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A Safety Study of MM-121 With Cetuximab and Irinotecan in Patients With Advanced Cancers

Sponsor
Merrimack Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01451632
Collaborator
Sanofi (Industry)
48
Enrollment
4
Locations
2
Arms
32
Duration (Months)
12
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and tolerability of escalating doses of the MM-121 plus cetuximab and the MM-121 plus cetuximab plus irinotecan combination.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

This study was a Phase 1 and pharmacologic dose-escalation trial of MM-121 plus cetuximab plus irinotecan. The study assessed the safety, tolerability, and pharmacokinetics of MM-121, cetuximab and irinotecan.

Study Design

Study Type:
Interventional
Actual Enrollment :
48 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1 Study of MM-121 in Combination With Cetuximab and Irinotecan in Patients With Advanced Cancers
Study Start Date :
Oct 1, 2011
Actual Primary Completion Date :
Nov 1, 2013
Actual Study Completion Date :
Jun 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1: MM-121 + cetuximab

increasing doses of weekly MM-121 + weekly cetuximab

Drug: MM-121
escalating doses MM-121 IV QW
Other Names:
  • Seribantumab, SAR256212

    • Drug: Cetuximab
    escalating doses cetuximab IV QW
    Other Names:
  • Erbitux

    		•
    Experimental: Part 2: MM-121 + cetuximab + irinotecan

    increasing doses of irinotecan + the Recommended Phase 2 Dose/Maximum Tolerated Dose (RP2D/MTD) of MM121 + cetuximab as determined in Part 1

    Drug: MM-121
    escalating doses MM-121 IV QW
    Other Names:
  • Seribantumab, SAR256212

    • Drug: Irinotecan
    180 mg/m2 IV Q2W
    Other Names:
  • Camptosar

    • Drug: Cetuximab
    escalating doses cetuximab IV QW
    Other Names:
  • Erbitux

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Dose Escalation: To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Plus Cetuximab and the MM-121 Plus Cetuximab Plus Irinotecan Combination [From date of first dose to 30 days after termination, the longest 48.1 weeks]

      To establish the safety of escalating doses of MM-121 in combination with cetuximab or in combination with cetuximab and irinotecan in order to determine the recommended phase 2 dose.. Dose-escalation conducted using standard 3+3 model to determine maximum tolerated dose. Reports of Dose-Limiting Toxicities (DLTs) were assessed to determine the MTD.

    2. To Further Determine the Safety Parameters of the MM-121 + Cetuximab and MM-121 + Cetuximab + Irinotecan Combination by Determining the Recommended Phase 2 Dose (RP2D) of the Combination(s) (Via Recording of Maximum Tolerated Dose (MTD)): MM-121 Doses [From date of first dose to 30 days after termination, the longest 48.1 weeks]

      Using a 3+3 dose escalation model, the maximum tolerated dose of each combination was determined by assessing dose-limiting toxicities in each cohort. RP2D = one dose lever lower than the MTD Part 1: Cohort 1: MM-121: 12 mg/kg MM-121 QW + Cetuximab: 400 mg/m2 loading dose/200 mg/m2 (400/200) QW maintenance Cohort 2a: MM-121: 20 mg/kg IV QW + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 2b: MM-121: 12 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 3a: MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW (40/20) + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 3b: MM-121 20 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 4: MM-121: 40/20 mg/kg IV QW + Cetuximab: 400 / 250 mg/m2 maintenance IV QW Part 2: Cohort 1: MM-121: 20 mg/kg IV QW + Cetuximab: 400/200 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2 IV Q2W Cohort 2: MM-121: 40 / 20 mg/kg IV QW + Cetuximab: 400/250 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2

    3. To Further Determine the Safety Parameters of the MM-121 + Cetuximab and MM-121 + Cetuximab + Irinotecan Combination by Determining the Recommended Phase 2 Dose (RP2D) of the Combination(s): Cetuximab and Irinotecan [From date of first dose to 30 days after termination, the longest 48.1 weeks]

