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NAPOLI-1: Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer

Sponsor
Merrimack Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01494506
Collaborator
(none)
417
Enrollment
79
Locations
3
Arms
47
Duration (Months)
5.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study is an open label, randomized phase 3 study of MM-398 with or without 5-Fluorouracil (5-FU) and Leucovorin (also known as folinic acid), versus 5-FU and leucovorin in metastatic pancreatic cancer patients who have progressed on prior gemcitabine based therapy.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
417 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open Label Phase 3 Study of MM-398, With or Without 5-Fluorouracil and Leucovorin, Versus 5 Fluorouracil and Leucovorin in Patients With Metastatic Pancreatic Cancer Who Have Failed Prior Gemcitabine-based Therapy
Study Start Date :
Nov 1, 2011
Actual Primary Completion Date :
Feb 1, 2014
Actual Study Completion Date :
Oct 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: MM-398

MM-398 120 mg/m2 Q3W IV. Note: The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 120 mg/m2 dose of irinotecan hydrochloride trihydrate is equivalent to 100 mg/ m2 of irinotecan free base.

Drug: MM-398
Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W
Other Names:
  • PEP02

    		•
    Active Comparator: 5 Fluorouracil and Leucovorin IV

    5 Fluorouracil and Leucovorin IV

    Drug: 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
    Other Names:
  • 5-FU

    • Drug: 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
    Other Names:
  • Folinic Acid

    		•
    Experimental: MM-398, 5-FU and Leucovorin

    MM-398 80 mg/m2, 5-FU and Leucovorin Q2W IV. Note: The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m2 dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base.

    Drug: MM-398
    Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W
    Other Names:
  • PEP02

    • Drug: 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
    Other Names:
  • 5-FU

    • Drug: 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
    Other Names:
  • Folinic Acid

    		•

    Outcome Measures

    Primary Outcome Measures

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

      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.

    Secondary Outcome Measures

    1. Progression Free Survival [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.]

      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.

    2. Objective Response Rate [Assessment every 6 weeks after initial response; Day 1 to data cut off of 14 Feb 2014; maximum time on study 25 months.]

      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.

    3. Time to Treatment Failure [Randomization to treatment discontinuation (any cause). The maximum time in follow up was 25 months]

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

    4. Percentage of Patients With Clinical Benefit Response [Randomization to treatment discontinuation.The maximum time in follow up was 25 months]

      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.

    5. Percentage of Patients With Tumor Marker (CA 19-9) Response [Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months]

      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.

    6. EORTC-QLQ-C30 [Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months]

      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.

    7. Pharmacokinetic Measurements of Total Irinotecan [6 weeks after first study drug administration]

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically or cytologically confirmed adenocarcinoma of the exocrine pancreas

    • Metastatic disease

    • Documented disease progression after prior gemcitabine based therapy

    • KPS >/= 70

    • Adequate bone marrow function

    • Adequate hepatic function

    • Adequate renal function

    Exclusion Criteria:

