcome

Timeframe: Months 6

Population: All subjects in the acute phase study were also assessed for their eligibility for cataract assessment procedures according to predefined criteria. If a subject was not eligible for cataract assessment procedures, the subject could still have been eligible for inclusion in the study but was exempt from the cataract assessments.

To study the change in cataract from baseline visit to months 6, three cataract main types: nuclear, cortical and posterior subcapsular measured on the Lens Opacities Classification System III (LOCS III) Scale. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in theLOCS III score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist uses a slit lamp for examining the lens of the eye. The classification evaluates: P,C and NO. NO is graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 6. Summary of difference from baseline in P	0.01 units on a scale Standard Deviation 0.08	0.12 units on a scale Standard Deviation 0.40	—
Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 6. Summary of difference from baseline in C	0.14 units on a scale Standard Deviation 0.29	0.15 units on a scale Standard Deviation 0.28	—
Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 6. Summary of difference from baseline in NO	0.12 units on a scale Standard Deviation 0.26	0.35 units on a scale Standard Deviation 0.59	—

SECONDARY outcome

Timeframe: Months 12

To study the change in cataract from baseline visit to months 12, regarding the three cataract main types: nuclear, cortical and posterior subcapsular measured on the Lens Opacities Classification System III (LOCS III) Scale. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist uses a slit lamp for examining the lens of the eye. The classification evaluates: P,C and NO. NO is graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 12. Summary of difference from baseline in P	0.05 units on a scale Standard Deviation 0.12	0.25 units on a scale Standard Deviation 0.56	—
Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 12. Summary of difference from baseline in C	0.14 units on a scale Standard Deviation 0.25	0.22 units on a scale Standard Deviation 0.36	—
Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 12. Summary of difference from baseline in NO	0.12 units on a scale Standard Deviation 0.26	0.35 units on a scale Standard Deviation 0.59	—

SECONDARY outcome

Timeframe: Months 6

To study if the treatment has effected on the visual acuity from baseline to months 6, by using Best Corrected Visual Acuity (BCVA) as measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO).

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 6 Incidence of decrease in letters read - Yes	2 participants	4 participants	—
Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 6 Incidence of decrease in letters read - No	15 participants	48 participants	—
Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 6 Subjects who discontinued at Month 6	5 participants	27 participants	—

SECONDARY outcome

Timeframe: Month 12

To study if the treatment has effected on the visual acuity from baseline to months 12, by using Best Corrected Visual Acuity (BCVA) as measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO).

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=22 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=79 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 12. Incidence of decrease in letters read - Yes	0 participants	3 participants	—
Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 12. Incidence of decrease in letters read - No	14 participants	49 participants	—
Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 12. Subjects who discontinued at month 12	8 participants	27 participants	—

SECONDARY outcome

Timeframe: at Day 32

Incidence of Adverse Events CTCAE grade 3 or higher reported

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=111 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=109 Participants Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of Adverse Events and Laboratory Abnormalities	56 Participants	26 Participants	65 Participants

SECONDARY outcome

Timeframe: During long-term follow up phase (maximum of 10 years)

Population: A total of 277 subjects were included in the Safety subset of the original study report (220 Palifermin and 57 placebo). Follow-up time for all subjects, defined as the date of randomization to the last known alive date. For subjects who were alive at the last contact the number of subjects for the palifermin group was 162 and for the placebo 47

Overall survival (OS) is based on death from any cause, not just the condition being treated, thus it picks up death from side effects of the treatment, and effects on survival after relapse.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=220 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Overall Survival	50.6 Months Interval 35.9 to Quartile 3 value is not available because a small number of participants died.	NA Months Interval 44.1 to Median and quartile 3 values are not available because a small number of participants died.	—

SECONDARY outcome

Timeframe: During long-term follow up phase (maximum of 10 years)

Progression-free survival (PFS) is the length of time during and after the treatment during which the disease being treated does not get worse. In this study the event for Progression-free survival was death from all causes or disease progression. Time to each event was defined as the time elapsed between the date of the first dose of investigational product, and the date of the given event.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=220 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Progression Free Survival	15.1 Months Interval 8.4 to 24.0	18.3 Months Interval 11.9 to 27.5	—

SECONDARY outcome

Timeframe: During long-term follow up phase (maximum of 10 years)

For the analysis of time to disease progression, competing risks time-to-event analysis was used, since a subject destined to develop disease progression could die from unrelated causes before the disease progression event takes place. Kaplan-Meier survival estimates, with death due to other causes than progression considered as a competing risk, were provided: event rate at 3 month intervals, with 95% confidence interval, the number of subjects at risk at the beginning of the time period, and the number of events of interest.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=220 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Time Death or Disease Progression	15.1 months Interval 8.4 to 24.0	18.3 months Interval 11.9 to 27.5	—

SECONDARY outcome

Timeframe: During long-term follow up phase (maximum of 10 years)

Population: total of 277 subjects were included in the Safety subset of the original study report (220 Palifermin and 57 placebo). Follow-up time for all subjects, defined as the date of randomization to the last known alive date. For subjects who were alive at the last contact the number of subjects for the palifermin group was 162 and for the placebo 47.