      Using a 3+3 dose escalation model, the maximum tolerated dose of each combination was determined by assessing dose-limiting toxicities in each cohort. RP2D = one dose lever lower than the MTD Part 1: Cohort 1: MM-121: 12 mg/kg MM-121 QW + Cetuximab: 400 mg/m2 loading dose/200 mg/m2 (400/200) QW maintenance Cohort 2a: MM-121: 20 mg/kg IV QW + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 2b: MM-121: 12 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 3a: MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW (40/20) + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 3b: MM-121 20 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 4: MM-121: 40/20 mg/kg IV QW + Cetuximab: 400 / 250 mg/m2 maintenance IV QW Part 2: Cohort 1: MM-121: 20 mg/kg IV QW + Cetuximab: 400/200 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2 IV Q2W Cohort 2: MM-121: 40 / 20 mg/kg IV QW + Cetuximab: 400/250 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2

    Secondary Outcome Measures

    1. Objective Response Rate [Patients were assessed for objective response from time of first dose through treatment termination, the longest treatment duration being 48.1 weeks]

      To determine the number of patients reporting an objective response using RECIST v 1.1 where a Partial Response (PR) is defined as >20% decrease in tumor burden from baseline and a Complete Response (CR) is defined as complete disappearance from tumor burden from baseline. Objective Response is presented as the total # patients with PR or CR.

    2. Pharmacokinetics [Collections taken for all patients at Cycle 1, Week 1 at pre-infusion, at the end of the infusion, and 2.5, 4, 6 and 24 hours after starting the infusion of MM-121]

      Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first six weeks of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. Non-compartmental analysis (NCA) was performed to calculate standard PK parameters, including the maximum observed concentration (Cmax). Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (12 mg/kg, 20 mg/kg, or 40/20 mg/kg) and per study part (Part 1 or Part 2)

    3. Pharmacokinetic Parameters of MM-121 [Collections taken for all patients at Cycle 1, Week 1 at pre-infusion, at the end of the infusion, and 2.5, 4, 6 and 24 hours after starting the infusion of MM-121]

      Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first six weeks of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. Non-compartmental analysis (NCA) was performed to calculate standard PK parameters, including the AUClast. Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (12 mg/kg, 20 mg/kg, or 40/20 mg/kg) and per study part (Part 1 or Part 2)

    4. Immunogenicity [Samples were collected for all patients pre-dose on all cycles for duration of treatment, the longest of which was 48.1 weeks, and a collection was made post-infusion in any case of infusion reaction]

      Samples were collected to determine the presence of an immunologic reaction to MM-121 (i.e. human anti-human antibodies).

    Eligibility Criteria

    Criteria

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

    • No standard options remaining

    • Adequate liver and kidney functions

    • 18 years of age or above

    Exclusion Criteria:

    • History of any secondary active cancer in the last 3 years.

    • Pregnant or breast feeding

    • History of severe allergic reactions or contraindications to cetuximab or irinotecan

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 San Francisco California United States 94115
    2 Boston Massachusetts United States 02115
    3 Chapel Hill North Carolina United States 27599
    4 Salt Lake City Utah United States 84112

