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Safety Study of MM-121 in Combination With Multiple Anticancer Therapies in Patients With Advanced Solid Tumors

This study has been completed.
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Merrimack Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01447225
First received: October 3, 2011
Last updated: September 13, 2016
Last verified: September 2016
  Purpose
To evaluate the safety and tolerability of escalating doses of MM-121 + certain anticancer therapies

Condition Intervention Phase
Solid Tumors
Drug: MM-121
Drug: Carboplatin
Drug: Pemetrexed
Drug: Cabazitaxel
Drug: Gemcitabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Pharmacologic and Pharmacodynamic Study of MM-121 in Combination With Multiple Anticancer Therapies in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Merrimack Pharmaceuticals:

Primary Outcome Measures:
  • To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Anticancer Therapies [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]
    Safety and tolerability data presented in detail in the adverse events and serious adverse events section of the results posting

  • To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: MM-121 Doses [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]

    Using a 3+3 dose escalation model, the maximum tolerated dose of each therapy combination was determined by assessing dose-limiting toxicities in each cohort. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose.

    Dose Levels (3 week cycles) MM-121 doses tested: 20 mg/kg IV one-time loading dose then 12 mg/kg IV QW (20/12 mg/kg); 40/20 mg/kg Gemcitabine doses tested: 1000 mg/m2 Day 1 and 8 Pemetrexed doses tested: 500 mg/m2 Day 1 Carboplatin doses tested: 5 or 6 AUC Day 1 Cabazitaxel doses tested: 20 or 25 mg/m2 Day 1 of 3


  • To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Gemcitabine [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]

    Using a 3+3 dose escalation model, the maximum tolerated dose of each therapy combination was determined by assessing dose-limiting toxicities in each cohort. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose.

    Dose Levels (3 week cycles) MM-121 doses tested: 20 mg/kg IV one-time loading dose then 12 mg/kg IV QW (20/12 mg/kg); 40/20 mg/kg Gemcitabine doses tested: 1000 mg/m2 Day 1 and 8


  • To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Carboplatin [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]

    Maximum Tolerated Dose reported in Target AUC, as calculated by the Calvert Formula

    Using a 3+3 dose escalation model, the maximum tolerated dose of each therapy combination was determined by assessing dose-limiting toxicities in each cohort. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose.

    Dose Levels (3 week cycles) MM-121 doses tested: 20 mg/kg IV one-time loading dose then 12 mg/kg IV QW (20/12 mg/kg); 40/20 mg/kg Carboplatin doses tested: 5 or 6 AUC Day 1


  • To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Pemetrexed [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]

    Using a 3+3 dose escalation model, the maximum tolerated dose of each therapy combination was determined by assessing dose-limiting toxicities in each cohort. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose.

    Dose Levels (3 week cycles) MM-121 doses tested: 20 mg/kg IV one-time loading dose then 12 mg/kg IV QW (20/12 mg/kg); 40/20 mg/kg Pemetrexed doses tested: 500 mg/m2 Day 1


  • To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Cabazitaxel [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]

    Using a 3+3 dose escalation model, the maximum tolerated dose of each therapy combination was determined by assessing dose-limiting toxicities in each cohort. If 3 patients were treated and passed the observation window, escalation to the next cohort was initiated. If a DLT was reported, 3-4 additional patients were enrolled and observed. If a DLT was observed in expanded cohort, this dose was considered to be the maximum tolerated dose. The maximum tolerated dose was defined at the cohort in which two dose-limiting toxicities were observed, or as the highest target dose tested in the absence of DLTs. The determined MTD was considered the Recommended Phase 2 Dose.

    Dose Levels (3 week cycles) MM-121 doses tested: 20 mg/kg IV one-time loading dose then 12 mg/kg IV QW (20/12 mg/kg); 40/20 mg/kg Cabazitaxel doses tested: 20 or 25 mg/m2 Day 1 of 3


  • To Characterize Dose-limiting Toxicities (DLTs) Associated With the Combination of MM-121 With Anticancer Therapies [ Time Frame: From date of first dose to 30 days after termination, the longest 88.1 weeks ] [ Designated as safety issue: Yes ]
    To establish the safety of escalating doses of MM-121 administered in combination with multiple anti-cancer therapies 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 to be used for the expansion cohort. DLTs were not measured in the Expansion Cohort.


Secondary Outcome Measures:
  • Objective Response Rate [ Time Frame: patients were assessed for response during their time on study, the longest of which was 88.1 weeks ] [ Designated as safety issue: No ]
    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.

