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

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ClinicalTrials.gov Identifier: NCT01494506
Recruitment Status : Completed
First Posted : December 19, 2011
Results First Posted : February 12, 2016
Last Update Posted : June 17, 2016
Sponsor:
Information provided by (Responsible Party):
Merrimack Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Metastatic Pancreatic Cancer
Interventions Drug: MM-398
Drug: 5 Fluorouracil
Drug: Leucovorin
Enrollment 417

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 Details 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)
Hide 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 [1] 149 117
Treated Population 147 [2] 134 117 [3]
Completed 3 [4] 6 14
Not Completed 148 143 103
Reason Not Completed
Lack of Efficacy             77             83             57
Adverse Event             17             10             11
Death             9             5             2
Physician Decision             7             5             4
Withdrawal by Subject             17             20             14
Clinical Deterioration             21             17             13
Sponsor Decision             0             0             1
Other             0             3             1
[1]
Started = Intent to Treat Population and includes all randomized participants
[2]
Treated population: Patients who received at least 1 dose of study drug.
[3]
2 randomized Arm C patients did not receive study drug. 1 patient each in A and B received Arm C.
[4]
Completed = Subjects remaining on treatment at the time of the primary analysis data cut off.
Arm/Group Title MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin Total
Hide 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 Number of Baseline Participants 151 149 117 417
Hide Baseline Analysis Population Description
All randomized patients.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 151 participants 149 participants 117 participants 417 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
151
 100.0%
149
 100.0%
117
 100.0%
417
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 151 participants 149 participants 117 participants 417 participants
63.6  (10.13) 61.8  (9.65) 63.2  (9.06) 62.8  (9.68)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 151 participants 149 participants 117 participants 417 participants
Female
64
  42.4%
68
  45.6%
48
  41.0%
180
  43.2%
Male
87
  57.6%
81
  54.4%
69
  59.0%
237
  56.8%
RACE (NIH/OMB)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 151 participants 149 participants 117 participants 417 participants
American Indian or Alaska Native 1 0 0 1
Asian 52 50 34 136
Black or African American 3 3 4 10
White 89 92 72 253
other race 6 4 7 17
Karnofsky Performance Status (Baseline KPS)[1]   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 151 participants 149 participants 117 participants 417 participants
100% = normal, no complaints, no signs of disease 22 22 18 62
90% = normal activity, few symptoms of disease 64 54 51 169
80% = normal activity, some symptoms of disease 50 61 38 149
70% = caring for self, unable to work 15 11 7 33
60% [2] = needs help, can manage most tasks 0 0 2 2
50%[2]= needs help often and medical care 0 0 1 1
Not recorded 0 1 0 1
[1]
Measure Description:
  1. One patient in the 5-FU/LV arm did not have a recorded Baseline KPS value.
  2. Designation of the KPS level for the randomization strata is made during the screening period prior to knowledge of the treatment assignment. Baseline KPS is the last observed KPS value prior to treatment in treated patients and the last observed value in patients who were randomized and did not receive study drug. The observed baseline KPS value may be recorded post-randomization.
Pancreatic Primary Tumor Location  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 151 participants 149 participants 117 participants 417 participants
Head 92 77 70 239
Body 16 26 12 54
Tail 24 24 14 62
Multiple locations including head 7 4 6 17
Multiple locations not including head 7 14 9 30
Unknown = not specified 5 4 6 15
1.Primary Outcome
Title Overall Survival
Hide 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 151 149 117 119
Median (95% Confidence Interval)
Unit of Measure: months
4.9
(4.23 to 5.62)
4.2
(3.58 to 4.86)
6.1
(4.76 to 8.87)
4.2
(3.29 to 5.32)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9416
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.012
Comments [Not Specified]
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
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Progression Free Survival
Hide 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 151 149 117 119
Median (95% Confidence Interval)
Unit of Measure: months
2.7
(2.13 to 2.89)
1.6
(1.41 to 1.84)
3.1
(2.69 to 4.17)
1.5
(1.41 to 1.84)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.100
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.81
Confidence Interval (2-Sided) 95%
0.63 to 1.04
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.56
Confidence Interval (2-Sided) 95%
0.41 to 0.75
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Objective Response Rate
Hide 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.