    Sponsors and Collaborators

    • Merrimack Pharmaceuticals
    • Sanofi

    Investigators

    • Study Director: Victor Moyo, MD, Merrimack Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Merrimack Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01451632
    Other Study ID Numbers:
    • MM-121-05-01-05 (TCD11696)
    First Posted:
    Oct 13, 2011
    Last Update Posted:
    Sep 8, 2016
    Last Verified:
    Sep 1, 2016
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Merrimack Pharmaceuticals
    Metastatic Colorectal cancer
    Kras wild-type
    Squamous cell head and neck cancer
    Non-small cell lung cancer
    Triple negative breast cancer
    EGFR
    ErbB3
    MM-121
    Cetuximab
    Irinotecan
    Additional relevant MeSH terms:
    Carcinoma, Non-Small-Cell Lung
    Colorectal Neoplasms
    Head and Neck Neoplasms
    Triple Negative Breast Neoplasms
    Irinotecan
    Cetuximab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Part 1: Cohort 1 Part 1: Cohort 2a Part 1: Cohort 2b Part 1: Cohort 3a Part 1: Cohort 3b Part 1: Cohort 4 Part 1: Expansion Cohort Part 2: Cohort 1 Part 2: Cohort 2 Part 2: Expansion Cohort
    Arm/Group Description MM-121: 12 mg/kg IV weekly in 4-week cycles Cetuximab: 400 mg/m2 IV one-time loading dose followed by 200 mg/m2 IV weekly maintenance doses MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg one time loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 one-time loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W
    Period Title: Overall Study
    STARTED 8 4 3 3 4 4 8 6 4 4
    COMPLETED 8 4 3 3 4 4 8 6 4 4
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan Total
    Arm/Group Description increasing doses of weekly MM-121 + weekly cetuximab MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) increasing doses of irinotecan + the RP2D of MM121 + cetuximab as determined in Part 1 MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Irinotecan: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Total of all reporting groups
    Overall Participants 34 14 48
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    56.1
    (14.19)
    56.6
    (11.38)
    56.35
    (12.79)
    Sex: Female, Male (Count of Participants)
    Female
    13
    38.2%
    9
    64.3%
    22
    45.8%
    Male
    21
    61.8%
    5
    35.7%
    26
    54.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    5.9%
    1
    7.1%
    3
    6.3%
    Not Hispanic or Latino
    31
    91.2%
    13
    92.9%
    44
    91.7%
    Unknown or Not Reported
    1
    2.9%
    0
    0%
    1
    2.1%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    3
    8.8%
    0
    0%
    3
    6.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    3
    8.8%
    0
    0%
    3
    6.3%
    White
    26
    76.5%
    13
    92.9%
    39
    81.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    5.9%
    1
    7.1%
    3
    6.3%
    Region of Enrollment (participants) [Number]
    United States
    34
    100%
    14
    100%
    48
    100%

    Outcome Measures

    1. Primary Outcome
    Title Dose Escalation: To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Plus Cetuximab and the MM-121 Plus Cetuximab Plus Irinotecan Combination
    Description To establish the safety of escalating doses of MM-121 in combination with cetuximab or in combination with cetuximab and irinotecan in order to determine the recommended phase 2 dose.. Dose-escalation conducted using standard 3+3 model to determine maximum tolerated dose. Reports of Dose-Limiting Toxicities (DLTs) were assessed to determine the MTD.
    Time Frame From date of first dose to 30 days after termination, the longest 48.1 weeks

    Outcome Measure Data

    Analysis Population Description
    Patients participating in dose escalation
    Arm/Group Title Part 1: Cohort 1 Part 1: Cohort 2a Part 1: Cohort 2b Part 1: Cohort 3a Part 1: Cohort 3b Part 1: Cohort 4 Part 2: Cohort 1 Part 2: Cohort 2
    Arm/Group Description MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W
    Measure Participants 8 4 3 3 4 4 6 4
    Number [participants reporting DLTs]
    1
    2.9%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    2
    NaN
    2. Primary Outcome
    Title To Further Determine the Safety Parameters of the MM-121 + Cetuximab and MM-121 + Cetuximab + Irinotecan Combination by Determining the Recommended Phase 2 Dose (RP2D) of the Combination(s) (Via Recording of Maximum Tolerated Dose (MTD)): MM-121 Doses
    Description Using a 3+3 dose escalation model, the maximum tolerated dose of each combination was determined by assessing dose-limiting toxicities in each cohort. RP2D = one dose lever lower than the MTD Part 1: Cohort 1: MM-121: 12 mg/kg MM-121 QW + Cetuximab: 400 mg/m2 loading dose/200 mg/m2 (400/200) QW maintenance Cohort 2a: MM-121: 20 mg/kg IV QW + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 2b: MM-121: 12 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 3a: MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW (40/20) + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 3b: MM-121 20 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 4: MM-121: 40/20 mg/kg IV QW + Cetuximab: 400 / 250 mg/m2 maintenance IV QW Part 2: Cohort 1: MM-121: 20 mg/kg IV QW + Cetuximab: 400/200 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2 IV Q2W Cohort 2: MM-121: 40 / 20 mg/kg IV QW + Cetuximab: 400/250 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2
    Time Frame From date of first dose to 30 days after termination, the longest 48.1 weeks

