Study of Nanoliposomal Irinotecan (Nal-IRI)-Containing Regimens Versus Nab-paclitaxel Plus Gemcitabine in Patients With Previously Untreated, Metastatic Pancreatic Adenocarcinoma

• ClinicalTrials.gov Identifier: NCT02551991
• Recruitment Status: Completed
• First Posted: September 16, 2015
• Results First Posted: October 10, 2022
• Last Update Posted: October 10, 2022
• Sponsor: Ipsen
• Information provided by (Responsible Party): Ipsen

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pancreatic Cancer
• Interventions: Drug: nal-IRI; Drug: 5 fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin
• Enrollment: 56

Participant Flow

Recruitment Details	This Phase 2 non-comparative, open-label study was conducted in previously untreated metastatic pancreatic cancer participants at 15 investigational sites in Australia, Spain and USA between 19 October 2015 and 15 February 2021.
Pre-assignment Details	This study was divided into 2 parts: Part 1 (dose exploration [Part 1A] followed by dose expansion [Part 1B] of the irinotecan liposome injection + 5 fluorouracil [5-FU]/leucovorin [LV] + oxaliplatin regimen) and Part 2 (comparison of irinotecan liposome injection-containing regimen versus [vs] nab-paclitaxel plus gemcitabine). Overall, 56 participants were enrolled in this study.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1
Arm/Group Description	Participants received irinotecan liposome injection 70 milligram per square meter (mg/m^2) followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Period Title: Overall Study
Started	7	7	10	7	25
Completed	0	0	0	0	0
Not Completed	7	7	10	7	25
Reason Not Completed
Death	5	7	8	7	17
Withdrawal by Subject	1	0	0	0	2
Lost to Follow-up	0	0	1	0	0
Sponsor Decision	1	0	1	0	5
Other	0	0	0	0	1

Baseline Characteristics

Arm/Group Title		Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Total
Arm/Group Description		Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Total of all reporting groups
Overall Number of Baseline Participants		7	7	10	7	25	56
Baseline Analysis Population Description		Safety population included participants who received at least 1 dose of any study treatment.
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	7 participants	10 participants	7 participants	25 participants	56 participants
	< 65 years	4	4	3	4	19	34
	>= 65 years	3	3	7	3	6	22
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	7 participants	10 participants	7 participants	25 participants	56 participants
	Female	6	4	2	2	14	28
	Male	1	3	8	5	11	28
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	7 participants	10 participants	7 participants	25 participants	56 participants
	White	6	7	9	7	21	50
	Black or African American	0	0	0	0	2	2
	Asian	1	0	1	0	1	3
	Not Reportable	0	0	0	0	1	1
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	7 participants	10 participants	7 participants	25 participants	56 participants
	Hispanic or Latino	0	0	0	0	4	4
	Not Hispanic or Latino	7	7	10	7	21	52

Outcome Measures

1. Primary Outcome

Title	Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)
Description	Adverse events (AEs) were considered to be DLTs if they occurred during the safety evaluation period (i.e, 28 days of Cycle 1; or 14 days after the second dose of study treatment if there was a treatment delay) and were deemed related to the study treatment regimen. Any AE that was related to disease progression was not considered a DLT.
Time Frame	From the start of the first study treatment (Cycle 1 Day 1) up to 14 days after the second dose of study treatment, maximum of 42 days

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	7	7	10	7
Measure Type: Count of Participants; Unit of Measure: Participants
	2	1	2	0

2. Secondary Outcome

Title	Median Progression Free Survival (PFS)
Description	The PFS was defined as the time from date of first study treatment to the first documented radiographical progression of disease (PD), per investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, or death from any cause, whichever comes first. The PFS was calculated using Kaplan-Meier technique.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter (maximum of 278 weeks).

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	7	7	10	7	25	32
Median (95% Confidence Interval); Unit of Measure: months
	9.7 [1]; (2.96 to NA)	32.3 [1]; (0.53 to NA)	9.2 [1]; (0.46 to NA)	3.8; (1.22 to 5.78)	9.2; (7.59 to 11.20)	9.2; (7.59 to 11.96)

[1]

Upper limit of confidence interval was not evaluable due to below the level of detection.

