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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01447225

Enrollment

Registered

2011-10-06

Start date

2011-10-31

Completion date

2014-01-31

Last updated

2016-09-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Solid Tumors

Keywords

Advanced-stage, Solid Tumors, MM-121, Carboplatin, Pemetrexed, Gemcitabine, Cabazitaxel, ErbB3, Phase I, Cancer

Brief summary

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

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.

Interventions

DRUGPemetrexed

administered IV at 500 mg/m2

DRUGMM-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

DRUGCarboplatin

administered at AUC 6

DRUGCabazitaxel

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

DRUGGemcitabine

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

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
To Characterize Dose-limiting Toxicities (DLTs) Associated With the Combination of MM-121 With Anticancer Therapies	From date of first dose to 30 days after termination, the longest 88.1 weeks	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 Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Gemcitabine	From date of first dose to 30 days after termination, the longest 88.1 weeks	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	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 Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Anticancer Therapies	From date of first dose to 30 days after termination, the longest 88.1 weeks	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	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

Secondary

Measure	Time frame	Description
Pharmacokinetics	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	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)	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	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	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	Samples were collected to determine the presence of an immunologic reaction to MM-121 (i.e. human anti-human antibodies).
Objective Response Rate	patients were assessed for response during their time on study, the longest of which was 88.1 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.

Countries

France, United States

Participant flow

Participants by arm

Arm	Count
MM-121 Plus Gemcitabine 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	11
MM-121 Plus Carboplatin 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	11
MM-121 Plus Pemetrexed 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	10
MM-121 Plus Cabazitaxel 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	11
Total	43

Baseline characteristics

Characteristic	MM-121 Plus Gemcitabine	Total	MM-121 Plus Cabazitaxel	MM-121 Plus Pemetrexed	MM-121 Plus Carboplatin
Age, Continuous	58.3 years STANDARD_DEVIATION 7.79	61.28 years STANDARD_DEVIATION 8.98	64.1 years STANDARD_DEVIATION 6.66	60.0 years STANDARD_DEVIATION 12.29	62.7 years STANDARD_DEVIATION 9.18
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants	42 Participants	11 Participants	10 Participants	11 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	10 Participants	41 Participants	11 Participants	9 Participants	11 Participants
Region of Enrollment France	3 participants	9 participants	3 participants	3 participants	0 participants
Region of Enrollment United States	8 participants	34 participants	8 participants	7 participants	11 participants
Sex: Female, Male Female	8 Participants	22 Participants	2 Participants	7 Participants	5 Participants
Sex: Female, Male Male	3 Participants	21 Participants	9 Participants	3 Participants	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	11 / 11	11 / 11	10 / 10	11 / 11
serious Total, serious adverse events	9 / 11	7 / 11	3 / 10	2 / 11

Outcome results

Primary

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

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.