    • Active CNS metastasis

    • Clinically significant GI disorders

    • Severe arterial thromboembolic events less than 6 months before inclusion

    • NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure

    • Active infection or uncontrolled fever

    • Pregnant or breast feeding patients

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Gilbert Arizona United States
    2 Glendale Arizona United States
    3 Scottsdale Arizona United States
    4 Burbank California United States
    5 Duarte California United States
    6 Fresno California United States
    7 LaVerne California United States
    8 San Luis Obispo California United States
    9 Boyton Beach Florida United States
    10 Atlanta Georgia United States
    11 Kansas City Missouri United States
    12 St Louis Missouri United States
    13 Henderson Nevada United States
    14 Albuquerque New Mexico United States
    15 Buffalo New York United States
    16 Columbus Ohio United States
    17 Norman Oklahoma United States
    18 Greenville South Carolina United States
    19 Bedford Texas United States
    20 Dallas Texas United States
    21 Tyler Texas United States
    22 Fairfax Virginia United States
    23 Norfolk Virginia United States
    24 Buenos Aires Argentina
    25 Rosario Argentina
    26 Santa Fe Argentina
    27 Westmead New South Wales Australia
    28 Kurralta Park South Australia Australia
    29 Boxhill Victoria Australia
    30 Heidelberg Victoria Australia
    31 Melbourne Victoria Australia
    32 Nedlands Western Australia Australia
    33 Belo Horizonte Brazil
    34 Ijui Brazil
    35 Passo Fundo Brazil
    36 Porto Alegre Brazil
    37 Sao Paulo Brazil
    38 Montreal Quebec Canada
    39 Horovice Czech Republic
    40 Olomouc Czech Republic
    41 Prague Czech Republic
    42 Pribram Czech Republic
    43 Bordeaux France
    44 Lille France
    45 Marseille France
    46 Berlin Germany
    47 Jens Germany
    48 Munich Germany
    49 Ulm Germany
    50 Budapest Hungary
    51 Pecs Hungary
    52 Szeged Hungary
    53 Szolnok Hungary
    54 Szombathely Hungary
    55 Castellana Grotte Italy
    56 Genova Italy
    57 Legnano Italy
    58 Naples Italy
    59 Roma Italy
    60 Hwasun-gun Korea, Republic of
    61 Seoul Korea, Republic of
    62 Port Elizabeth South Africa
    63 Pretoria South Africa
    64 Western Cape South Africa
    65 Alicante Spain
    66 Barcelona Spain
    67 Madrid Spain
    68 Santander Spain
    69 Valencia Spain
    70 Chiayi Taiwan
    71 Kaohsiung Taiwan
    72 Taiching Taiwan
    73 Tainan Taiwan
    74 Taipei Taiwan
    75 Taoyuan Taiwan
    76 Liverpool United Kingdom
    77 London United Kingdom
    78 Manchester United Kingdom
    79 Sutton United Kingdom

    Sponsors and Collaborators

    • Merrimack Pharmaceuticals

    Investigators

    • Study Director: Eliel Bayever, MD, Merrimack Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Merrimack Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01494506
    Other Study ID Numbers:
    • MM-398-07-03-01
    First Posted:
    Dec 19, 2011
    Last Update Posted:
    Jun 17, 2016
    Last Verified:
    Jun 1, 2016
    Keywords provided by Merrimack Pharmaceuticals
    Pancreatic cancer
    MM-398
    PEP02
    Metastatic pancreatic cancer
    Gemcitabine refractory pancreatic cancer
    Second line pancreatic cancer treatment
    Pancreatic cancer post gemcitabine therapy
    Additional relevant MeSH terms:
    Pancreatic Neoplasms
    Leucovorin
    Fluorouracil

    Study Results

    Participant Flow

    Recruitment Details 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).
    Pre-assignment Detail All patients were screened for UGT1A1*28 allele at baseline.
    Arm/Group Title MM-398 (Arm A) 5-FU + Leucovorin (Arm B) MM-398 + 5-FU + Leucovorin (Arm C)
    Arm/Group Description • 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 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 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
    Period Title: Overall Study
    STARTED 151 149 117
    Treated Population 147 134 117
    COMPLETED 3 6 14
    NOT COMPLETED 148 143 103

