Trial Outcomes & Findings for Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer (NCT NCT01494506)

Last Updated: 2016-06-17

Results Overview

Overall survival was the primary efficacy endpoint of the study and was defined as the time from the date of patient randomization to the date of death or the date the patient was last known to be alive. OS was summarized by Kaplan-Meier methodology for each treatment group. Pairwise treatment group comparisons were carried out using unstratified log rank analyses on the ITT population. Hazard ratio estimates are from Cox regression analysis. The comparison of Arm C is based only on patients who were randomized under the 3-arm version of the protocol. Consequently, the 5-FU+Leucovorin (Combo Therapy Comparison) group is a subset of all patients randomized to 5-FU+Leucovorin, which is the Mono Therapy Comparison control and contains patients randomized under both the 2-arm and 3-arm versions of the protocol.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

417 participants

Primary outcome timeframe

From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.

Results posted on

2016-06-17

Participant Flow

Patients were randomized over a period of 1.9 years starting from 2012-01-11 to 2013-09-11. The study was initially a two-arm study with MM-398 monotherapy and 5-FU/LV control (protocol version 1) . A third arm of MM-398+5-FU/LV was added later (protocol version 2).

All patients were screened for UGT1A1\*28 allele at baseline.

Participant milestones

Participant milestones
Measure	MM-398 (Arm A) • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin (Arm C) * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks
Overall Study STARTED	151	149	117
Overall Study Treated Population	147	134	117
Overall Study COMPLETED	3	6	14
Overall Study NOT COMPLETED	148	143	103

Reasons for withdrawal

Reasons for withdrawal
Measure	MM-398 (Arm A) • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin (Arm C) * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks
Overall Study Lack of Efficacy	77	83	57
Overall Study Adverse Event	17	10	11
Overall Study Death	9	5	2
Overall Study Physician Decision	7	5	4
Overall Study Withdrawal by Subject	17	20	14
Overall Study Clinical Deterioration	21	17	13
Overall Study Sponsor Decision	0	0	1
Overall Study Other	0	3	1

Baseline Characteristics

Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MM-398 n=151 Participants MM-398 Q3W IV MM-398: Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W	5 Fluorouracil and Leucovorin IV n=149 Participants 5 Fluorouracil and Leucovorin IV 5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks	MM-398, 5-FU and Leucovorin n=117 Participants MM-398, 5-FU and Leucovorin Q2W IV MM-398: Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W 5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks	Total n=417 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	151 Participants n=5 Participants	149 Participants n=7 Participants	117 Participants n=5 Participants	417 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	63.6 years STANDARD_DEVIATION 10.13 • n=5 Participants	61.8 years STANDARD_DEVIATION 9.65 • n=7 Participants	63.2 years STANDARD_DEVIATION 9.06 • n=5 Participants	62.8 years STANDARD_DEVIATION 9.68 • n=4 Participants
Sex: Female, Male Female	64 Participants n=5 Participants	68 Participants n=7 Participants	48 Participants n=5 Participants	180 Participants n=4 Participants
Sex: Female, Male Male	87 Participants n=5 Participants	81 Participants n=7 Participants	69 Participants n=5 Participants	237 Participants n=4 Participants
RACE (NIH/OMB) American Indian or Alaska Native	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
RACE (NIH/OMB) Asian	52 participants n=5 Participants	50 participants n=7 Participants	34 participants n=5 Participants	136 participants n=4 Participants
RACE (NIH/OMB) Black or African American	3 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants	10 participants n=4 Participants
RACE (NIH/OMB) White	89 participants n=5 Participants	92 participants n=7 Participants	72 participants n=5 Participants	253 participants n=4 Participants
RACE (NIH/OMB) other race	6 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants	17 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] 100% = normal, no complaints, no signs of disease	22 participants n=5 Participants	22 participants n=7 Participants	18 participants n=5 Participants	62 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] 90% = normal activity, few symptoms of disease	64 participants n=5 Participants	54 participants n=7 Participants	51 participants n=5 Participants	169 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] 80% = normal activity, some symptoms of disease	50 participants n=5 Participants	61 participants n=7 Participants	38 participants n=5 Participants	149 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] 70% = caring for self, unable to work	15 participants n=5 Participants	11 participants n=7 Participants	7 participants n=5 Participants	33 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] 60% [2] = needs help, can manage most tasks	0 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	2 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] 50%[2]= needs help often and medical care	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Karnofsky Performance Status (Baseline KPS)[1] Not recorded	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Pancreatic Primary Tumor Location Head	92 participants n=5 Participants	77 participants n=7 Participants	70 participants n=5 Participants	239 participants n=4 Participants
Pancreatic Primary Tumor Location Body	16 participants n=5 Participants	26 participants n=7 Participants	12 participants n=5 Participants	54 participants n=4 Participants
Pancreatic Primary Tumor Location Tail	24 participants n=5 Participants	24 participants n=7 Participants	14 participants n=5 Participants	62 participants n=4 Participants
Pancreatic Primary Tumor Location Multiple locations including head	7 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants	17 participants n=4 Participants
Pancreatic Primary Tumor Location Multiple locations not including head	7 participants n=5 Participants	14 participants n=7 Participants	9 participants n=5 Participants	30 participants n=4 Participants
Pancreatic Primary Tumor Location Unknown = not specified	5 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants	15 participants n=4 Participants