3. Secondary Outcome

Title	Best Overall Response (BOR)
Description	The BOR was defined as the best response (complete response [CR] + partial response [PR] + stable disease [SD]) recorded from the start of study treatment until disease progression or start of new anticancer therapy using RECIST Version 1.1.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	7	7	10	7	25	32
Measure Type: Count of Participants; Unit of Measure: Participants
	2	6	4	4	20	26

4. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	The ORR was defined as the percentage of participants with a BOR characterized as either a CR or PR relative to the total number of evaluable participants using RECIST Version 1.1. Evaluable participants were defined as treated participants with measurable disease at baseline.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	7	7	10	7	25	32
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	0; (0 to 41.0)	42.9; (9.9 to 81.6)	30.0; (6.7 to 65.2)	14.3; (0.4 to 57.9)	32.0; (14.9 to 53.5)	34.4; (18.6 to 53.2)

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	The DCR was defined as percentage of participants with CR or PR or SD or Non-PD/Non-CR, per RECIST Version 1.1 relative to total number of treated participants with measurable disease at baseline.
Time Frame	At Week 16

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	7	7	10	7	25	32
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	42.9; (9.9 to 81.6)	71.4; (29.0 to 96.3)	40.0; (12.2 to 73.8)	28.6; (3.7 to 71.0)	72.0; (50.6 to 87.9)	71.9; (53.3 to 86.3)

6. Secondary Outcome

Title	Median Overall Survival (OS)
Description	The OS was the time from date of first study treatment to the date of death from any cause. Participant survival data were collected from all available sources. The OS was calculated using Kaplan-Meier technique.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	7	7	10	7	25	32
Median (95% Confidence Interval); Unit of Measure: months
	12.6; (3.98 to 21.03)	12.5; (0.53 to 12.71)	16.6; (0.69 to 26.74)	5.8; (1.35 to 14.65)	12.7; (8.18 to 23.66)	12.6; (8.74 to 19.12)

7. Secondary Outcome

Title	Median Duration of Response (DoR)
Description	The DoR was defined as the time from the first date of response (CR or PR) to first date of documented radiographical PD, per investigator using RECIST Version 1.1. This only applied to participants with CR or PR. If a participant was given a new anticancer therapy prior to first response, DoR was not calculated. The DoR was calculated using Kaplan-Meier technique.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least 1 dose of any study treatment. Only participants with DoR events were analyzed for this outcome measure.

Arm/Group Title	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Arm/Group Description:	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.	Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
Overall Number of Participants Analyzed	0	2	1	0	4	6
Median (95% Confidence Interval); Unit of Measure: months
		28.4 [1]; (3.52 to NA)	NA [2]; (NA to 16.39)		9.4 [1]; (2.20 to NA)	9.4 [1]; (3.52 to NA)

[1]

Upper limit of confidence interval was not evaluable due to below the level of detection.

[2]

Median and lower limit of confidence interval was not evaluable due to below the level of detection.