    Baseline Characteristics

    Arm/Group Title MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin Total
    Arm/Group Description 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 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 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 of all reporting groups
    Overall Participants 151 149 117 417
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    151
    100%
    149
    100%
    117
    100%
    417
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.6
    (10.13)
    61.8
    (9.65)
    63.2
    (9.06)
    62.8
    (9.68)
    Sex: Female, Male (Count of Participants)
    Female
    64
    42.4%
    68
    45.6%
    48
    41%
    180
    43.2%
    Male
    87
    57.6%
    81
    54.4%
    69
    59%
    237
    56.8%
    RACE (NIH/OMB) (participants) [Number]
    American Indian or Alaska Native
    1
    0.7%
    0
    0%
    0
    0%
    1
    0.2%
    Asian
    52
    34.4%
    50
    33.6%
    34
    29.1%
    136
    32.6%
    Black or African American
    3
    2%
    3
    2%
    4
    3.4%
    10
    2.4%
    White
    89
    58.9%
    92
    61.7%
    72
    61.5%
    253
    60.7%
    other race
    6
    4%
    4
    2.7%
    7
    6%
    17
    4.1%
    Karnofsky Performance Status (Baseline KPS)[1] (participants) [Number]
    100% = normal, no complaints, no signs of disease
    22
    14.6%
    22
    14.8%
    18
    15.4%
    62
    14.9%
    90% = normal activity, few symptoms of disease
    64
    42.4%
    54
    36.2%
    51
    43.6%
    169
    40.5%
    80% = normal activity, some symptoms of disease
    50
    33.1%
    61
    40.9%
    38
    32.5%
    149
    35.7%
    70% = caring for self, unable to work
    15
    9.9%
    11
    7.4%
    7
    6%
    33
    7.9%
    60% [2] = needs help, can manage most tasks
    0
    0%
    0
    0%
    2
    1.7%
    2
    0.5%
    50%[2]= needs help often and medical care
    0
    0%
    0
    0%
    1
    0.9%
    1
    0.2%
    Not recorded
    0
    0%
    1
    0.7%
    0
    0%
    1
    0.2%
    Pancreatic Primary Tumor Location (participants) [Number]
    Head
    92
    60.9%
    77
    51.7%
    70
    59.8%
    239
    57.3%
    Body
    16
    10.6%
    26
    17.4%
    12
    10.3%
    54
    12.9%
    Tail
    24
    15.9%
    24
    16.1%
    14
    12%
    62
    14.9%
    Multiple locations including head
    7
    4.6%
    4
    2.7%
    6
    5.1%
    17
    4.1%
    Multiple locations not including head
    7
    4.6%
    14
    9.4%
    9
    7.7%
    30
    7.2%
    Unknown = not specified
    5
    3.3%
    4
    2.7%
    6
    5.1%
    15
    3.6%

    Outcome Measures

    1. Primary Outcome
    Title Overall Survival
    Description 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.
    Time Frame From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 151 149 117 119
    Median (95% Confidence Interval) [months]
    4.9
    4.2
    6.1
    4.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9416
    Comments
    Method Log Rank
    Comments Unstratified logrank test.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.77 to 1.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.012
    Comments
    Method Log Rank
    Comments Unstratified logrank test.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.67
    Confidence Interval (2-Sided) 95%
    0.49 to 0.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Progression Free Survival
    Description 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.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 151 149 117 119
    Median (95% Confidence Interval) [months]
    2.7
    1.6
    3.1
    1.5
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.100
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.81
    Confidence Interval (2-Sided) 95%
    0.63 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.56
    Confidence Interval (2-Sided) 95%
    0.41 to 0.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Objective Response Rate
    Description 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.
    Time Frame Assessment every 6 weeks after initial response; Day 1 to data cut off of 14 Feb 2014; maximum time on study 25 months.

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 151 149 117 119
    Number (95% Confidence Interval) [percentage with confirmed response]
    3.31
    0.67
    7.69
    0.84
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.214
    Comments
    Method Fisher Exact
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.0264
    Confidence Interval (2-Sided) 95%
    -0.005 to 0.058
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.010
    Comments
    Method Fisher Exact
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 0.069
    Confidence Interval (2-Sided) 95%
    0.018 to 0.120
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Time to Treatment Failure
    Description Time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity or death.
    Time Frame Randomization to treatment discontinuation (any cause). The maximum time in follow up was 25 months

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 151 149 117 119
    Median (95% Confidence Interval) [months]
    1.7
    1.4
    2.3
    1.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1008
    Comments
    Method Log Rank
    Comments Unstratified log rank test.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.82
    Confidence Interval (2-Sided) 95%
    0.65 to 1.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method Log Rank
    Comments Unstratified log rank test
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.60
    Confidence Interval (2-Sided) 95%
    0.45 to 0.78
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Percentage of Patients With Clinical Benefit Response
    Description 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.
    Time Frame Randomization to treatment discontinuation.The maximum time in follow up was 25 months

    Outcome Measure Data

    Analysis Population Description
    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
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 92 80 78 60
    Number [percentage of participants with CBR]
    14
    9.3%
    13
    8.7%
    14
    12%
    12
    2.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.82
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.80
    Comments
    Method Fisher Exact
    Comments
    6. Secondary Outcome
    Title Percentage of Patients With Tumor Marker (CA 19-9) Response
    Description 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.
    Time Frame Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