PRIMARY outcome

Timeframe: From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.

Population: Intent to Treat population (ITT population) consisted of all randomized participants. Efficacy analyses in the ITT population consider treatment group according to randomization. Comparisons of the MM-398+5-FU/LV to 5-FU/LV were carried out only on patients who were randomized under protocol version 2 or later.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=151 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=149 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=117 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=119 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Overall Survival	4.9 months Interval 4.23 to 5.62	4.2 months Interval 3.58 to 4.86	6.1 months Interval 4.76 to 8.87	4.2 months Interval 3.29 to 5.32

SECONDARY outcome

Timeframe: Randomization until disease progression or death from any cause; Until the data cut off of 14 Feb 2014. The maximum time in follow up was 25 months.

Population: ITT Population

Progression-free survival was defined as the time from the date of randomization to the date of disease progression, or death (any cause) on or prior to the clinical cutoff date, whichever occurred earlier. Participants who did not have disease progression or had not died were censored at the date of the last tumor assessment. Patients with two or more consecutive missing response assessments prior to a visit with documented progression (or death) were censored at the last date of tumor assessment when the patient was documented to be progression free. PFS was summarized using Kaplan-Meier methods. The comparison of Arm C is based only on patients who were randomized under the 3-arm version of the protocol. Consequently, the 5-FU+Leucovorin (Combo Therapy Comparison) group is a subset of all patients randomized to 5-FU+Leucovorin, which is the Mono Therapy Comparison control and contains patients randomized under both the 2-arm and 3-arm versions of the protocol.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=151 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=149 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=117 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=119 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Progression Free Survival	2.7 months Interval 2.13 to 2.89	1.6 months Interval 1.41 to 1.84	3.1 months Interval 2.69 to 4.17	1.5 months Interval 1.41 to 1.84

SECONDARY outcome

Timeframe: Assessment every 6 weeks after initial response; Day 1 to data cut off of 14 Feb 2014; maximum time on study 25 months.

Population: ITT Population

The objective response rate was a secondary efficacy endpoint of the study and was defined by the percentage of patients in the study population with a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator. Best overall response was defined per RECIST (version 1.1) recorded from randomization until progression or end of study. RECIST (v 1.1) criteria does not require confirmation of response, but an additional, more stringent analysis was also conducted, with designation of CR (or PR) requiring confirmation of response at least 4 weeks following the initial assessment of CR (or PR). Stable disease (SD) required an assessment of SD at least 6 weeks after starting treatment. Subjects with insufficient data for response classification were classified as Not Evaluable for best overall response, and as a non-responder for objective response, in the ITT population. Treatment groups are as indicated for the primary outcome of OS.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=151 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=149 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=117 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=119 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Objective Response Rate	3.31 percentage with confirmed response Interval 0.46 to 6.17	0.67 percentage with confirmed response Interval 0.0 to 1.98	7.69 percentage with confirmed response Interval 2.86 to 12.52	0.84 percentage with confirmed response Interval 0.0 to 2.48

SECONDARY outcome

Timeframe: Randomization to treatment discontinuation (any cause). The maximum time in follow up was 25 months

Population: ITT Population

Time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity or death.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=151 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=149 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=117 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=119 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Time to Treatment Failure	1.7 months Interval 1.5 to 2.7	1.4 months Interval 1.3 to 1.4	2.3 months Interval 1.6 to 2.8	1.4 months Interval 1.3 to 1.4

SECONDARY outcome

Timeframe: Randomization to treatment discontinuation.The maximum time in follow up was 25 months