Adverse Events

Time Frame	Treatment-emergent adverse events are reported from the time of first study treatment administration (Day 1) up to 30 days after the date of last study treatment administration or until the start of alternative anticancer therapy, approximately 1008 days. All-Cause Mortality are reported from first participant enrolled to last participant died, approximately 1946 days.
Adverse Event Reporting Description	Safety population included participants who received at least 1 dose of any study treatment.
Arm/Group Title	Dose Exploration: Cohort 1		Dose Exploration: Cohort -1		Dose Exploration: Cohort -2B		Dose Exploration: Cohort -3		Dose Expansion: Cohort -1
Arm/Group Description	Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.		Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.		Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.		Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.		Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.
All-Cause Mortality
	Dose Exploration: Cohort 1		Dose Exploration: Cohort -1		Dose Exploration: Cohort -2B		Dose Exploration: Cohort -3		Dose Expansion: Cohort -1
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	5/7 (71.43%)		7/7 (100.00%)		8/10 (80.00%)		7/7 (100.00%)		17/25 (68.00%)
Serious Adverse Events
	Dose Exploration: Cohort 1		Dose Exploration: Cohort -1		Dose Exploration: Cohort -2B		Dose Exploration: Cohort -3		Dose Expansion: Cohort -1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.71%)		2/7 (28.57%)		7/10 (70.00%)		4/7 (57.14%)		15/25 (60.00%)
Blood and lymphatic system disorders
Febrile Neutropenia † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Anaemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	3
Anaemia of Malignant Disease † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Cardiac disorders
Arteriospasm Coronary † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Gastrointestinal disorders
Diarrhoea † 1	2/7 (28.57%)	2	1/7 (14.29%)	1	1/10 (10.00%)	1	1/7 (14.29%)	1	1/25 (4.00%)	2
Vomiting † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	2/10 (20.00%)	2	0/7 (0.00%)	0	3/25 (12.00%)	3
Abdominal Pain † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	3/7 (42.86%)	3	1/25 (4.00%)	1
Nausea † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	3/25 (12.00%)	3
Colitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	2/7 (28.57%)	2	1/25 (4.00%)	1
Enterocolitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	1
Small Intestinal Obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	1/25 (4.00%)	2
Constipation † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Duodenal Ulcer † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Enteritis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Intestinal Obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Large Intestinal Obstruction † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Malignant Gastrointestinal Obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Oesophageal Varices Haemorrhage † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Pancreatitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Stomatitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Upper Gastrointestinal Haemorrhage † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
General disorders
Disease Progression † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Fatigue † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Pyrexia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hepatobiliary disorders
Bile Duct Obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Biliary Dilatation † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Cholangitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Infections and infestations
Bacterial Sepsis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Clostridium Difficile Colitis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Neutropenic Sepsis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Pneumonia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Sepsis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	2
Urinary Tract Infection † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Injury, poisoning and procedural complications
Subdural Haematoma † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Metabolism and nutrition disorders
Dehydration † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Hyperglycaemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hypokalaemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back Pain † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Renal and urinary disorders
Acute Kidney Injury † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Nephrolithiasis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	1/25 (4.00%)	1
Dyspnoea † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Vascular disorders
Deep Vein Thrombosis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hypotension † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Orthostatic Hypotension † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Dose Exploration: Cohort 1		Dose Exploration: Cohort -1		Dose Exploration: Cohort -2B		Dose Exploration: Cohort -3		Dose Expansion: Cohort -1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100.00%)		7/7 (100.00%)		10/10 (100.00%)		7/7 (100.00%)		25/25 (100.00%)
Blood and lymphatic system disorders
Neutropenia † 1	2/7 (28.57%)	4	3/7 (42.86%)	13	5/10 (50.00%)	6	1/7 (14.29%)	2	10/25 (40.00%)	29
Thrombocytopenia † 1	0/7 (0.00%)	0	2/7 (28.57%)	10	4/10 (40.00%)	4	0/7 (0.00%)	0	9/25 (36.00%)	18
Anaemia † 1	1/7 (14.29%)	2	1/7 (14.29%)	1	3/10 (30.00%)	5	2/7 (28.57%)	2	7/25 (28.00%)	35
Febrile neutropenia † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	3/25 (12.00%)	4
Leukocytosis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	3/25 (12.00%)	3
Leukopenia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	2	1/7 (14.29%)	1	1/25 (4.00%)	1
Neutrophilia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Anaemia of malignant disease † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Cytopenia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Splenic infarction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Splenic vein thrombosis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Cardiac disorders
