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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)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merrimack Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01494506
First received: December 14, 2011
Last updated: June 16, 2016
Last verified: June 2016
Results First Received: November 25, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Metastatic Pancreatic Cancer
Interventions: Drug: MM-398
Drug: 5 Fluorouracil
Drug: Leucovorin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
All patients were screened for UGT1A1*28 allele at baseline.

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

Participant Flow:   Overall Study
    MM-398 (Arm A)     5-FU + Leucovorin (Arm B)     MM-398 + 5-FU + Leucovorin (Arm C)  
STARTED     151 [1]   149     117  
Treated Population     147 [2]   134     117 [3]
COMPLETED     3 [4]   6     14  
NOT COMPLETED     148     143     103  
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  
Unknown                 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.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All randomized patients.

Reporting Groups
  Description
MM-398

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 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

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 Total of all reporting groups

Baseline Measures
    MM-398     5 Fluorouracil and Leucovorin IV     MM-398, 5-FU and Leucovorin     Total  
Number of Participants  
[units: participants]
  151     149     117     417  
Age  
[units: participants]
       
<=18 years     0     0     0     0  
Between 18 and 65 years     151     149     117     417  
>=65 years     0     0     0     0  
Age  
[units: years]
Mean (Standard Deviation)
  63.6  (10.13)     61.8  (9.65)     63.2  (9.06)     62.8  (9.68)  
Gender  
[units: participants]
       
Female     64     68     48     180  
Male     87     81     69     237  
RACE (NIH/OMB)  
[units: 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]
[units: 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  
Pancreatic Primary Tumor Location  
[units: 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]
  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.



  Outcome Measures
  Show All Outcome Measures

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

2.  Secondary:   Progression Free Survival   [ 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. ]

3.  Secondary:   Objective Response Rate   [ 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. ]

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

5.  Secondary:   Percentage of Patients With Clinical Benefit Response   [ Time Frame: Randomization to treatment discontinuation.The maximum time in follow up was 25 months ]

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

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

8.  Secondary:   Pharmacokinetic Measurements of Total Irinotecan   [ Time Frame: 6 weeks after first study drug administration ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Dr. Eliel Bayever
Organization: Merrimack Pharmaceuticals, Inc.
phone: 6174411000 ext 7676
e-mail: EBayever@merrimack.com


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

Responsible Party: Merrimack Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01494506     History of Changes
Other Study ID Numbers: MM-398-07-03-01
Study First Received: December 14, 2011
Results First Received: November 25, 2015
Last Updated: June 16, 2016
Health Authority: United States: Food and Drug Administration