Population: Clinical Benefit Response Evaluable Population: Patients who received study drug and met at least one of the following criteria were defined as eligible for evaluation of CBR: * baseline pain intensity ≥ 20 (out of 100) * baseline morphine consumption ≥ 10 mg/day PO morphine equivalents * baseline KPS of 70 to 90 points

Composite measure based on patient-reported pain (per VAS), patient-reported pain medication, KPS, and weight. Clinical benefit is indicated by either: (a) improvement in pain (less pain intensity with stable or decreased pain medication; or less pain medication with stable or decreased pain intensity) with stable or improved KPS; or (b) improvement in KPS with stable or improved pain. With stable for KPS and pain, clinical benefit may be indicated with an observation of positive weight change. Clinical benefit response (CBR) was classified weekly and a patient was considered a clinical benefit responder if clinical benefit was observed and maintained over a 4 week period.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=92 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=80 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=78 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=60 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Percentage of Patients With Clinical Benefit Response	14 percentage of participants with CBR	13 percentage of participants with CBR	14 percentage of participants with CBR	12 percentage of participants with CBR

SECONDARY outcome

Timeframe: Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

Population: Patients with elevated baseline CA19-9 value (\> 30 U/mL) who received study drug.

Tumor marker response (TMR) was evaluated by the change in CA19-9 serum levels. Response was defined as a decrease of 50% of CA19-9 in relation to the baseline level at least once during the treatment period.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=123 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=105 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=97 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=81 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Percentage of Patients With Tumor Marker (CA 19-9) Response	23.6 percent of participants with TMR	11.4 percent of participants with TMR	28.9 percent of participants with TMR	8.6 percent of participants with TMR

SECONDARY outcome

Timeframe: Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

Population: ITT patients who had baseline and at least one-post baseline EORTC-QLQ-C30 assessment.