Tachycardia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Arteriospasm coronary † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Palpitations † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Sinus tachycardia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Endocrine disorders
Hypothyroidism † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Eye disorders
Eye disorder † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Eyelid oedema † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Vision blurred † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Gastrointestinal disorders
Nausea † 1	5/7 (71.43%)	9	6/7 (85.71%)	7	9/10 (90.00%)	19	5/7 (71.43%)	6	23/25 (92.00%)	49
Diarrhoea † 1	6/7 (85.71%)	18	5/7 (71.43%)	22	6/10 (60.00%)	14	6/7 (85.71%)	14	22/25 (88.00%)	54
Vomiting † 1	5/7 (71.43%)	12	4/7 (57.14%)	7	5/10 (50.00%)	8	3/7 (42.86%)	4	14/25 (56.00%)	28
Constipation † 1	3/7 (42.86%)	3	4/7 (57.14%)	9	4/10 (40.00%)	5	1/7 (14.29%)	2	13/25 (52.00%)	22
Abdominal pain † 1	2/7 (28.57%)	5	3/7 (42.86%)	5	3/10 (30.00%)	3	4/7 (57.14%)	6	8/25 (32.00%)	16
Stomatitis † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	2/10 (20.00%)	7	1/7 (14.29%)	1	7/25 (28.00%)	9
Abdominal distension † 1	3/7 (42.86%)	3	2/7 (28.57%)	2	2/10 (20.00%)	2	0/7 (0.00%)	0	3/25 (12.00%)	3
Dry mouth † 1	2/7 (28.57%)	4	1/7 (14.29%)	1	1/10 (10.00%)	1	3/7 (42.86%)	3	3/25 (12.00%)	3
Flatulence † 1	0/7 (0.00%)	0	4/7 (57.14%)	5	2/10 (20.00%)	2	1/7 (14.29%)	1	1/25 (4.00%)	1
Abdominal pain upper † 1	2/7 (28.57%)	2	1/7 (14.29%)	1	1/10 (10.00%)	1	0/7 (0.00%)	0	2/25 (8.00%)	2
Haemorrhoids † 1	1/7 (14.29%)	1	2/7 (28.57%)	3	0/10 (0.00%)	0	1/7 (14.29%)	1	2/25 (8.00%)	2
Pancreatic failure † 1	0/7 (0.00%)	0	3/7 (42.86%)	3	0/10 (0.00%)	0	1/7 (14.29%)	1	1/25 (4.00%)	1
Colitis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	2/7 (28.57%)	3	1/25 (4.00%)	1
Dyspepsia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	4/25 (16.00%)	6
Anal fissure † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	2/10 (20.00%)	3	0/7 (0.00%)	0	0/25 (0.00%)	0
Small intestinal obstruction † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	1/25 (4.00%)	2
Toothache † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Anal haemorrhage † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	1/7 (14.29%)	1	0/25 (0.00%)	0
Dysphagia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Enterocolitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	1
Gastrooesophageal reflux disease † 1	0/7 (0.00%)	0	2/7 (28.57%)	3	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Mouth ulceration † 1	0/7 (0.00%)	0	2/7 (28.57%)	2	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Proctalgia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	2/10 (20.00%)	4	0/7 (0.00%)	0	0/25 (0.00%)	0
Abdominal pain lower † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Abdominal rigidity † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	4
Anal incontinence † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Anal inflammation † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Angular cheilitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Ascites † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	2	0/7 (0.00%)	0	0/25 (0.00%)	0
Duodenal ulcer † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	2	0/7 (0.00%)	0	0/25 (0.00%)	0
Enteritis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Epigastric discomfort † 1	0/7 (0.00%)	0	1/7 (14.29%)	2	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Eructation † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Faeces discoloured † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Gastritis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Gastrointestinal oedema † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Haematemesis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Intestinal obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Large intestinal obstruction † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Large intestine perforation † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Lower gastrointestinal haemorrhage † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Malignant gastrointestinal obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Odynophagia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Oesophageal ulcer † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Oesophageal varices haemorrhage † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	2
Oesophagitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Oral pain † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Pancreatitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Rectal haemorrhage † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	2
Steatorrhoea † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Tongue discolouration † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Varices oesophageal † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
General disorders
Fatigue † 1	5/7 (71.43%)	9	5/7 (71.43%)	10	7/10 (70.00%)	13	5/7 (71.43%)	6	16/25 (64.00%)	21
Pyrexia † 1	3/7 (42.86%)	3	1/7 (14.29%)	1	2/10 (20.00%)	2	1/7 (14.29%)	1	5/25 (20.00%)	14
Asthenia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	1/7 (14.29%)	1	8/25 (32.00%)	15
Oedema peripheral † 1	3/7 (42.86%)	3	2/7 (28.57%)	2	1/10 (10.00%)	3	1/7 (14.29%)	1	2/25 (8.00%)	2
Chills † 1	2/7 (28.57%)	3	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	2
Mucosal inflammation † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	3/25 (12.00%)	7
Malaise † 1	0/7 (0.00%)	0	2/7 (28.57%)	2	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Temperature intolerance † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Axillary pain † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Catheter site erythema † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Catheter site extravasation † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Catheter site haemorrhage † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Catheter site pain † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Cyst † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Disease progression † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Localised oedema † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Non-cardiac chest pain † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hepatobiliary disorders