    Outcome Measure Data

    Analysis Population Description
    Number of patients participating in dose-escalation portion (excluding expansion cohort patients who were not evaluated for DLTs) MTD of cetuximab and irinotecan for the combination(s) are presented in a separate endpoint entry
    Arm/Group Title Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan
    Arm/Group Description increasing doses of weekly MM-121 + weekly cetuximab MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) increasing doses of irinotecan + the RP2D of MM121 + cetuximab as determined in Part 1 MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Irinotecan: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV)
    Measure Participants 26 10
    MM-121 loading dose
    40
    NA
    MM-121 maintenance dose
    20
    20
    3. Primary Outcome
    Title To Further Determine the Safety Parameters of the MM-121 + Cetuximab and MM-121 + Cetuximab + Irinotecan Combination by Determining the Recommended Phase 2 Dose (RP2D) of the Combination(s): Cetuximab and Irinotecan
    Description Using a 3+3 dose escalation model, the maximum tolerated dose of each combination was determined by assessing dose-limiting toxicities in each cohort. RP2D = one dose lever lower than the MTD Part 1: Cohort 1: MM-121: 12 mg/kg MM-121 QW + Cetuximab: 400 mg/m2 loading dose/200 mg/m2 (400/200) QW maintenance Cohort 2a: MM-121: 20 mg/kg IV QW + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 2b: MM-121: 12 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 3a: MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW (40/20) + Cetuximab: 400 / 200 mg/m2 maintenance IV QW Cohort 3b: MM-121 20 mg/kg IV QW + Cetuximab: 400 /250 mg/m2 maintenance IV QW Cohort 4: MM-121: 40/20 mg/kg IV QW + Cetuximab: 400 / 250 mg/m2 maintenance IV QW Part 2: Cohort 1: MM-121: 20 mg/kg IV QW + Cetuximab: 400/200 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2 IV Q2W Cohort 2: MM-121: 40 / 20 mg/kg IV QW + Cetuximab: 400/250 mg/m2 maintenance IV QW + Irinotecan: 180 mg/m2
    Time Frame From date of first dose to 30 days after termination, the longest 48.1 weeks

    Outcome Measure Data

    Analysis Population Description
    Number of patients participating in dose-escalation portion (excluding expansion cohort patients who were not evaluated for DLTs and thus not included in determining MTD/RP2D) NOTE: MTD of MM-121 provided in separate endpoint entry
    Arm/Group Title Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan
    Arm/Group Description increasing doses of weekly MM-121 + weekly cetuximab MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) increasing doses of irinotecan + the RP2D of MM121 + cetuximab as determined in Part 1 MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Irinotecan: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV)
    Measure Participants 26 10
    Cetuximab loading dose
    400
    400
    Cetuximab maintenance dose
    250
    250
    Irinotecan
    NA
    180
    4. Secondary Outcome
    Title Objective Response Rate
    Description To determine the number of patients reporting an objective response using RECIST v 1.1 where a Partial Response (PR) is defined as >20% decrease in tumor burden from baseline and a Complete Response (CR) is defined as complete disappearance from tumor burden from baseline. Objective Response is presented as the total # patients with PR or CR.
    Time Frame Patients were assessed for objective response from time of first dose through treatment termination, the longest treatment duration being 48.1 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Part 1: Cohort 1 Part 1: Cohort 2a Part 1: Cohort 2b Part 1: Cohort 3a Part 1: Cohort 3b Part 1: Cohort 4 Part 1: Expansion Cohort Part 2: Cohort 1 Part 2: Cohort 2 Part 2: Expansion Cohort
    Arm/Group Description MM-121: 12 mg/kg IV weekly in 4-week cycles Cetuximab: 400 mg/m2 IV one-time loading dose followed by 200 mg/m2 IV weekly maintenance doses MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg one time loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 one-time loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W
    Measure Participants 8 4 3 3 4 4 8 6 4 4
    Number [participants with objective response]
    1
    2.9%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    1
    NaN
    0
    NaN
    0
    NaN
    5. Secondary Outcome
    Title Pharmacokinetics
    Description Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first six weeks of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. Non-compartmental analysis (NCA) was performed to calculate standard PK parameters, including the maximum observed concentration (Cmax). Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (12 mg/kg, 20 mg/kg, or 40/20 mg/kg) and per study part (Part 1 or Part 2)
    Time Frame Collections taken for all patients at Cycle 1, Week 1 at pre-infusion, at the end of the infusion, and 2.5, 4, 6 and 24 hours after starting the infusion of MM-121