This patient recorded outcome consists of 15 subscales in 3 independent domains: global health-related quality of life (HRQoL), functional scales (cognitive, emotional, physical, role and social functioning), and symptom scales (appetite loss, constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and vomiting, and pain). For each subscale, patients were classified as improved, worsened or stable. Improvement is indicated by achievement of subscale score at least 10% improved from baseline and maintained for at least 6 weeks. Worsened is indicated by subscale score at least 10% worse than baseline. Stable is indicated by neither improvement nor worsened. Achievement of improvement prior to worsening was classified as improvement.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=105 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=83 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison n=71 Participants * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) n=57 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
EORTC-QLQ-C30 Global Health Status: Improved	10 percent of patients in category	11 percent of patients in category	17 percent of patients in category	12 percent of patients in category
EORTC-QLQ-C30 Global Health Status: Stable	31 percent of patients in category	41 percent of patients in category	38 percent of patients in category	44 percent of patients in category
EORTC-QLQ-C30 Global Health Status: Worsened	57 percent of patients in category	48 percent of patients in category	45 percent of patients in category	44 percent of patients in category
EORTC-QLQ-C30 Physical Functioning: Improved	10 percent of patients in category	11 percent of patients in category	10 percent of patients in category	11 percent of patients in category
EORTC-QLQ-C30 Physical Functioning: Stable	29 percent of patients in category	37 percent of patients in category	41 percent of patients in category	40 percent of patients in category
EORTC-QLQ-C30 Physical Functioning: Worsened	61 percent of patients in category	52 percent of patients in category	49 percent of patients in category	49 percent of patients in category
EORTC-QLQ-C30 Role Functioning: Improved	6 percent of patients in category	10 percent of patients in category	15 percent of patients in category	11 percent of patients in category
EORTC-QLQ-C30 Role Functioning: Stable	29 percent of patients in category	39 percent of patients in category	32 percent of patients in category	37 percent of patients in category
EORTC-QLQ-C30 Role Functioning: Worsened	66 percent of patients in category	52 percent of patients in category	52 percent of patients in category	53 percent of patients in category
EORTC-QLQ-C30 Emotional Functioning:Improved	10 percent of patients in category	8 percent of patients in category	20 percent of patients in category	9 percent of patients in category
EORTC-QLQ-C30 Emotional Functioning:Stable	32 percent of patients in category	59 percent of patients in category	46 percent of patients in category	58 percent of patients in category
EORTC-QLQ-C30 Emotional Functioning:Worsened	56 percent of patients in category	33 percent of patients in category	34 percent of patients in category	33 percent of patients in category
EORTC-QLQ-C30 Cognitive Functioning:Improved	12 percent of patients in category	6 percent of patients in category	11 percent of patients in category	7 percent of patients in category
EORTC-QLQ-C30 Cognitive Functioning:Stable	32 percent of patients in category	42 percent of patients in category	48 percent of patients in category	44 percent of patients in category
EORTC-QLQ-C30 Cognitive Functioning:Worsened	54 percent of patients in category	52 percent of patients in category	41 percent of patients in category	49 percent of patients in category
EORTC-QLQ-C30 Social Functioning:Improved	11 percent of patients in category	11 percent of patients in category	13 percent of patients in category	11 percent of patients in category
EORTC-QLQ-C30 Social Functioning:Stable	26 percent of patients in category	43 percent of patients in category	34 percent of patients in category	47 percent of patients in category
EORTC-QLQ-C30 Social Functioning:Worsened	62 percent of patients in category	46 percent of patients in category	54 percent of patients in category	42 percent of patients in category
EORTC-QLQ-C30 Fatigue:Improved	13 percent of patients in category	11 percent of patients in category	14 percent of patients in category	12 percent of patients in category
EORTC-QLQ-C30 Fatigue:Stable	18 percent of patients in category	30 percent of patients in category	20 percent of patients in category	33 percent of patients in category
EORTC-QLQ-C30 Fatigue:Worsened	69 percent of patients in category	59 percent of patients in category	66 percent of patients in category	54 percent of patients in category
EORTC-QLQ-C30 Nausea and Vomiting:Improved	5 percent of patients in category	6 percent of patients in category	13 percent of patients in category	4 percent of patients in category
EORTC-QLQ-C30 Nausea and Vomiting:Stable	37 percent of patients in category	42 percent of patients in category	32 percent of patients in category	46 percent of patients in category
EORTC-QLQ-C30 Nausea and Vomiting:Worsened	58 percent of patients in category	52 percent of patients in category	55 percent of patients in category	51 percent of patients in category
EORTC-QLQ-C30 Pain:Improved	20 percent of patients in category	10 percent of patients in category	27 percent of patients in category	11 percent of patients in category
EORTC-QLQ-C30 Pain:Stable	30 percent of patients in category	37 percent of patients in category	34 percent of patients in category	40 percent of patients in category
EORTC-QLQ-C30 Pain:Worsened	50 percent of patients in category	53 percent of patients in category	39 percent of patients in category	49 percent of patients in category
EORTC-QLQ-C30 Dyspnoea:Improved	10 percent of patients in category	6 percent of patients in category	7 percent of patients in category	5 percent of patients in category
EORTC-QLQ-C30 Dyspnoea:Stable	47 percent of patients in category	69 percent of patients in category	51 percent of patients in category	68 percent of patients in category
EORTC-QLQ-C30 Dyspnoea:Worsoned	44 percent of patients in category	24 percent of patients in category	42 percent of patients in category	25 percent of patients in category
EORTC-QLQ-C30 Insomnia:Improved	9 percent of patients in category	4 percent of patients in category	18 percent of patients in category	5 percent of patients in category
EORTC-QLQ-C30 Insomnia:Stable	43 percent of patients in category	49 percent of patients in category	34 percent of patients in category	49 percent of patients in category
EORTC-QLQ-C30 Insomnia:Worsened	48 percent of patients in category	47 percent of patients in category	48 percent of patients in category	46 percent of patients in category
EORTC-QLQ-C30 Appetite Loss:Improved	9 percent of patients in category	6 percent of patients in category	11 percent of patients in category	5 percent of patients in category
EORTC-QLQ-C30 Appetite Loss:Stable	38 percent of patients in category	42 percent of patients in category	45 percent of patients in category	46 percent of patients in category
EORTC-QLQ-C30 Appetite Loss:Worsened	53 percent of patients in category	52 percent of patients in category	44 percent of patients in category	49 percent of patients in category
EORTC-QLQ-C30 Constipation:Improved	13 percent of patients in category	4 percent of patients in category	13 percent of patients in category	4 percent of patients in category
EORTC-QLQ-C30 Constipation:Stable	47 percent of patients in category	63 percent of patients in category	56 percent of patients in category	67 percent of patients in category
EORTC-QLQ-C30 Constipation:Worsened	39 percent of patients in category	34 percent of patients in category	31 percent of patients in category	30 percent of patients in category
EORTC-QLQ-C30 Diarrhoea:Improved	4 percent of patients in category	4 percent of patients in category	6 percent of patients in category	4 percent of patients in category
EORTC-QLQ-C30 Diarrhoea: Stable	35 percent of patients in category	58 percent of patients in category	39 percent of patients in category	58 percent of patients in category
EORTC-QLQ-C30 Diarrhoea: Worsened	59 percent of patients in category	39 percent of patients in category	55 percent of patients in category	39 percent of patients in category
EORTC-QLQ-C30 Financial Difficulties: Improved	6 percent of patients in category	1 percent of patients in category	8 percent of patients in category	0 percent of patients in category
EORTC-QLQ-C30 Financial Difficulties: Stable	51 percent of patients in category	67 percent of patients in category	51 percent of patients in category	74 percent of patients in category
EORTC-QLQ-C30 Financial Difficulties: Worsened	42 percent of patients in category	31 percent of patients in category	41 percent of patients in category	26 percent of patients in category