Bile duct obstruction † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Biliary dilatation † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Cholangitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Cholecystitis † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Hepatotoxicity † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Portal vein thrombosis † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Immune system disorders
Drug hypersensitivity † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Infections and infestations
Oral candidiasis † 1	1/7 (14.29%)	1	1/7 (14.29%)	2	1/10 (10.00%)	1	1/7 (14.29%)	1	2/25 (8.00%)	2
Pneumonia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	2/10 (20.00%)	2	0/7 (0.00%)	0	1/25 (4.00%)	1
Nasopharyngitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	1
Bacterial sepsis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Candida infection † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Clostridium difficile colitis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Fungal infection † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Gingivitis † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Helicobacter infection † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Herpes zoster † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Neutropenic infection † 1	1/7 (14.29%)	2	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Neutropenic sepsis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Paronychia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Pharyngitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Sepsis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	2
Septic shock † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Tooth infection † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Upper respiratory tract infection † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Urinary tract infection † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	2
Vulvovaginitis trichomonal † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Injury, poisoning and procedural complications
Fall † 1	1/7 (14.29%)	4	1/7 (14.29%)	1	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Contusion † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	1
Tooth fracture † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Animal scratch † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Ligament sprain † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Skin abrasion † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Subdural haematoma † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Investigations
Weight decreased † 1	1/7 (14.29%)	2	2/7 (28.57%)	3	4/10 (40.00%)	6	2/7 (28.57%)	4	5/25 (20.00%)	7
Alanine aminotransferase increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	1/7 (14.29%)	1	9/25 (36.00%)	17
Aspartate aminotransferase increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	2/10 (20.00%)	2	0/7 (0.00%)	0	9/25 (36.00%)	15
Platelet count decreased † 1	1/7 (14.29%)	2	1/7 (14.29%)	2	1/10 (10.00%)	2	0/7 (0.00%)	0	5/25 (20.00%)	17
White blood cell count decreased † 1	1/7 (14.29%)	1	1/7 (14.29%)	1	2/10 (20.00%)	2	0/7 (0.00%)	0	4/25 (16.00%)	10
Neutrophil count decreased † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	1/10 (10.00%)	7	1/7 (14.29%)	1	4/25 (16.00%)	12
Blood alkaline phosphatase increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	4/25 (16.00%)	17
Blood bilirubin increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	4/25 (16.00%)	4
Lymphocyte count decreased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	3/25 (12.00%)	23
Gamma-glutamyltransferase increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Alanine aminotransferase † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Blood creatinine increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	4
Blood magnesium decreased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Cardiac murmur † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Liver function test increased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Lung diffusion test decreased † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Urine output decreased † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	5/7 (71.43%)	10	6/7 (85.71%)	9	4/10 (40.00%)	8	3/7 (42.86%)	4	12/25 (48.00%)	15
Hypokalaemia † 1	4/7 (57.14%)	5	2/7 (28.57%)	3	5/10 (50.00%)	6	3/7 (42.86%)	11	12/25 (48.00%)	34
Dehydration † 1	4/7 (57.14%)	5	3/7 (42.86%)	3	3/10 (30.00%)	4	2/7 (28.57%)	2	5/25 (20.00%)	7
Hypomagnesaemia † 1	3/7 (42.86%)	4	0/7 (0.00%)	0	2/10 (20.00%)	3	2/7 (28.57%)	2	4/25 (16.00%)	21
Hypoalbuminaemia † 1	2/7 (28.57%)	4	0/7 (0.00%)	0	2/10 (20.00%)	3	1/7 (14.29%)	1	3/25 (12.00%)	9
Hypocalcaemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	2/10 (20.00%)	2	0/7 (0.00%)	0	2/25 (8.00%)	10
Hyperglycaemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	2/25 (8.00%)	18
Hyponatraemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	2/25 (8.00%)	18
Hypophosphataemia † 1	1/7 (14.29%)	1	1/7 (14.29%)	1	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Hyperphosphataemia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hypovolaemia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Metabolic acidosis † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain † 1	1/7 (14.29%)	1	1/7 (14.29%)	2	1/10 (10.00%)	1	0/7 (0.00%)	0	2/25 (8.00%)	6
Arthralgia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	3/25 (12.00%)	3
Muscular weakness † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	1/25 (4.00%)	1
Myalgia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	3/25 (12.00%)	3
Arthritis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	1/25 (4.00%)	1