    Outcome Measure Data

    Analysis Population Description
    Patients with elevated baseline CA19-9 value (> 30 U/mL) who received study drug.
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 123 105 97 81
    Number [percent of participants with TMR]
    23.6
    15.6%
    11.4
    7.7%
    28.9
    24.7%
    8.6
    2.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.024
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Fisher Exact
    Comments
    7. Secondary Outcome
    Title EORTC-QLQ-C30
    Description 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.
    Time Frame Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

    Outcome Measure Data

    Analysis Population Description
    ITT patients who had baseline and at least one-post baseline EORTC-QLQ-C30 assessment.
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison 5-FU + Leucovorin (Combo Therapy Comparison)
    Arm/Group Description • 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 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 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 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.
    Measure Participants 105 83 71 57
    Global Health Status: Improved
    10
    11
    17
    12
    Global Health Status: Stable
    31
    41
    38
    44
    Global Health Status: Worsened
    57
    48
    45
    44
    Physical Functioning: Improved
    10
    11
    10
    11
    Physical Functioning: Stable
    29
    37
    41
    40
    Physical Functioning: Worsened
    61
    52
    49
    49
    Role Functioning: Improved
    6
    10
    15
    11
    Role Functioning: Stable
    29
    39
    32
    37
    Role Functioning: Worsened
    66
    52
    52
    53
    Emotional Functioning:Improved
    10
    8
    20
    9
    Emotional Functioning:Stable
    32
    59
    46
    58
    Emotional Functioning:Worsened
    56
    33
    34
    33
    Cognitive Functioning:Improved
    12
    6
    11
    7
    Cognitive Functioning:Stable
    32
    42
    48
    44
    Cognitive Functioning:Worsened
    54
    52
    41
    49
    Social Functioning:Improved
    11
    11
    13
    11
    Social Functioning:Stable
    26
    43
    34
    47
    Social Functioning:Worsened
    62
    46
    54
    42
    Fatigue:Improved
    13
    11
    14
    12
    Fatigue:Stable
    18
    30
    20
    33
    Fatigue:Worsened
    69
    59
    66
    54
    Nausea and Vomiting:Improved
    5
    6
    13
    4
    Nausea and Vomiting:Stable
    37
    42
    32
    46
    Nausea and Vomiting:Worsened
    58
    52
    55
    51
    Pain:Improved
    20
    10
    27
    11
    Pain:Stable
    30
    37
    34
    40
    Pain:Worsened
    50
    53
    39
    49
    Dyspnoea:Improved
    10
    6
    7
    5
    Dyspnoea:Stable
    47
    69
    51
    68
    Dyspnoea:Worsoned
    44
    24
    42
    25
    Insomnia:Improved
    9
    4
    18
    5
    Insomnia:Stable
    43
    49
    34
    49
    Insomnia:Worsened
    48
    47
    48
    46
    Appetite Loss:Improved
    9
    6
    11
    5
    Appetite Loss:Stable
    38
    42
    45
    46
    Appetite Loss:Worsened
    53
    52
    44
    49
    Constipation:Improved
    13
    4
    13
    4
    Constipation:Stable
    47
    63
    56
    67
    Constipation:Worsened
    39
    34
    31
    30
    Diarrhoea:Improved
    4
    4
    6
    4
    Diarrhoea: Stable
    35
    58
    39
    58
    Diarrhoea: Worsened
    59
    39
    55
    39
    Financial Difficulties: Improved
    6
    1
    8
    0
    Financial Difficulties: Stable
    51
    67
    51
    74
    Financial Difficulties: Worsened
    42
    31
    41
    26
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Global Health Status
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6388
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison
    Comments Comparison of Global Health Status
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.8445
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Physical Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6388
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Physical Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9435
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Role functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2654
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Role functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7674
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Emotional Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1628
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Emotional Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Cognitive Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7738
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Cognitive Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Social Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3408
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Social Functioning
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Fatigue
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6766
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Fatigue
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Nausea and Vomiting
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6388
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Nausea and Vomiting
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7674
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Pain
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4993
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Pain
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Dyspnoea
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2654
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Dyspnoea
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Insomnia
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7617
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Insomnia
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 23
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Appetite loss
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9123
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 24
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Appetite loss
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 25
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Constipation
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7617
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 26
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Constipation
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 27
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Diarrhoea
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1628
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 28
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Diarrhoea
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6712
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 29
    Statistical Analysis Overview Comparison Group Selection MM-398 Arm A (Mono Therapy Comparison), 5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)
    Comments Comparison of Financial difficulties
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6388
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    Statistical Analysis 30
    Statistical Analysis Overview Comparison Group Selection MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison, 5-FU + Leucovorin (Combo Therapy Comparison)
    Comments Comparison of Financial difficulties
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7308
    Comments For each experimental arm comparison p-values were adjusted for multiple domain comparisons using the Hochberg method.
    Method Cochran-Mantel-Haenszel
    Comments
    8. Secondary Outcome
    Title Pharmacokinetic Measurements of Total Irinotecan
    Description Plasma concentration-time data for MM-398 will be analyzed using population pharmacokinetic methods.
    Time Frame 6 weeks after first study drug administration