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Part 1: 12 mg/kg Part 1: 20 mg/kg Part 1: 40/20 mg/kg Part 2: 20 mg/kg Part 2: 40/20 mg/kg
    Arm/Group Description MM-121 mg/kg plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2 MM-121: 20 mg/kg Plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2 MM-121: 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance doses Plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2 MM-121: 20 mg/kg plus cetuximab at 400/250 mg/m2 plus irinotecan at 180 mg/m2 MM-121: 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance doses plus cetuximab 400/250 mg/m2 plus irinotecan 180 mg/m2
    Measure Participants 11 8 15 10 4
    Geometric Mean (Geometric Coefficient of Variation) [ug/mL]
    316.8
    (23.6)
    611.0
    (45.8)
    794.1
    (58.2)
    505.8
    (10.2)
    1278.2
    (25)
    6. Secondary Outcome
    Title Pharmacokinetic Parameters of MM-121
    Description Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first six weeks of the study and then on day 1 of each additional cycle to assess pre-treatment trough concentrations of MM-121. Non-compartmental analysis (NCA) was performed to calculate standard PK parameters, including the AUClast. Serum levels of MM-121 were measured at a central lab using an enzyme-linked immunosorbent assay (ELISA). Data is presented per dose level of MM-121 (12 mg/kg, 20 mg/kg, or 40/20 mg/kg) and per study part (Part 1 or Part 2)
    Time Frame Collections taken for all patients at Cycle 1, Week 1 at pre-infusion, at the end of the infusion, and 2.5, 4, 6 and 24 hours after starting the infusion of MM-121

    Outcome Measure Data

    Analysis Population Description
    Data presented by dose level of MM-121, regardless of the cohort (i.e. 15 patients in Part 1 were administered the 40/20 dose level of MM-121: 3 in cohort 3b, 4 in cohort 4, and 8 in the Part 1 expansion)
    Arm/Group Title Part 1: 12 mg/kg Part 1: 20 mg/kg Part 1: 40/20 mg/kg Part 2: 20 mg/kg Part 2: 40/20 mg/kg
    Arm/Group Description MM-121 mg/kg plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2 MM-121: 20 mg/kg Plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2 MM-121: 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance doses Plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2 MM-121: 20 mg/kg plus cetuximab at 400/250 mg/m2 plus irinotecan at 180 mg/m2 MM-121: 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance doses plus cetuximab 400/250 mg/m2 plus irinotecan 180 mg/m2
    Measure Participants 11 8 15 10 4
    Geometric Mean (Geometric Coefficient of Variation) [hr* ug/mL]
    24190.5
    (22.0)
    53063.1
    (46.1)
    91111.9
    (39.9)
    47681.5
    (14.2)
    98387.7
    (16.2)
    7. Secondary Outcome
    Title Immunogenicity
    Description Samples were collected to determine the presence of an immunologic reaction to MM-121 (i.e. human anti-human antibodies).
    Time Frame Samples were collected for all patients pre-dose on all cycles for duration of treatment, the longest of which was 48.1 weeks, and a collection was made post-infusion in any case of infusion reaction

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Part 1: Cohort 1 Part 1: Cohort 2a Part 1: Cohort 2b Part 1: Cohort 3a Part 1: Cohort 3b Part 1: Cohort 4 Part 1: Expansion Cohort Part 2: Cohort 1 Part 2: Cohort 2 Part 2: Expansion Cohort
    Arm/Group Description MM-121: 12 mg/kg IV weekly in 4-week cycles Cetuximab: 400 mg/m2 IV one-time loading dose followed by 200 mg/m2 IV weekly maintenance doses MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg one time loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 one-time loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 40 mg/kg loading dose followed by 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW Irinotecan: 180 mg/m2 IV Q2W
    Measure Participants 8 4 3 3 4 4 8 6 4 4
    Number
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA