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 151 149 117 119
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage with confirmed response
3.31
(0.46 to 6.17)
0.67
(0.0 to 1.98)
7.69
(2.86 to 12.52)
0.84
(0.0 to 2.48)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.214
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.0264
Confidence Interval (2-Sided) 95%
-0.005 to 0.058
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.069
Confidence Interval (2-Sided) 95%
0.018 to 0.120
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time to Treatment Failure
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 151 149 117 119
Median (95% Confidence Interval)
Unit of Measure: months
1.7
(1.5 to 2.7)
1.4
(1.3 to 1.4)
2.3
(1.6 to 2.8)
1.4
(1.3 to 1.4)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1008
Comments [Not Specified]
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
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
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
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Patients With Clinical Benefit Response
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 92 80 78 60
Measure Type: Number
Unit of Measure: percentage of participants with CBR
14 13 14 12
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.80
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Patients With Tumor Marker (CA 19-9) Response
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 123 105 97 81
Measure Type: Number
Unit of Measure: percent of participants with TMR
23.6 11.4 28.9 8.6
Show Statistical Analysis 1 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.024
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
7.Secondary Outcome
Title EORTC-QLQ-C30
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 105 83 71 57
Measure Type: Number
Unit of Measure: percent of patients in category
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
Show Statistical Analysis 1 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 3 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 4 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 5 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 6 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 7 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 8 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 9 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 10 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 11 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 12 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 13 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 14 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 15 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 16 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 17 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 18 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 19 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 20 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 21 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 22 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.6712
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 23 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 24 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 25 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 26 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 27 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 28 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 29 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 30 Hide 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 [Not Specified]
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 [Not Specified]
8.Secondary Outcome
Title Pharmacokinetic Measurements of Total Irinotecan
Hide Description Plasma concentration-time data for MM-398 will be analyzed using population pharmacokinetic methods.