    Outcome Measure Data

    Analysis Population Description
    PK population was based on Protocol, all participants who received the appropriate dose of MM-398.
    Arm/Group Title MM-398 Arm A (Mono Therapy Comparison) MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison
    Arm/Group Description • 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. 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
    Measure Participants 143 114
    Total Irinotecan-Cavg
    2550.00
    (197.4)
    2120.00
    (209.7)
    Total Irinotecan-Cmax
    40550.00
    (172.3)
    28460.00
    (69.3)
    Total SN38-Cavg
    0.82
    (119.2)
    0.68
    (132.7)
    Total SN38-Cmax
    3.93
    (119.6)
    2.58
    (121.9)

    Adverse Events

    Time Frame Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 764 days.
    Adverse Event Reporting Description 5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1
    Arm/Group Title MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin
    Arm/Group Description 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 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 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
    All Cause Mortality
    MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 90/147 (61.2%) 58/134 (43.3%) 56/117 (47.9%)
    Blood and lymphatic system disorders
    Anemia 2/147 (1.4%) 2/134 (1.5%) 1/117 (0.9%)
    Febrile Neutropenia 6/147 (4.1%) 1/134 (0.7%) 2/117 (1.7%)
    Neutropenia 2/147 (1.4%) 0/134 (0%) 1/117 (0.9%)
    Pancytopenia 0/147 (0%) 0/134 (0%) 2/117 (1.7%)
    Gastrointestinal disorders
    Abdominal Pain 6/147 (4.1%) 6/134 (4.5%) 5/117 (4.3%)
    Abdominal Pain Upper 4/147 (2.7%) 1/134 (0.7%) 1/117 (0.9%)
    Ascites 1/147 (0.7%) 2/134 (1.5%) 1/117 (0.9%)
    Diarrhoea 19/147 (12.9%) 2/134 (1.5%) 7/117 (6%)
    Duodenal Ulcer 0/147 (0%) 0/134 (0%) 2/117 (1.7%)
    Gastro Intestinal Haemorrhage 1/147 (0.7%) 1/134 (0.7%) 2/117 (1.7%)
    Intestinal Obstruction 2/147 (1.4%) 1/134 (0.7%) 0/117 (0%)
    Nausea 5/147 (3.4%) 1/134 (0.7%) 4/117 (3.4%)
    Small Intestinal Obstruction 3/147 (2%) 0/134 (0%) 0/117 (0%)
    Upper Gastrointestinal Haemorrhage 0/147 (0%) 2/134 (1.5%) 0/117 (0%)
    Vomiting 14/147 (9.5%) 2/134 (1.5%) 11/117 (9.4%)
    General disorders
    Asthenia 2/147 (1.4%) 1/134 (0.7%) 2/117 (1.7%)
    General Physical Health Deterioration 3/147 (2%) 1/134 (0.7%) 0/117 (0%)
    Non-Cardiac Chest Pain 0/147 (0%) 2/134 (1.5%) 0/117 (0%)
    Pyrexia 5/147 (3.4%) 2/134 (1.5%) 3/117 (2.6%)
    Hepatobiliary disorders
    Bile Duct Obstruction 2/147 (1.4%) 2/134 (1.5%) 2/117 (1.7%)
    Cholangitis 2/147 (1.4%) 1/134 (0.7%) 1/117 (0.9%)