All comparisons for the long-term safety endpoints were based on the combined palifermin group versus placebo (placebo over palifermin). Incidence of new or secondary malignancies by treatment group was provided (incidence of new or secondary malignancies at the follow-up visit - yes, no, no assessment -, and number of subjects with new or secondary malignancies, per type of malignancies). The long-term safety evaluations were summarized for the subgroups defined by the factors used for randomization using descriptive statistics.

Outcome measures

Outcome measures
Measure	Palifermin Before Only n=220 Participants Subjects to receive palifermin before-high dose chemotherapy and matched placebo after-high dose chemotherapy	Placebo n=57 Participants Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After Subjects to receive palifermin before- and after-high dose chemotherapy
Incidence of Second Primary Malignancies or Other Malignancies	1 participants	6 participants	—

Adverse Events

Palifermin Before Only

Serious events: 13 serious events

Other events: 110 other events

Deaths: 0 deaths

Placebo

Serious events: 3 serious events

Other events: 56 other events

Deaths: 0 deaths

Palifermin Before and After

Serious events: 18 serious events

Other events: 109 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director

Swedish Orphan Biovitrum AB

Phone: +4686972000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits sponsor a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Sponsor may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Palifermin Before Only n=111 participants at risk Subjects to receive palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses). A total of 109 subjects were randomized to treatment and 107 received at least one dose of study treatment. Due to protocol deviations 4 patients randomized to Palifermin Before and After group were included Palifermin Before Only group and therefore a total of 111 subjects were included in this safety analysis set.	Placebo n=57 participants at risk Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=109 participants at risk Subjects to receive palifermin before- and after-high dose chemotherapy (total of 6 doses). A total of 115 subjects were randomized to treatment and 113 received at least one dose of study treatment. Due to protocol deviations additional 4 patients randomized to Palifermin Before and After group were included Palifermin Before Only group and therefore a total of 109 subjects were included in this safety analysis set.
Cardiac disorders Atrial fibrillation	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Bacteraemia	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Bronchopneumonia	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Cardiac disorders Cardiac arrest	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Cardiac disorders Cardiac failure	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Catheter related infection	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Clostridium difficile colitis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Psychiatric disorders Confusional state	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Metabolism and nutrition disorders Dehydration	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Diarrhoea	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Diarrhoea haemorrhagic	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Nervous system disorders Dizziness	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Dysphagia	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Edema	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Epiglottitis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Nervous system disorders Epilepsy	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Face oedema	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Gastroenteritis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
General disorders General physical health deterioration	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Injury, poisoning and procedural complications Graft complication	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Vascular disorders Hypotension	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Infection	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Intervertebral discitis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Mediastinitis	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Skin and subcutaneous tissue disorders Melanodermia	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Nausea	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Oesophagitis	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Pneumonia	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	1.8% 2/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Pneumonia primary atypical	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Skin and subcutaneous tissue disorders Rash	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	1.8% 2/109 • Adverse Events were collected for a period of up to 222 days.
Skin and subcutaneous tissue disorders Rash vesicular	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Renal and urinary disorders Renal failure acute	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Sepsis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Septic shock	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Sinusitis	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Nervous system disorders Syncope	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Tongue discolouration	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Urinary tract infection	0.00% 0/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.92% 1/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Vomiting	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.
Investigations Weight decreased	0.90% 1/111 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/57 • Adverse Events were collected for a period of up to 222 days.	0.00% 0/109 • Adverse Events were collected for a period of up to 222 days.