    Adverse Events

    Time Frame AEs were collected from a patient's first dose until 30 days after treatment termination. SAEs were collected from time of informed consent until 30 days after termination. If related, events could be reported at any time after termination.
    Adverse Event Reporting Description All related AEs ongoing at the time of treatment discontinuation were followed until resolution. Investigators were to report any AEs/SAEs assumed to be related any time, even if occurring more than 30 days after last dose. Though different for each patient, on average, patients could be followed for related AEs/SAEs for ~1 year after termination
    Arm/Group Title Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan
    Arm/Group Description increasing doses of weekly MM-121 + weekly cetuximab MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) increasing doses of irinotecan + the RP2D of MM121 + cetuximab as determined in Part 1 MM-121 (SAR256212): MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Irinotecan: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV) Cetuximab: MM-121 (SAR256212) (IV) plus Cetuximab (IV) and Irinotecan (IV)
    All Cause Mortality
    Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 15/34 (44.1%) 6/14 (42.9%)
    Blood and lymphatic system disorders
    Neutropenia 0/34 (0%) 1/14 (7.1%)
    Cardiac disorders
    Pericardial effusion 1/34 (2.9%) 1/14 (7.1%)
    Supraventricular tachycardia 1/34 (2.9%) 0/14 (0%)
    Cardiac Arrest 0/34 (0%) 1/14 (7.1%)
    Gastrointestinal disorders
    Abdominal Pain 1/34 (2.9%) 0/14 (0%)
    Constipation 1/34 (2.9%) 0/14 (0%)
    Diarrhea 1/34 (2.9%) 2/14 (14.3%)
    Intestinal Obstruction 0/34 (0%) 1/14 (7.1%)
    Nausea 0/34 (0%) 1/14 (7.1%)
    Stomatitis 0/34 (0%) 1/14 (7.1%)
    Vomiting 0/34 (0%) 1/14 (7.1%)
    General disorders
    Disease Progression 1/34 (2.9%) 0/14 (0%)
    Mucosal Inflammation 1/34 (2.9%) 0/14 (0%)
    Pyrexia 1/34 (2.9%) 0/14 (0%)
    Non-cardiac chest pain 0/34 (0%) 1/14 (7.1%)
    Hepatobiliary disorders
    Bile Duct Stenosis 1/34 (2.9%) 0/14 (0%)
    Infections and infestations
    Abdominal Abscess 1/34 (2.9%) 0/14 (0%)
    Device Related Infection 1/34 (2.9%) 0/14 (0%)
    Lung Infection 1/34 (2.9%) 0/14 (0%)
    Urinary Tract Infection 0/34 (0%) 1/14 (7.1%)
    Injury, poisoning and procedural complications
    Infusion Related Reaction 1/34 (2.9%) 0/14 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/34 (0%) 1/14 (7.1%)
    Musculoskeletal and connective tissue disorders
    Back Pain 1/34 (2.9%) 0/14 (0%)
    Pain in Extremity 1/34 (2.9%) 0/14 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    metastases to central nervous system 1/34 (2.9%) 0/14 (0%)
    Nervous system disorders
    Vocal cord paralysis 1/34 (2.9%) 0/14 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism 1/34 (2.9%) 1/14 (7.1%)
    Dyspnea 0/34 (0%) 1/14 (7.1%)