    Hepatic Failure 0/147 (0%) 2/134 (1.5%) 0/117 (0%)
    Jaundice Cholestatic 2/147 (1.4%) 0/134 (0%) 0/117 (0%)
    Infections and infestations
    Biliary Tract Infection 1/147 (0.7%) 2/134 (1.5%) 2/117 (1.7%)
    Clostridium Difficile Colitis 2/147 (1.4%) 0/134 (0%) 0/117 (0%)
    Device Related Infection 1/147 (0.7%) 0/134 (0%) 3/117 (2.6%)
    Gastroenteritis 2/147 (1.4%) 0/134 (0%) 2/117 (1.7%)
    Lower Respiratory Tract Infection 0/147 (0%) 2/134 (1.5%) 0/117 (0%)
    Pneumonia 1/147 (0.7%) 1/134 (0.7%) 3/117 (2.6%)
    Sepsis 3/147 (2%) 1/134 (0.7%) 4/117 (3.4%)
    Septic Shock 3/147 (2%) 1/134 (0.7%) 2/117 (1.7%)
    Urinary Tract Infection 2/147 (1.4%) 2/134 (1.5%) 0/117 (0%)
    Injury, poisoning and procedural complications
    Overdose 0/147 (0%) 2/134 (1.5%) 1/117 (0.9%)
    Metabolism and nutrition disorders
    Decrease Appetite 6/147 (4.1%) 1/134 (0.7%) 1/117 (0.9%)
    Dehydration 3/147 (2%) 2/134 (1.5%) 3/117 (2.6%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Haemorrhage 0/147 (0%) 2/134 (1.5%) 0/117 (0%)
    Tumour Pain 2/147 (1.4%) 0/134 (0%) 0/117 (0%)
    Nervous system disorders
    Cerebrovascular Accident 1/147 (0.7%) 2/134 (1.5%) 1/117 (0.9%)
    Renal and urinary disorders
    Acute Prerenal Failure 1/147 (0.7%) 0/134 (0%) 2/117 (1.7%)
    Hydronephrosis 0/147 (0%) 2/134 (1.5%) 0/117 (0%)
    Renal Failure Acute 2/147 (1.4%) 0/134 (0%) 0/117 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion 2/147 (1.4%) 2/134 (1.5%) 0/117 (0%)
    Pulmonary Embolism 3/147 (2%) 1/134 (0.7%) 0/117 (0%)
    Vascular disorders
    Deep Vein Thrombosis 2/147 (1.4%) 3/134 (2.2%) 0/117 (0%)
    Other (Not Including Serious) Adverse Events
    MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 145/147 (98.6%) 132/134 (98.5%) 116/117 (99.1%)
    Blood and lymphatic system disorders
    Anaemia 48/147 (32.7%) 31/134 (23.1%) 44/117 (37.6%)
    Neutropenia 22/147 (15%) 4/134 (3%) 27/117 (23.1%)
    Neutrophil Count Decreased 15/147 (10.2%) 2/134 (1.5%) 17/117 (14.5%)
    White Blood Cell Count Decreased 10/147 (6.8%) 2/134 (1.5%) 17/117 (14.5%)
    Leukopenia 6/147 (4.1%) 1/134 (0.7%) 12/117 (10.3%)
    Platelet Count Decreased 3/147 (2%) 3/134 (2.2%) 12/117 (10.3%)
    Gastrointestinal disorders
    Diarrhoea 103/147 (70.1%) 35/134 (26.1%) 116/117 (99.1%)
    Vomiting 80/147 (54.4%) 35/134 (26.1%) 61/117 (52.1%)
    Nausea 89/147 (60.5%) 46/134 (34.3%) 60/117 (51.3%)
    Abdominal Pain 50/147 (34%) 42/134 (31.3%) 27/117 (23.1%)
    Constipation 26/147 (17.7%) 32/134 (23.9%) 26/117 (22.2%)
    Asthenia 35/147 (23.8%) 22/134 (16.4%) 24/117 (20.5%)
    Stomatitis 5/147 (3.4%) 8/134 (6%) 16/117 (13.7%)
