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

Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01447225
• Other study ID #: MM-121-06-01-06 (TCD11694)
• Status: Completed
• Phase: Phase 1
• First received: October 3, 2011
• Last updated: September 13, 2016
• Start date: October 2011
• Est. completion date: January 2014

Study information

• Verified date: September 2016
• Source: Merrimack Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: January 2014
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Solid Tumors

Intervention

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
• Carboplatin
administered at AUC 6
• Pemetrexed
administered IV at 500 mg/m2
• Cabazitaxel
administered IV at 20 mg/m2 or 25 mg/m2
• Gemcitabine
administered IV at 1000 mg/m2 or 1250 mg/m2

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Merrimack Pharmaceuticals	Sanofi

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To Evaluate the Safety and Tolerability of Escalating Doses of the MM-121 Anticancer Therapies	Safety and tolerability data presented in detail in the adverse events and serious adverse events section of the results posting	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
Primary	To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: MM-121 Doses	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
Primary	To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Gemcitabine	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
Primary	To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Carboplatin	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
Primary	To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Pemetrexed	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
Primary	To Determine the Maximum Tolerated Dose (MTD) of MM-121 in Combination With Anticancer Therapies: Cabazitaxel	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	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
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.	From date of first dose to 30 days after termination, the longest 88.1 weeks	Yes
Secondary	Objective Response Rate	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.	patients were assessed for response during their time on study, the longest of which was 88.1 weeks	No
Secondary	Pharmacokinetics	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).	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	No
Secondary	Pharmacokinetics (AUClast)	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).	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	No
Secondary	Immunogenicity	Samples were collected to determine the presence of an immunologic reaction to MM-121 (i.e. human anti-human antibodies).	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	No