    Respiratory Failure 0/34 (0%) 1/14 (7.1%)
    Skin and subcutaneous tissue disorders
    Photosensitivity Reaction 1/34 (2.9%) 0/14 (0%)
    Skin Ulcer 1/34 (2.9%) 0/14 (0%)
    Vascular disorders
    Deep Vein Thrombosis 1/34 (2.9%) 0/14 (0%)
    Hypotension 1/34 (2.9%) 0/14 (0%)
    Lyphoedema 1/34 (2.9%) 0/14 (0%)
    Other (Not Including Serious) Adverse Events
    Part 1: MM-121 + Cetuximab Part 2: MM-121 + Cetuximab + Irinotecan
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 34/34 (100%) 14/14 (100%)
    Blood and lymphatic system disorders
    Anemia 6/34 (17.6%) 1/14 (7.1%)
    Neutropenia 0/34 (0%) 1/14 (7.1%)
    Cardiac disorders
    Pericardial effusion 2/34 (5.9%) 1/14 (7.1%)
    Tachycardia 2/34 (5.9%) 0/14 (0%)
    Cardiac Arrest 0/34 (0%) 1/14 (7.1%)
    Eye disorders
    Vision Blurred 3/34 (8.8%) 1/14 (7.1%)
    Conjunctivitis 2/34 (5.9%) 1/14 (7.1%)
    Lacrimation increased 2/34 (5.9%) 0/14 (0%)
    Ocular Hyperaemia 1/34 (2.9%) 1/14 (7.1%)
    Gastrointestinal disorders
    Diarrhea 17/34 (50%) 13/14 (92.9%)
    Stomatitis 9/34 (26.5%) 5/14 (35.7%)
    Nausea 8/34 (23.5%) 8/14 (57.1%)
    Abdominal Pain 7/34 (20.6%) 1/14 (7.1%)
    Constipation 5/34 (14.7%) 0/14 (0%)
    Vomiting 5/34 (14.7%) 5/14 (35.7%)
    Dyspepsia 4/34 (11.8%) 1/14 (7.1%)
    Dry Mouth 2/34 (5.9%) 0/14 (0%)
    Hemorrhoids 2/34 (5.9%) 2/14 (14.3%)
    Oral Pain 2/34 (5.9%) 0/14 (0%)
    Cheilitis 1/34 (2.9%) 1/14 (7.1%)
    Glossodynia 0/34 (0%) 1/14 (7.1%)
    Haematochezia 0/34 (0%) 1/14 (7.1%)
    Intestinal Obstruction 0/34 (0%) 1/14 (7.1%)
    General disorders
    Fatigue 22/34 (64.7%) 9/14 (64.3%)
    Mucosal Inflammation 8/34 (23.5%) 4/14 (28.6%)
    Chills 3/34 (8.8%) 0/14 (0%)
    Non-Cardiac Chest Pain 2/34 (5.9%) 1/14 (7.1%)
    Asthenia 1/34 (2.9%) 1/14 (7.1%)
    Impaired healing 0/34 (0%) 1/14 (7.1%)
    Pyrexia 4/34 (11.8%) 1/14 (7.1%)
    Infections and infestations
    Paronychia 9/34 (26.5%) 0/14 (0%)
    Fungal Skin Infection 2/34 (5.9%) 1/14 (7.1%)
    Urinary Tract Infection 2/34 (5.9%) 3/14 (21.4%)
    Bronchitis 0/34 (0%) 1/14 (7.1%)
    Nail Infection 0/34 (0%) 1/14 (7.1%)
    Oral Infection 0/34 (0%) 1/14 (7.1%)
    Tinea Cruris 0/34 (0%) 1/14 (7.1%)
    Vulvovaginal Mycotic Infection 1/34 (2.9%) 1/14 (7.1%)
    Injury, poisoning and procedural complications
    Infusion Related Reaction 5/34 (14.7%) 2/14 (14.3%)
    Post-Procedural Swelling 0/34 (0%) 1/14 (7.1%)
    Investigations
    Weight Decreased 8/34 (23.5%) 7/14 (50%)
    Blood Magnesium Decreased 2/34 (5.9%) 0/14 (0%)
    White Blood Cell Count Decreased 0/34 (0%) 2/14 (14.3%)
    Neutrophil Count Decreased 0/34 (0%) 1/14 (7.1%)
    Metabolism and nutrition disorders
    Hypomagnesemia 18/34 (52.9%) 5/14 (35.7%)
    Decreased Appetite 12/34 (35.3%) 7/14 (50%)
    Hypokalemia 10/34 (29.4%) 9/14 (64.3%)
    Hypocalcemia 6/34 (17.6%) 4/14 (28.6%)
    Hypophosphatemia 6/34 (17.6%) 3/14 (21.4%)