    Abdominal Pain Upper 17/147 (11.6%) 10/134 (7.5%) 11/117 (9.4%)
    Abdominal Distension 12/147 (8.2%) 8/134 (6%) 10/117 (8.5%)
    Gastrooesophageal Reflux Disease 2/147 (1.4%) 6/134 (4.5%) 6/117 (5.1%)
    Ascites 14/147 (9.5%) 11/134 (8.2%) 4/117 (3.4%)
    General disorders
    Fatigue 54/147 (36.7%) 37/134 (27.6%) 47/117 (40.2%)
    Pyrexia 29/147 (19.7%) 15/134 (11.2%) 27/117 (23.1%)
    Weight Decreased 29/147 (19.7%) 9/134 (6.7%) 20/117 (17.1%)
    Alopecia 32/147 (21.8%) 6/134 (4.5%) 16/117 (13.7%)
    Dizziness 17/147 (11.6%) 13/134 (9.7%) 15/117 (12.8%)
    Back Pain 12/147 (8.2%) 16/134 (11.9%) 15/117 (12.8%)
    Oedema Peripheral 28/147 (19%) 20/134 (14.9%) 13/117 (11.1%)
    Insomnia 12/147 (8.2%) 5/134 (3.7%) 9/117 (7.7%)
    Mouth Ulceration 6/147 (4.1%) 3/134 (2.2%) 8/117 (6.8%)
    Hypotension 6/147 (4.1%) 2/134 (1.5%) 7/117 (6%)
    Headache 8/147 (5.4%) 6/134 (4.5%) 6/117 (5.1%)
    Hepatobiliary disorders
    Mucosal Inflammation 8/147 (5.4%) 5/134 (3.7%) 12/117 (10.3%)
    Infections and infestations
    Oral Candidiasis 4/147 (2.7%) 2/134 (1.5%) 6/117 (5.1%)
    Investigations
    Alanine Aminotransferase Increased 5/147 (3.4%) 2/134 (1.5%) 8/117 (6.8%)
    Hypomagnesaemia 20/147 (13.6%) 5/134 (3.7%) 7/117 (6%)
    Aspartate Aminotransferase Increased 9/147 (6.1%) 3/134 (2.2%) 2/117 (1.7%)
    Blood Alkaline Phosphatase Increased 8/147 (5.4%) 5/134 (3.7%) 2/117 (1.7%)
    Metabolism and nutrition disorders
    Decreased Appetite 72/147 (49%) 43/134 (32.1%) 52/117 (44.4%)
    Hypokalaemia 32/147 (21.8%) 12/134 (9%) 14/117 (12%)
    Dehydration 15/147 (10.2%) 9/134 (6.7%) 9/117 (7.7%)
    Hypoalbumineamia 19/147 (12.9%) 8/134 (6%) 7/117 (6%)
    Hyperglycaemia 10/147 (6.8%) 9/134 (6.7%) 5/117 (4.3%)
    Hyponatraemia 11/147 (7.5%) 3/134 (2.2%) 4/117 (3.4%)
    Hypocalcaemia 8/147 (5.4%) 4/134 (3%) 3/117 (2.6%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 11/147 (7.5%) 6/134 (4.5%) 9/117 (7.7%)
    Cough 9/147 (6.1%) 6/134 (4.5%) 6/117 (5.1%)
    Skin and subcutaneous tissue disorders
    Pruritus 8/147 (5.4%) 5/134 (3.7%) 1/117 (0.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    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.

    Results Point of Contact

    Name/Title Dr. Eliel Bayever
    Organization Merrimack Pharmaceuticals, Inc.
    Phone 6174411000 ext 7676
    Email EBayever@merrimack.com
    Responsible Party:
    Merrimack Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01494506
    Other Study ID Numbers:
    • MM-398-07-03-01
    First Posted:
    Dec 19, 2011
    Last Update Posted:
    Jun 17, 2016
    Last Verified:
    Jun 1, 2016