Neoplasms

Skin and Connective Tissue Diseases

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Respiratory Tract (Lung and Bronchial) Diseases

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Carcinoma, Non-Small-Cell Lung

Head and Neck Neoplasms

Lung Neoplasms

Carcinoma

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Gastrointestinal Diseases

Colonic Diseases

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Rectal Diseases

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Irinotecan

Cetuximab

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

increasing doses of weekly MM-121 + weekly cetuximab

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

MM-121

Victor Moyo, MD

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.

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.

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

A Phase 1 Study of MM-121 in Combination With Cetuximab and Irinotecan in Patients With Advanced Cancers

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.

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

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.

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)

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)

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

Sanofi

Merrimack Pharmaceuticals

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

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)

Part 1: MM-121 + Cetuximab

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)

Part 2: MM-121 + Cetuximab + Irinotecan

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Clinical Trial Manager

MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW

Part 1: Cohort 1

MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 200 mg/m2 maintenance IV QW

Part 1: Cohort 2a

MM-121: 12 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW

Part 1: Cohort 2b

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

Part 1: Cohort 3a

MM-121: 20 mg/kg IV QW Cetuximab: 400 mg/m2 loading dose followed by 250 mg/m2 maintenance IV QW

Part 1: Cohort 3b

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

Part 1: Cohort 4

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

Part 2: Cohort 1

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

Part 2: Cohort 2

Patients participating in dose escalation

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

MM-121 loading dose

MM-121 maintenance dose

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

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

Cetuximab loading dose

Cetuximab maintenance dose

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

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

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: 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

Part 1: Expansion Cohort

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

Part 2: Expansion Cohort

Objective Response Rate

MM-121 mg/kg plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2

Part 1: 12 mg/kg

MM-121: 20 mg/kg Plus cetuximab at either 400/200 mg/m2 or 400/250 mg/m2

Part 1: 20 mg/kg

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

Part 1: 40/20 mg/kg

MM-121: 20 mg/kg plus cetuximab at 400/250 mg/m2 plus irinotecan at 180 mg/m2

Part 2: 20 mg/kg

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

Part 2: 40/20 mg/kg

Pharmacokinetics

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)

Spots Global Cancer Trial Database for A Safety Study of MM-121 With Cetuximab and Irinotecan in Patients With Advanced Cancers

Trial Identification

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Study Description

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