Time Frame 6 weeks after first study drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 143 114
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Total irinotecan = ug/L; SN38= ug/L
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%)
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   90/147 (61.22%)   58/134 (43.28%)   56/117 (47.86%) 
Blood and lymphatic system disorders       
Anemia  1  2/147 (1.36%)  2/134 (1.49%)  1/117 (0.85%) 
Febrile Neutropenia  1  6/147 (4.08%)  1/134 (0.75%)  2/117 (1.71%) 
Neutropenia  1  2/147 (1.36%)  0/134 (0.00%)  1/117 (0.85%) 
Pancytopenia  1  0/147 (0.00%)  0/134 (0.00%)  2/117 (1.71%) 
Gastrointestinal disorders       
Abdominal Pain  1  6/147 (4.08%)  6/134 (4.48%)  5/117 (4.27%) 
Abdominal Pain Upper  1  4/147 (2.72%)  1/134 (0.75%)  1/117 (0.85%) 
Ascites  1  1/147 (0.68%)  2/134 (1.49%)  1/117 (0.85%) 
Diarrhoea  1  19/147 (12.93%)  2/134 (1.49%)  7/117 (5.98%) 
Duodenal Ulcer  1  0/147 (0.00%)  0/134 (0.00%)  2/117 (1.71%) 
Gastro Intestinal Haemorrhage  1  1/147 (0.68%)  1/134 (0.75%)  2/117 (1.71%) 
Intestinal Obstruction  1  2/147 (1.36%)  1/134 (0.75%)  0/117 (0.00%) 
Nausea  1  5/147 (3.40%)  1/134 (0.75%)  4/117 (3.42%) 
Small Intestinal Obstruction  1  3/147 (2.04%)  0/134 (0.00%)  0/117 (0.00%) 
Upper Gastrointestinal Haemorrhage  1  0/147 (0.00%)  2/134 (1.49%)  0/117 (0.00%) 
Vomiting  1  14/147 (9.52%)  2/134 (1.49%)  11/117 (9.40%) 
General disorders       
Asthenia  1  2/147 (1.36%)  1/134 (0.75%)  2/117 (1.71%) 
General Physical Health Deterioration  1  3/147 (2.04%)  1/134 (0.75%)  0/117 (0.00%) 
Non-Cardiac Chest Pain  1  0/147 (0.00%)  2/134 (1.49%)  0/117 (0.00%) 
Pyrexia  1  5/147 (3.40%)  2/134 (1.49%)  3/117 (2.56%) 
Hepatobiliary disorders       
Bile Duct Obstruction  1  2/147 (1.36%)  2/134 (1.49%)  2/117 (1.71%) 
Cholangitis  1  2/147 (1.36%)  1/134 (0.75%)  1/117 (0.85%) 
Hepatic Failure  1  0/147 (0.00%)  2/134 (1.49%)  0/117 (0.00%) 
Jaundice Cholestatic  1  2/147 (1.36%)  0/134 (0.00%)  0/117 (0.00%) 
Infections and infestations       
Biliary Tract Infection  1  1/147 (0.68%)  2/134 (1.49%)  2/117 (1.71%) 
Clostridium Difficile Colitis  1  2/147 (1.36%)  0/134 (0.00%)  0/117 (0.00%) 
Device Related Infection  1  1/147 (0.68%)  0/134 (0.00%)  3/117 (2.56%) 
Gastroenteritis  1  2/147 (1.36%)  0/134 (0.00%)  2/117 (1.71%) 
Lower Respiratory Tract Infection  1  0/147 (0.00%)  2/134 (1.49%)  0/117 (0.00%) 
Pneumonia  1  1/147 (0.68%)  1/134 (0.75%)  3/117 (2.56%) 
Sepsis  1  3/147 (2.04%)  1/134 (0.75%)  4/117 (3.42%) 
Septic Shock  1  3/147 (2.04%)  1/134 (0.75%)  2/117 (1.71%) 
Urinary Tract Infection  1  2/147 (1.36%)  2/134 (1.49%)  0/117 (0.00%) 
Injury, poisoning and procedural complications       
Overdose  1  0/147 (0.00%)  2/134 (1.49%)  1/117 (0.85%) 
Metabolism and nutrition disorders       
Decrease Appetite  1  6/147 (4.08%)  1/134 (0.75%)  1/117 (0.85%) 
Dehydration  1  3/147 (2.04%)  2/134 (1.49%)  3/117 (2.56%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Tumour Haemorrhage  1  0/147 (0.00%)  2/134 (1.49%)  0/117 (0.00%) 
Tumour Pain  1  2/147 (1.36%)  0/134 (0.00%)  0/117 (0.00%) 
Nervous system disorders       
Cerebrovascular Accident  1  1/147 (0.68%)  2/134 (1.49%)  1/117 (0.85%) 
Renal and urinary disorders       
Acute Prerenal Failure  1  1/147 (0.68%)  0/134 (0.00%)  2/117 (1.71%) 
Hydronephrosis  1  0/147 (0.00%)  2/134 (1.49%)  0/117 (0.00%) 
Renal Failure Acute  1  2/147 (1.36%)  0/134 (0.00%)  0/117 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Pleural Effusion  1  2/147 (1.36%)  2/134 (1.49%)  0/117 (0.00%) 
Pulmonary Embolism  1  3/147 (2.04%)  1/134 (0.75%)  0/117 (0.00%) 
Vascular disorders       
Deep Vein Thrombosis  1  2/147 (1.36%)  3/134 (2.24%)  0/117 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (14.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MM-398 5 Fluorouracil and Leucovorin IV MM-398, 5-FU and Leucovorin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   145/147 (98.64%)   132/134 (98.51%)   116/117 (99.15%) 