SECONDARY outcome

Timeframe: 6 weeks after first study drug administration

Population: PK population was based on Protocol, all participants who received the appropriate dose of MM-398.

Plasma concentration-time data for MM-398 will be analyzed using population pharmacokinetic methods.

Outcome measures

Outcome measures
Measure	MM-398 Arm A (Mono Therapy Comparison) n=143 Participants • MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.	5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) n=114 Participants * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.	MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison * MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2. 5-FU 2400 mg/m2 IV over 46-hours, and * Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks	5-FU + Leucovorin (Combo Therapy Comparison) * 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle * Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.
Pharmacokinetic Measurements of Total Irinotecan Total Irinotecan-Cavg	2550.00 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 197.4	2120.00 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 209.7	—	—
Pharmacokinetic Measurements of Total Irinotecan Total Irinotecan-Cmax	40550.00 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 172.3	28460.00 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 69.3	—	—
Pharmacokinetic Measurements of Total Irinotecan Total SN38-Cavg	0.82 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 119.2	0.68 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 132.7	—	—
Pharmacokinetic Measurements of Total Irinotecan Total SN38-Cmax	3.93 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 119.6	2.58 Total irinotecan = ug/L; SN38= ug/L Geometric Coefficient of Variation 121.9	—	—

Adverse Events

MM-398

Serious events: 90 serious events

Other events: 145 other events

Deaths: 0 deaths

5 Fluorouracil and Leucovorin IV

Serious events: 58 serious events

Other events: 132 other events

Deaths: 0 deaths

MM-398, 5-FU and Leucovorin

Serious events: 56 serious events

Other events: 116 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Eliel Bayever

Merrimack Pharmaceuticals, Inc.

Phone: 6174411000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Authorship/contents of any publication is determined by site and provides sponsor a publication prior to submission. Sponsor has 60 days to review and avoid editorial changes but may request site delete confidential data. If publication contains patentable matter, site agrees to delay publication for 60 days. If study is part of multicenter protocol, site agrees not to independently publish. If multicenter publication is not forthcoming in 18 months after study end, site may proceed accordingly.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	MM-398 n=147 participants at risk MM-398 Q3W IV MM-398: Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W	5 Fluorouracil and Leucovorin IV n=134 participants at risk 5 Fluorouracil and Leucovorin IV 5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks	MM-398, 5-FU and Leucovorin n=117 participants at risk MM-398, 5-FU and Leucovorin Q2W IV MM-398: Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W 5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks
Blood and lymphatic system disorders Anemia	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Febrile Neutropenia	4.1% 6/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Neutropenia	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Pancytopenia	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Abdominal Pain	4.1% 6/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.5% 6/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.3% 5/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Abdominal Pain Upper	2.7% 4/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Ascites	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Diarrhoea	12.9% 19/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 7/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Duodenal Ulcer	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Gastro Intestinal Haemorrhage	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Intestinal Obstruction	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Nausea	3.4% 5/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.4% 4/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Small Intestinal Obstruction	2.0% 3/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Upper Gastrointestinal Haemorrhage	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Vomiting	9.5% 14/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	9.4% 11/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Asthenia	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders General Physical Health Deterioration	2.0% 3/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Non-Cardiac Chest Pain	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Pyrexia	3.4% 5/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.6% 3/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Hepatobiliary disorders Bile Duct Obstruction	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Hepatobiliary disorders Cholangitis	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Hepatobiliary disorders Hepatic Failure	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Hepatobiliary disorders Jaundice Cholestatic	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Biliary Tract Infection	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Clostridium Difficile Colitis	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Device Related Infection	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.6% 3/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Gastroenteritis	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Lower Respiratory Tract Infection	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Pneumonia	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.6% 3/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Sepsis	2.0% 3/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.4% 4/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Septic Shock	2.0% 3/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Urinary Tract Infection	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Injury, poisoning and procedural complications Overdose	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Decrease Appetite	4.1% 6/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Dehydration	2.0% 3/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.6% 3/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour Haemorrhage	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour Pain	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Nervous system disorders Cerebrovascular Accident	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.85% 1/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Renal and urinary disorders Acute Prerenal Failure	0.68% 1/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.7% 2/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Renal and urinary disorders Hydronephrosis	0.00% 0/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.00% 0/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1