  • Pharmacokinetics [ Time Frame: Collections taken at Cycle 1, Week 1 for all patients at start of the infusion (pretreatment), at the end of the infusion, and at 2, 4, 24 and 48 hours after the start of the MM-121 infusion ] [ Designated as safety issue: No ]
    Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first cycle 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).

  • Pharmacokinetics (AUClast) [ Time Frame: Collections taken at Cycle 1, Week 1 for all patients at the start of the infusion (pretreatment), at the end of the infusion, and at 2, 4, 24 and 48 hours after the start of the MM-121 infusion ] [ Designated as safety issue: No ]
    Pharmacokinetic (PK) evaluation was performed on plasma samples obtained weekly for the first cycle 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).

  • Immunogenicity [ Time Frame: Samples were collected for all patients pre-dose on all cycles for duration of treatment, the longest of which was 88.1 weeks, and a collection was made post-infusion in any case of infusion reaction ] [ Designated as safety issue: No ]
    Samples were collected to determine the presence of an immunologic reaction to MM-121 (i.e. human anti-human antibodies).


Enrollment: 43
Study Start Date: October 2011
Study Completion Date: January 2014
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MM-121 plus Gemcitabine
escalating doses of MM-121 and gemcitabine on Day 1 and Day 8 of every 3 week cycle
Drug: MM-121
MM-121 administered at 20 mg/kg IV loading dose followed by12mg/kg/week IV or 40 mg/kg IV loading dose followed by 20mg/kg/week IV
Other Name: Seribantumab, SAR256212
Drug: Gemcitabine
administered IV at 1000 mg/m2 or 1250 mg/m2
Other Name: Gemzar
Experimental: MM-121 plus Carboplatin
carboplatin at AUC 6 with escalating doses of MM-121 on Day 1 of every 3 week cycle
Drug: MM-121
MM-121 administered at 20 mg/kg IV loading dose followed by12mg/kg/week IV or 40 mg/kg IV loading dose followed by 20mg/kg/week IV
Other Name: Seribantumab, SAR256212
Drug: Carboplatin
administered at AUC 6
Experimental: MM-121 plus Pemetrexed
pemetrexed at 500 mg/m2 with escalating doses of MM-121 on Day 1 of every 3 week cycle
Drug: MM-121
MM-121 administered at 20 mg/kg IV loading dose followed by12mg/kg/week IV or 40 mg/kg IV loading dose followed by 20mg/kg/week IV
Other Name: Seribantumab, SAR256212
Drug: Pemetrexed
administered IV at 500 mg/m2
Other Name: ALIMTA
Experimental: MM-121 plus Cabazitaxel
escalating doses of MM-121 and cabazitaxel on Day 1 of every 3 week cycle
Drug: MM-121
MM-121 administered at 20 mg/kg IV loading dose followed by12mg/kg/week IV or 40 mg/kg IV loading dose followed by 20mg/kg/week IV
Other Name: Seribantumab, SAR256212
Drug: Cabazitaxel
administered IV at 20 mg/m2 or 25 mg/m2
Other Name: Jevtana

Detailed Description:
This study was a Phase 1 and pharmacologic dose-escalation trial of MM-121 in combination with certain anticancer therapies. The dose-escalation portion of the study employed a 3 + 3 design to assess the safety, tolerability, and pharmacokinetics of MM-121 administered weekly in combination with certain anticancer therapies in patients with advanced/recurrent cancer. Doses of MM-121 and/or the anticancer therapy were escalated until either the MTD is identified or the combination was shown to be tolerable at the highest planned doses.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Advanced-stage solid tumors
  • ≥ 18 years of age
  • Adequate liver and kidney function

Exclusion Criteria:

  • Any other active malignancy
  • No known HIV, Hepatitis C or B
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01447225

Locations
United States, Indiana
Lafayette, Indiana, United States, 47905
United States, New York
Buffalo, New York, United States, 14263
United States, Ohio
Cincinnati, Ohio, United States, 45267
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19111
France
Villejuif, France
Sponsors and Collaborators
Merrimack Pharmaceuticals
Sanofi
Investigators
Study Director: Victor Moyo, MD Merrimack Pharmaceuticals
  More Information

Responsible Party: Merrimack Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01447225     History of Changes
Other Study ID Numbers: MM-121-06-01-06 (TCD11694) 
Study First Received: October 3, 2011
Results First Received: July 12, 2016
Last Updated: September 13, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Merrimack Pharmaceuticals:
Advanced-stage
Solid Tumors
MM-121
Carboplatin
Pemetrexed
Gemcitabine
Cabazitaxel
ErbB3
Phase I
Cancer

Additional relevant MeSH terms:
Gemcitabine
Pemetrexed
Carboplatin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 28, 2016