Blood and lymphatic system disorders       
Anaemia  1  48/147 (32.65%)  31/134 (23.13%)  44/117 (37.61%) 
Neutropenia  1  22/147 (14.97%)  4/134 (2.99%)  27/117 (23.08%) 
Neutrophil Count Decreased  1  15/147 (10.20%)  2/134 (1.49%)  17/117 (14.53%) 
White Blood Cell Count Decreased  1  10/147 (6.80%)  2/134 (1.49%)  17/117 (14.53%) 
Leukopenia  1  6/147 (4.08%)  1/134 (0.75%)  12/117 (10.26%) 
Platelet Count Decreased  1  3/147 (2.04%)  3/134 (2.24%)  12/117 (10.26%) 
Gastrointestinal disorders       
Diarrhoea  1  103/147 (70.07%)  35/134 (26.12%)  116/117 (99.15%) 
Vomiting  1  80/147 (54.42%)  35/134 (26.12%)  61/117 (52.14%) 
Nausea  1  89/147 (60.54%)  46/134 (34.33%)  60/117 (51.28%) 
Abdominal Pain  1  50/147 (34.01%)  42/134 (31.34%)  27/117 (23.08%) 
Constipation  1  26/147 (17.69%)  32/134 (23.88%)  26/117 (22.22%) 
Asthenia  1  35/147 (23.81%)  22/134 (16.42%)  24/117 (20.51%) 
Stomatitis  1  5/147 (3.40%)  8/134 (5.97%)  16/117 (13.68%) 
Abdominal Pain Upper  1  17/147 (11.56%)  10/134 (7.46%)  11/117 (9.40%) 
Abdominal Distension  1  12/147 (8.16%)  8/134 (5.97%)  10/117 (8.55%) 
Gastrooesophageal Reflux Disease  1  2/147 (1.36%)  6/134 (4.48%)  6/117 (5.13%) 
Ascites  1  14/147 (9.52%)  11/134 (8.21%)  4/117 (3.42%) 
General disorders       
Fatigue  1  54/147 (36.73%)  37/134 (27.61%)  47/117 (40.17%) 
Pyrexia  1  29/147 (19.73%)  15/134 (11.19%)  27/117 (23.08%) 
Weight Decreased  1  29/147 (19.73%)  9/134 (6.72%)  20/117 (17.09%) 
Alopecia  1  32/147 (21.77%)  6/134 (4.48%)  16/117 (13.68%) 
Dizziness  1  17/147 (11.56%)  13/134 (9.70%)  15/117 (12.82%) 
Back Pain  1  12/147 (8.16%)  16/134 (11.94%)  15/117 (12.82%) 
Oedema Peripheral  1  28/147 (19.05%)  20/134 (14.93%)  13/117 (11.11%) 
Insomnia  1  12/147 (8.16%)  5/134 (3.73%)  9/117 (7.69%) 
Mouth Ulceration  1  6/147 (4.08%)  3/134 (2.24%)  8/117 (6.84%) 
Hypotension  1  6/147 (4.08%)  2/134 (1.49%)  7/117 (5.98%) 
Headache  1  8/147 (5.44%)  6/134 (4.48%)  6/117 (5.13%) 
Hepatobiliary disorders       
Mucosal Inflammation  1  8/147 (5.44%)  5/134 (3.73%)  12/117 (10.26%) 
Infections and infestations       
Oral Candidiasis  1  4/147 (2.72%)  2/134 (1.49%)  6/117 (5.13%) 
Investigations       
Alanine Aminotransferase Increased  1  5/147 (3.40%)  2/134 (1.49%)  8/117 (6.84%) 
Hypomagnesaemia  1  20/147 (13.61%)  5/134 (3.73%)  7/117 (5.98%) 
Aspartate Aminotransferase Increased  1  9/147 (6.12%)  3/134 (2.24%)  2/117 (1.71%) 
Blood Alkaline Phosphatase Increased  1  8/147 (5.44%)  5/134 (3.73%)  2/117 (1.71%) 
Metabolism and nutrition disorders       
Decreased Appetite  1  72/147 (48.98%)  43/134 (32.09%)  52/117 (44.44%) 
Hypokalaemia  1  32/147 (21.77%)  12/134 (8.96%)  14/117 (11.97%) 
Dehydration  1  15/147 (10.20%)  9/134 (6.72%)  9/117 (7.69%) 
Hypoalbumineamia  1  19/147 (12.93%)  8/134 (5.97%)  7/117 (5.98%) 
Hyperglycaemia  1  10/147 (6.80%)  9/134 (6.72%)  5/117 (4.27%) 
Hyponatraemia  1  11/147 (7.48%)  3/134 (2.24%)  4/117 (3.42%) 
Hypocalcaemia  1  8/147 (5.44%)  4/134 (2.99%)  3/117 (2.56%) 
Respiratory, thoracic and mediastinal disorders       
Dyspnoea  1  11/147 (7.48%)  6/134 (4.48%)  9/117 (7.69%) 
Cough  1  9/147 (6.12%)  6/134 (4.48%)  6/117 (5.13%) 
Skin and subcutaneous tissue disorders       
Pruritus  1  8/147 (5.44%)  5/134 (3.73%)  1/117 (0.85%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (14.1)
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.
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
Responsible Party: Merrimack Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01494506     History of Changes
Other Study ID Numbers: MM-398-07-03-01
First Submitted: December 14, 2011
First Posted: December 19, 2011
Results First Submitted: November 25, 2015
Results First Posted: February 12, 2016
Last Update Posted: June 17, 2016