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escalating doses of MM-121 and gemcitabine on Day 1 and Day 8 of every 3 week cycle

carboplatin at AUC 6 with escalating doses of MM-121 on Day 1 of every 3 week cycle

pemetrexed at 500 mg/m2 with escalating doses of MM-121 on Day 1 of every 3 week cycle

escalating doses of MM-121 and cabazitaxel on Day 1 of every 3 week cycle

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

MM-121

Cabazitaxel

administered IV at 1000 mg/m2 or 1250 mg/m2

Victor Moyo, MD

To evaluate the safety and tolerability of escalating doses of MM-121 + certain anticancer therapies

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.

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

A Phase 1, Pharmacologic and Pharmacodynamic Study of MM-121 in Combination With Multiple Anticancer Therapies in Patients With Advanced Solid Tumors

Safety and tolerability data presented in detail in the adverse events and serious adverse events section of the results posting

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

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

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

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

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 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.

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 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).

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).

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

escalating doses of MM-121 and gemcitabine on Day 1 and Day 8 of every 3 week cycle

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

MM-121 Plus Gemcitabine

carboplatin at AUC 6 with escalating doses of MM-121 on Day 1 of every 3 week cycle

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

Carboplatin: administered at AUC 6

MM-121 Plus Carboplatin

pemetrexed at 500 mg/m2 with escalating doses of MM-121 on Day 1 of every 3 week cycle

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

Pemetrexed: administered IV at 500 mg/m2

MM-121 Plus Pemetrexed

escalating doses of MM-121 and cabazitaxel on Day 1 of every 3 week cycle

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

Cabazitaxel: administered IV at 20 mg/m2 or 25 mg/m2

MM-121 Plus Cabazitaxel

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

France

Region of Enrollment

Clinical Trial Manager

MM-121 20 mg/kg one-time loading dose on Cycle 1, Week 1 followed 12 mg/kg IV maintenance doses weekly for 3-week cycles

gemcitabine 1000 mg/m2 IV on Days 1 and 8 of each 3-week cycle

MM-121 Plus Gemcitabine: Cohort 1

MM-121 40 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 20 mg/kg IV maintenance doses weekly for each 3-week cycle

Gemcitabine: 1000 mg/m2 IV on Day 1 And Day 8 of each 3-week cycle

MM-121 Plus Gemcitabine: Cohort 2

MM-121: 20 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 12 mg/kg IV maintenance doses weekly for each 3-week cycle

Carboplatin at AUC 6 Day 1 of every 3 week cycle

MM-121 Plus Carboplatin: Cohort 1

MM-121: 20 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 12 mg/kg IV maintenance doses weekly for each 3-week cycle

Carboplatin at AUC 5 Day 1 of every 3 week cycle

MM-121 Plus Carboplatin: Cohort 2

MM-121: 40 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 20 mg/kg IV maintenance doses weekly for each 3-week cycle

Carboplatin at AUC 5 Day 1 of every 3 week cycle

MM-121 Plus Carboplatin: Cohort 3

MM-121: 20 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 12 mg/kg IV maintenance dose weekly for every 3-week cycle

Pemetrexed at 500 mg/m2 IV on Day 1 of every 3 week cycle

MM-121 Plus Pemetrexed: Cohort 1

MM-121: 40 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 20 mg/kg IV maintenance dose weekly for every 3-week cycle

Pemetrexed at 500 mg/m2 IV on Day 1 of every 3 week cycle

MM-121 Plus Pemetrexed: Cohort 2

MM-121: 20 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 12mg/kg IV maintenance doses weekly for each 3-week cycle

Cabazitaxel: 20 mg/m2 IV on Day 1 of each 3-week cycle

MM-121 Plus Cabazitaxel: Cohort 1

MM-121: 40 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 20 mg/kg maintenance doses weekly for each 3-week cycle

Cabazitaxel: 20 mg/m2 IV on Day 1 of each 3-week cycle

MM-121 Plus Cabazitaxel: Cohort 2

MM-121: 40 mg/kg IV one-time loading dose on Cycle 1, Week 1 followed by 20 mg/kg maintenance doses weekly for each 3-week cycle

Cabazitaxel: 25 mg/m2 IV on Day 1 of each 3-week cycle

MM-121 Plus Cabazitaxel: Cohort 3

To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Anticancer Therapies

one-time loading dose

maintenance dose

escalating doses of MM-121 and gemcitabine on Day 1 and Day 8 of every 3 week cycle

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

Gemcitabine: administered IV at 1000 mg/m2 or 1250 mg/m2

Note: data provided below is for MM-121 doses only for the combination. Combination therapy MTDs are provided in separate endpoint measures.

To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: MM-121 Doses

MM-121 + Gemcitabine

NOTE: Maximum tolerated dose is for the combination of gemcitabine and MM-121. MTD of MM-121 is provided in separate endpoint.

To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Gemcitabine

MTD of the MM-121 + Carboplatin combination NOTE: MTD of MM-121 for this combination provided in separate endpoint

MM-121 + Carboplatin

To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Carboplatin

MTD of combination of MM-121 + Pemetrexed - NOTE: MTD of MM-121 for this combination provided in separate endpoint

MM-121 + Pemetrexed

To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Pemetrexed

MTD of MM-121 + Cabazitaxel combination - NOTE: MTD of MM-121 for this combination provided in separate endpoint

MM-121 + Cabazitaxel

To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Cabazitaxel

To Characterize Dose-limiting Toxicities (DLTs) Associated With the Combination of MM-121 With Anticancer Therapies

Objective Response Rate

MM-121 20 mg/kg loading dose followed by 12 mg/kg weekly maintenance dose plus gemcitabine 1000mg/m² or 1250mg/m²

MM-121 + Gemcitabine: 20/12 mg/kg

MM-121 20 mg/kg loading dose followed by 12 mg/kg weekly maintenance dose Plus carboplatin AUC 6

MM-121 + Carboplatin: 20/12 mg/kg

MM-121 20 mg/kg loading dose followed by 12 mg/kg weekly maintenance dose Plus pemetrexed 500 mg/m²

MM-121 + Pemetrexed: 20/12 mg/kg

MM-121 20 mg/kg loading dose followed by 12 mg/kg weekly maintenance dose Plus Cisplatin 20 mg/m2 or 25 mg/m2

MM-121 + Cisplatin: 20/12 mg/kg

MM-121 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose plus gemcitabine 1000mg/m² or 1250mg/m²

MM-121 + Gemcitabine: 40/20 mg/kg

MM-121 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose Plus carboplatin AUC 6

MM-121 + Carboplatin: 40/20 mg/kg

MM-121 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose Plus pemetrexed 500 mg/m²

MM-121 + Pemetrexed: 40/20 mg/kg

MM-121 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose Plus Cisplatin 25 mg/m2

Spots Global Cancer Trial Database for Safety Study of MM-121 in Combination With Multiple Anticancer Therapies in Patients With Advanced Solid Tumors

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