Flank pain † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Joint stiffness † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Muscle spasms † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Musculoskeletal chest pain † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Neck pain † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Pain in extremity † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Periarthritis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Nervous system disorders
Dizziness † 1	2/7 (28.57%)	5	2/7 (28.57%)	2	3/10 (30.00%)	6	2/7 (28.57%)	2	8/25 (32.00%)	9
Neuropathy peripheral † 1	1/7 (14.29%)	1	3/7 (42.86%)	6	2/10 (20.00%)	3	2/7 (28.57%)	5	7/25 (28.00%)	11
Dysgeusia † 1	1/7 (14.29%)	2	2/7 (28.57%)	2	2/10 (20.00%)	2	2/7 (28.57%)	2	4/25 (16.00%)	5
Headache † 1	2/7 (28.57%)	2	1/7 (14.29%)	1	1/10 (10.00%)	1	0/7 (0.00%)	0	4/25 (16.00%)	4
Peripheral sensory neuropathy † 1	2/7 (28.57%)	2	1/7 (14.29%)	1	3/10 (30.00%)	5	0/7 (0.00%)	0	2/25 (8.00%)	7
Taste disorder † 1	2/7 (28.57%)	2	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Lethargy † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Neurotoxicity † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	3
Cognitive disorder † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Dysaesthesia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hyperaesthesia † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Hypoaesthesia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Lhermitte's sign † 1	0/7 (0.00%)	0	1/7 (14.29%)	2	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Memory impairment † 1	1/7 (14.29%)	2	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Syncope † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Psychiatric disorders
Depression † 1	1/7 (14.29%)	1	5/7 (71.43%)	6	1/10 (10.00%)	1	1/7 (14.29%)	1	2/25 (8.00%)	2
Insomnia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	1/10 (10.00%)	1	2/7 (28.57%)	2	5/25 (20.00%)	6
Anxiety † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	1/10 (10.00%)	1	2/7 (28.57%)	2	3/25 (12.00%)	3
Confusional state † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Hallucination † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Irritability † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Renal and urinary disorders
Acute kidney injury † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	2/7 (28.57%)	2	0/25 (0.00%)	0
Micturition urgency † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Haematuria † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Nephrolithiasis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Oliguria † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Pollakiuria † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Ureterolithiasis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Urinary incontinence † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Urinary retention † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Reproductive system and breast disorders
Vulvovaginal swelling † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	2/7 (28.57%)	2	0/7 (0.00%)	0	2/10 (20.00%)	3	2/7 (28.57%)	2	2/25 (8.00%)	2
Cough † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	2/10 (20.00%)	6	0/7 (0.00%)	0	2/25 (8.00%)	2
Pulmonary embolism † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	2/7 (28.57%)	3	2/25 (8.00%)	2
Epistaxis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	3/25 (12.00%)	3
Hiccups † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	2/25 (8.00%)	2
Nasal congestion † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Oropharyngeal pain † 1	0/7 (0.00%)	0	2/7 (28.57%)	3	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Sinus congestion † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	1
Catarrh † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Dysphonia † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Dyspnoea exertional † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Haemoptysis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Hypoxia † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	2	0/25 (0.00%)	0
Laryngeal oedema † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	6
Nasal dryness † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Pharyngeal inflammation † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Pneumonitis † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Respiratory failure † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Upper-airway cough syndrome † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia † 1	1/7 (14.29%)	1	3/7 (42.86%)	3	0/10 (0.00%)	0	1/7 (14.29%)	1	4/25 (16.00%)	5
Dry skin † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	1
Rash † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	2/25 (8.00%)	2
Pruritus † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	1/25 (4.00%)	2
Decubitus ulcer † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	1/7 (14.29%)	1	0/25 (0.00%)	0
Ingrowing nail † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Nail discolouration † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Nail ridging † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Pain of skin † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Palmar-plantar erythrodysaesthesia syndrome † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Petechiae † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Prurigo † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
Vascular disorders
Hypertension † 1	2/7 (28.57%)	5	4/7 (57.14%)	8	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Deep vein thrombosis † 1	0/7 (0.00%)	0	1/7 (14.29%)	1	0/10 (0.00%)	0	0/7 (0.00%)	0	3/25 (12.00%)	3
Hypotension † 1	1/7 (14.29%)	1	0/7 (0.00%)	0	2/10 (20.00%)	3	1/7 (14.29%)	1	0/25 (0.00%)	0
Orthostatic hypotension † 1	2/7 (28.57%)	3	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	0/25 (0.00%)	0
Embolism † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	1/10 (10.00%)	1	0/7 (0.00%)	0	0/25 (0.00%)	0
Vascular occlusion † 1	0/7 (0.00%)	0	0/7 (0.00%)	0	0/10 (0.00%)	0	0/7 (0.00%)	0	1/25 (4.00%)	1
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