Measure	Palifermin Before Only n=111 participants at risk Subjects to receive palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses). A total of 109 subjects were randomized to treatment and 107 received at least one dose of study treatment. Due to protocol deviations 4 patients randomized to Palifermin Before and After group were included Palifermin Before Only group and therefore a total of 111 subjects were included in this safety analysis set.	Placebo n=57 participants at risk Subjects to receive matched placebo before- and after-high dose chemotherapy	Palifermin Before and After n=109 participants at risk Subjects to receive palifermin before- and after-high dose chemotherapy (total of 6 doses). A total of 115 subjects were randomized to treatment and 113 received at least one dose of study treatment. Due to protocol deviations additional 4 patients randomized to Palifermin Before and After group were included Palifermin Before Only group and therefore a total of 109 subjects were included in this safety analysis set.
Gastrointestinal disorders Abdominal pain	10.8% 12/111 • Adverse Events were collected for a period of up to 222 days.	14.0% 8/57 • Adverse Events were collected for a period of up to 222 days.	8.3% 9/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Abdominal pain upper	11.7% 13/111 • Adverse Events were collected for a period of up to 222 days.	14.0% 8/57 • Adverse Events were collected for a period of up to 222 days.	10.1% 11/109 • Adverse Events were collected for a period of up to 222 days.
Blood and lymphatic system disorders Anemia	17.1% 19/111 • Adverse Events were collected for a period of up to 222 days.	12.3% 7/57 • Adverse Events were collected for a period of up to 222 days.	15.6% 17/109 • Adverse Events were collected for a period of up to 222 days.
Metabolism and nutrition disorders Anorexia	9.0% 10/111 • Adverse Events were collected for a period of up to 222 days.	12.3% 7/57 • Adverse Events were collected for a period of up to 222 days.	11.0% 12/109 • Adverse Events were collected for a period of up to 222 days.
Psychiatric disorders Anxiety	5.4% 6/111 • Adverse Events were collected for a period of up to 222 days.	5.3% 3/57 • Adverse Events were collected for a period of up to 222 days.	6.4% 7/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Asthenia	7.2% 8/111 • Adverse Events were collected for a period of up to 222 days.	10.5% 6/57 • Adverse Events were collected for a period of up to 222 days.	12.8% 14/109 • Adverse Events were collected for a period of up to 222 days.
Musculoskeletal and connective tissue disorders Back pain	9.0% 10/111 • Adverse Events were collected for a period of up to 222 days.	8.8% 5/57 • Adverse Events were collected for a period of up to 222 days.	5.5% 6/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Constipation	20.7% 23/111 • Adverse Events were collected for a period of up to 222 days.	19.3% 11/57 • Adverse Events were collected for a period of up to 222 days.	13.8% 15/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Cough	11.7% 13/111 • Adverse Events were collected for a period of up to 222 days.	5.3% 3/57 • Adverse Events were collected for a period of up to 222 days.	6.4% 7/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Diarrhoea	72.1% 80/111 • Adverse Events were collected for a period of up to 222 days.	73.7% 42/57 • Adverse Events were collected for a period of up to 222 days.	74.3% 81/109 • Adverse Events were collected for a period of up to 222 days.
Nervous system disorders Dysgeusia	6.3% 7/111 • Adverse Events were collected for a period of up to 222 days.	5.3% 3/57 • Adverse Events were collected for a period of up to 222 days.	5.5% 6/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Dyspepsia	8.1% 9/111 • Adverse Events were collected for a period of up to 222 days.	1.8% 1/57 • Adverse Events were collected for a period of up to 222 days.	8.3% 9/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Dyspnea	4.5% 5/111 • Adverse Events were collected for a period of up to 222 days.	7.0% 4/57 • Adverse Events were collected for a period of up to 222 days.	4.6% 5/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Edema	11.7% 13/111 • Adverse Events were collected for a period of up to 222 days.	15.8% 9/57 • Adverse Events were collected for a period of up to 222 days.	14.7% 16/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Edema peripheral	11.7% 13/111 • Adverse Events were collected for a period of up to 222 days.	7.0% 4/57 • Adverse Events were collected for a period of up to 222 days.	15.6% 17/109 • Adverse Events were collected for a period of up to 222 days.
Skin and subcutaneous tissue disorders Erythema	18.0% 20/111 • Adverse Events were collected for a period of up to 222 days.	7.0% 4/57 • Adverse Events were collected for a period of up to 222 days.	23.9% 26/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Fatigue	11.7% 13/111 • Adverse Events were collected for a period of up to 222 days.	15.8% 9/57 • Adverse Events were collected for a period of up to 222 days.	10.1% 11/109 • Adverse Events were collected for a period of up to 222 days.