    Dehydration 0/34 (0%) 6/14 (42.9%)
    Hypoalbuminemia 0/34 (0%) 3/14 (21.4%)
    Hyponatremia 0/34 (0%) 2/14 (14.3%)
    Musculoskeletal and connective tissue disorders
    Back Pain 3/34 (8.8%) 0/14 (0%)
    Flank Pain 2/34 (5.9%) 0/14 (0%)
    Bone Pain 0/34 (0%) 1/14 (7.1%)
    Muscular Weakness 0/34 (0%) 1/14 (7.1%)
    Pain in Extremity 1/34 (2.9%) 1/14 (7.1%)
    Nervous system disorders
    Headache 7/34 (20.6%) 0/14 (0%)
    Dygeusia 4/34 (11.8%) 1/14 (7.1%)
    Ataxia 2/34 (5.9%) 0/14 (0%)
    Dizziness 1/34 (2.9%) 2/14 (14.3%)
    Peripheral Neuropathy 0/34 (0%) 2/14 (14.3%)
    Central Nervous System Lesion 0/34 (0%) 1/14 (7.1%)
    Neuralgia 0/34 (0%) 1/14 (7.1%)
    Peripheral Motor Neuropathy 0/34 (0%) 1/14 (7.1%)
    Psychiatric disorders
    Depression 3/34 (8.8%) 0/14 (0%)
    Insomnia 3/34 (8.8%) 1/14 (7.1%)
    Anxiety 2/34 (5.9%) 1/14 (7.1%)
    Confusional State 2/34 (5.9%) 0/14 (0%)
    Renal and urinary disorders
    Pollakiuria 0/34 (0%) 1/14 (7.1%)
    Respiratory, thoracic and mediastinal disorders
    Cough 6/34 (17.6%) 2/14 (14.3%)
    Epistaxis 5/34 (14.7%) 1/14 (7.1%)
    Dyspnea 3/34 (8.8%) 1/14 (7.1%)
    Rhinitis allergic 2/34 (5.9%) 0/14 (0%)
    Dysphonia 0/34 (0%) 1/14 (7.1%)
    Nasal Congestion 0/34 (0%) 1/14 (7.1%)
    Nasal Disorder 0/34 (0%) 1/14 (7.1%)
    Oropharyngeal Pain 1/34 (2.9%) 1/14 (7.1%)
    Pneumonitis 1/34 (2.9%) 1/14 (7.1%)
    Pulmonary Embolism 1/34 (2.9%) 1/14 (7.1%)
    Respiratory Failure 0/34 (0%) 1/14 (7.1%)
    Skin and subcutaneous tissue disorders
    Dermatitis Acneform 18/34 (52.9%) 4/14 (28.6%)
    Rash Maculopapular 10/34 (29.4%) 3/14 (21.4%)
    Rash 8/34 (23.5%) 1/14 (7.1%)
    Dry Skin 5/34 (14.7%) 3/14 (21.4%)
    Skin Fissures 5/34 (14.7%) 1/14 (7.1%)
    Palmar-Plantar Erythrodysaesthesia Syndrome 4/34 (11.8%) 4/14 (28.6%)
    Skin Ulcer 3/34 (8.8%) 0/14 (0%)
    Pruritis 2/34 (5.9%) 0/14 (0%)
    Pruritis Generalized 2/34 (5.9%) 0/14 (0%)
    Pain of skin 0/34 (0%) 3/14 (21.4%)
    Alopecia 0/34 (0%) 2/14 (14.3%)
    Nail Disorder 0/34 (0%) 2/14 (14.3%)
    Erythema 0/34 (0%) 1/14 (7.1%)
    Nail Discoloration 0/34 (0%) 1/14 (7.1%)
    Rash Erythematous 1/34 (2.9%) 1/14 (7.1%)
    Rash Papular 0/34 (0%) 1/14 (7.1%)
    Skin Irritation 1/34 (2.9%) 1/14 (7.1%)
    Vascular disorders
    Deep Vein Thrombosis 2/34 (5.9%) 0/14 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    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.

    Results Point of Contact

    Name/Title Clinical Trial Manager
    Organization Merrimack Pharmaceuticals, Inc.
    Phone 617-441-1000
    Email smathews@merrimack.com
    Responsible Party:
    Merrimack Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01451632
    Other Study ID Numbers:
    • MM-121-05-01-05 (TCD11696)
    First Posted:
    Oct 13, 2011
    Last Update Posted:
    Sep 8, 2016
    Last Verified:
    Sep 1, 2016