Other adverse events
Measure	MM-398 n=147 participants at risk MM-398 Q3W IV MM-398: Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W	5 Fluorouracil and Leucovorin IV n=134 participants at risk 5 Fluorouracil and Leucovorin IV 5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks	MM-398, 5-FU and Leucovorin n=117 participants at risk MM-398, 5-FU and Leucovorin Q2W IV MM-398: Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W 5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks
Gastrointestinal disorders Diarrhoea	70.1% 103/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	26.1% 35/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	99.1% 116/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Vomiting	54.4% 80/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	26.1% 35/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	52.1% 61/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Nausea	60.5% 89/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	34.3% 46/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	51.3% 60/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Decreased Appetite	49.0% 72/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	32.1% 43/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	44.4% 52/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Fatigue	36.7% 54/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	27.6% 37/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	40.2% 47/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Anaemia	32.7% 48/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	23.1% 31/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	37.6% 44/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Abdominal Pain	34.0% 50/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	31.3% 42/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	23.1% 27/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Pyrexia	19.7% 29/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	11.2% 15/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	23.1% 27/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Neutropenia	15.0% 22/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.0% 4/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	23.1% 27/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Constipation	17.7% 26/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	23.9% 32/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	22.2% 26/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Asthenia	23.8% 35/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	16.4% 22/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	20.5% 24/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Weight Decreased	19.7% 29/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.7% 9/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	17.1% 20/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Neutrophil Count Decreased	10.2% 15/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	14.5% 17/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders White Blood Cell Count Decreased	6.8% 10/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	14.5% 17/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Alopecia	21.8% 32/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.5% 6/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	13.7% 16/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Stomatitis	3.4% 5/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 8/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	13.7% 16/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Dizziness	11.6% 17/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	9.7% 13/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	12.8% 15/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Back Pain	8.2% 12/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	11.9% 16/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	12.8% 15/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Hypokalaemia	21.8% 32/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	9.0% 12/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	12.0% 14/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Oedema Peripheral	19.0% 28/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	14.9% 20/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	11.1% 13/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Hepatobiliary disorders Mucosal Inflammation	5.4% 8/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.7% 5/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	10.3% 12/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Leukopenia	4.1% 6/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	0.75% 1/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	10.3% 12/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Blood and lymphatic system disorders Platelet Count Decreased	2.0% 3/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.2% 3/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	10.3% 12/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Abdominal Pain Upper	11.6% 17/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	7.5% 10/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	9.4% 11/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Abdominal Distension	8.2% 12/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 8/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	8.5% 10/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Dehydration	10.2% 15/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.7% 9/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	7.7% 9/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Insomnia	8.2% 12/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.7% 5/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	7.7% 9/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.5% 11/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.5% 6/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	7.7% 9/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Mouth Ulceration	4.1% 6/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.2% 3/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.8% 8/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Investigations Alanine Aminotransferase Increased	3.4% 5/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.8% 8/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Investigations Hypomagnesaemia	13.6% 20/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.7% 5/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 7/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Hypoalbumineamia	12.9% 19/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 8/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 7/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Hypotension	4.1% 6/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.0% 7/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Respiratory, thoracic and mediastinal disorders Cough	6.1% 9/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.5% 6/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	5.1% 6/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
General disorders Headache	5.4% 8/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.5% 6/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	5.1% 6/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Infections and infestations Oral Candidiasis	2.7% 4/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	1.5% 2/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	5.1% 6/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Gastrooesophageal Reflux Disease	1.4% 2/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.5% 6/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	5.1% 6/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Hyperglycaemia	6.8% 10/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	6.7% 9/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	4.3% 5/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Gastrointestinal disorders Ascites	9.5% 14/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	8.2% 11/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.4% 4/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
Metabolism and nutrition disorders Hyponatraemia	7.5% 11/147 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	2.2% 3/134 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1	3.4% 4/117 • Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days. 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1