Blood and lymphatic system disorders Febrile neutropenia	14.4% 16/111 • Adverse Events were collected for a period of up to 222 days.	21.1% 12/57 • Adverse Events were collected for a period of up to 222 days.	17.4% 19/109 • Adverse Events were collected for a period of up to 222 days.
Vascular disorders Hypertension	13.5% 15/111 • Adverse Events were collected for a period of up to 222 days.	3.5% 2/57 • Adverse Events were collected for a period of up to 222 days.	10.1% 11/109 • Adverse Events were collected for a period of up to 222 days.
Metabolism and nutrition disorders Hypokalemia	18.0% 20/111 • Adverse Events were collected for a period of up to 222 days.	12.3% 7/57 • Adverse Events were collected for a period of up to 222 days.	14.7% 16/109 • Adverse Events were collected for a period of up to 222 days.
Vascular disorders Hypotension	6.3% 7/111 • Adverse Events were collected for a period of up to 222 days.	5.3% 3/57 • Adverse Events were collected for a period of up to 222 days.	6.4% 7/109 • Adverse Events were collected for a period of up to 222 days.
Infections and infestations Infection	5.4% 6/111 • Adverse Events were collected for a period of up to 222 days.	3.5% 2/57 • Adverse Events were collected for a period of up to 222 days.	6.4% 7/109 • Adverse Events were collected for a period of up to 222 days.
Psychiatric disorders Insomnia	9.0% 10/111 • Adverse Events were collected for a period of up to 222 days.	12.3% 7/57 • Adverse Events were collected for a period of up to 222 days.	10.1% 11/109 • Adverse Events were collected for a period of up to 222 days.
Blood and lymphatic system disorders Leukopenia	14.4% 16/111 • Adverse Events were collected for a period of up to 222 days.	7.0% 4/57 • Adverse Events were collected for a period of up to 222 days.	11.0% 12/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Nausea	78.4% 87/111 • Adverse Events were collected for a period of up to 222 days.	77.2% 44/57 • Adverse Events were collected for a period of up to 222 days.	70.6% 77/109 • Adverse Events were collected for a period of up to 222 days.
Blood and lymphatic system disorders Neutropenia	16.2% 18/111 • Adverse Events were collected for a period of up to 222 days.	8.8% 5/57 • Adverse Events were collected for a period of up to 222 days.	11.9% 13/109 • Adverse Events were collected for a period of up to 222 days.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	13.5% 15/111 • Adverse Events were collected for a period of up to 222 days.	15.8% 9/57 • Adverse Events were collected for a period of up to 222 days.	13.8% 15/109 • Adverse Events were collected for a period of up to 222 days.
Skin and subcutaneous tissue disorders Pruritus	9.0% 10/111 • Adverse Events were collected for a period of up to 222 days.	10.5% 6/57 • Adverse Events were collected for a period of up to 222 days.	13.8% 15/109 • Adverse Events were collected for a period of up to 222 days.
General disorders Pyrexia	43.2% 48/111 • Adverse Events were collected for a period of up to 222 days.	38.6% 22/57 • Adverse Events were collected for a period of up to 222 days.	43.1% 47/109 • Adverse Events were collected for a period of up to 222 days.
Skin and subcutaneous tissue disorders Rash	21.6% 24/111 • Adverse Events were collected for a period of up to 222 days.	21.1% 12/57 • Adverse Events were collected for a period of up to 222 days.	37.6% 41/109 • Adverse Events were collected for a period of up to 222 days.
Cardiac disorders Tachycardia	1.8% 2/111 • Adverse Events were collected for a period of up to 222 days.	3.5% 2/57 • Adverse Events were collected for a period of up to 222 days.	10.1% 11/109 • Adverse Events were collected for a period of up to 222 days.
Blood and lymphatic system disorders Thrombocytopenia	19.8% 22/111 • Adverse Events were collected for a period of up to 222 days.	15.8% 9/57 • Adverse Events were collected for a period of up to 222 days.	17.4% 19/109 • Adverse Events were collected for a period of up to 222 days.
Gastrointestinal disorders Vomiting	41.4% 46/111 • Adverse Events were collected for a period of up to 222 days.	43.9% 25/57 • Adverse Events were collected for a period of up to 222 days.	40.4% 44/109 • Adverse Events were collected for a period of up to 222 days.
Investigations Weight increased	3.6% 4/111 • Adverse Events were collected for a period of up to 222 days.	12.3% 7/57 • Adverse Events were collected for a period of up to 222 days.	4.6% 5/109 • Adverse Events were collected for a period of up to 222 days.
Nervous system disorders Headache	16.2% 18/111 • Adverse Events were collected for a period of up to 222 days.	10.5% 6/57 • Adverse Events were collected for a period of up to 222 days.	18.3% 20/109 • Adverse Events were collected for a period of up to 222 days.