The comparative Part 2 was removed in a protocol amendment, dated 11 April 2018, before it was initiated, as this comparative part of the study is being undertaken as a stand-alone Phase 3 study D-US-60010-001.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Medical Director
• Organization: Ipsen Bioscience, Inc.
• Phone: see email
• EMail: clinical.trials@ipsen.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Brendel K, Bekaii-Saab T, Boland PM, Dayyani F, Dean A, Macarulla T, Maxwell F, Mody K, Pedret-Dunn A, Wainberg ZA, Zhang B. Population pharmacokinetics of liposomal irinotecan in patients with cancer and exposure-safety analyses in patients with metastatic pancreatic cancer. CPT Pharmacometrics Syst Pharmacol. 2021 Dec;10(12):1550-1563. doi: 10.1002/psp4.12725. Epub 2021 Nov 20.

Wainberg ZA, Bekaii-Saab T, Boland PM, Dayyani F, Macarulla T, Mody K, Belanger B, Maxwell F, Moore Y, Thiagalingam A, Wang T, Zhang B, Dean A. First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. Eur J Cancer. 2021 Jul;151:14-24. doi: 10.1016/j.ejca.2021.03.028. Epub 2021 May 4.

Liu X, Jiang J, Chan R, Ji Y, Lu J, Liao YP, Okene M, Lin J, Lin P, Chang CH, Wang X, Tang I, Zheng E, Qiu W, Wainberg ZA, Nel AE, Meng H. Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer. ACS Nano. 2019 Jan 22;13(1):38-53. doi: 10.1021/acsnano.8b06164. Epub 2018 Dec 11.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT02551991
• Other Study ID Numbers: MM-398-07-02-03; 2015-003086-28 ( EudraCT Number )
• First Submitted: September 10, 2015
• First Posted: September 16, 2015
• Results First Submitted: May 20, 2022
• Results First Posted: October 10, 2022
• Last Update Posted: October 10, 2022