Back to resultsMM-398 (Nanoliposomal Irinotecan, Nal-IRI) to Determine Tumor Drug Levels and to Evaluate the Feasibility of Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated Macrophages and to Predict Patient Response to Treatment
Primary Purpose
Solid Tumors, ER/PR Positive Breast Cancer, Triple Negative Breast Cancer
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ferumoxytol
MM-398
Sponsored by
About this trial
This is an interventional other trial for Solid Tumors focused on measuring solid tumors, Triple Negative Breast Cancer, Colorectal Cancer, MM-398, nanoliposomal irinotecan, Ferumoxytol, ER/PR positive Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer, Gastro-Esophageal Junction Adenocarcinoma, Head and Neck Cancer, TNBC
Eligibility Criteria
Inclusion Criteria:
All subjects:
- Pathologically confirmed diagnosis of solid tumors
- Metastatic disease
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
- Adequate bone marrow, hepatic and renal function
- Normal Electrocardiogram (ECG)
- 18 years of age or above
- Able to understand and sign informed consent
Pilot study only:
- CRC, TNBC, ER/PR Breast Cancer, NSCLC, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer, Gastroesophageal Junction (GEJ) adenocarcinoma, Head and Neck Cancer
Expansion Phase Additional Criteria:
- Locally advanced or metastatic breast cancer
- Received at least one cytotoxic therapy in the locally advanced and metastatic setting
- Received ≤ 5 prior lines of chemotherapy in the metastatic setting
- Candidate for chemotherapy
Expansion Phase Cohort 3 additional inclusion criteria:
- Breast cancer with active brain metastasis
- Neurologically stable
Exclusion Criteria:
- Active Central nervous system (CNS) metastasis (applies to pilot phase and expansion phase cohort 1 and 2 only)
- Clinically significant GI disorders
- Prior irinotecan or bevacizumab therapy within last 6 months and for Expansion Phase patients, have received any prior treatment with Topol inhibitor
- Known hypersensitivity to MM-398 or ferumoxytol
- Inability to undergo MRI
- Active infection
- Pregnant or breast feeding
- Prior chemotherapy administered within 3 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to the first scheduled day of dosing in this study
- Received radiation therapy in the last 14 days
- Treated with parenteral iron in the previous 4 weeks
Sites / Locations
- Mayo Clinic
- HonorHealth
- UCSF Helen Diller Family Comprehensive Cancer Center
- Moffitt Cancer Center
- University of Michighan Comprehensive Cancer Center
- Washington University
- UNC- Lineberger Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Pilot Phase: Ferumoxytol followed by MM-398
Expansion Phase: Ferumoxytol followed by MM-398
Arm Description
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min on Days 1 and 15 of every 4 week cycle
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min dose 1 on Days 1 and 15 of every 4 week cycle Cohort 1: ER and/or PR-positive BC Cohort 2: TNBC Cohort 3: BC with active brain metastasis
Outcomes
Primary Outcome Measures
Pilot Phase: Tumour Levels of Irinotecan and SN-38 at Cycle 1 Day 4
Two tumour biopsies were collected 72 hours after the first MM-398 IV infusion during Cycle 1 of the MM-398 Treatment phase of the Pilot phase for determination of tumour levels of irinotecan and SN-38 (an active metabolite). The lesions selected for biopsy were based on the results of the FMX-MRI obtained on Days 1, 2 and 4 of the FMX phase, and were collected from a previously non-biopsied lesion. The first core biopsy was taken in the region of the tumour that showed the greatest signal change on either the T2 or T1 sequences, based on FMX-MRI. The second core biopsy was taken from the region that showed the least signal change based on FMX-MRI, avoiding areas of necrosis.
Expansion Phase: Impact of the Quality of MRI Scan on Tumour Evaluation
Feasibility of FMX quantitation in tumour lesion was assessed through the acquisition of baseline (pre-FMX dose) and follow-up (post FMX dose) scans of sufficient quality to enable quantitative analysis to be performed. Quality was assessed by summarising scans as adequate for tumour evaluation or suboptimal but for which evaluation was completed for evaluation. Two FMX-MRI scans were taken on Day 1 (pre-FMX dosing) and on Day 2 (16-24 hours post dose) of the FMX phase. One MRI scan was also taken at 1-4 hours post FMX dose (Day 1 of FMX phase) and at 2 weeks post FMX dose (Day 15 of the MM-398 phase). It was possible for a subject to have 2 FMX-MRI scans for the same visit and timepoint corresponding to a scan target location. The number of MRI scan results that were assessed to be adequate or suboptimal at each timepoint are presented.
Expansion Phase: Best Overall Tumour Response (BOR) by Tumour FMX Uptake Classification at 16 - 24 Hours Post-FMX Dose
FMX tumour uptake was classified as 'low tumour uptake' or 'high tumour uptake', and was determined for 16 to 24-hours post-FMX dosing. The FMX uptake in a subject's lesions was classified using the median of the baseline-corrected FMX values at that timepoint across all subjects. The best radiological overall tumour response to MM-398 from the beginning to the end of the study was assessed using both the Investigator and imaging results per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Non-central nervous system [CNS] assessments; Cohorts 1, 2 and 3). Tumour response was classified as a Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). BOR is presented by tumour uptake classification at 16-24 hours post-FMX dose by cohort for the non-CNS RECIST assessment.
Secondary Outcome Measures
Pilot Phase + Expansion Phase: Median Progression-free Survival (PFS) (Non-CNS Assessment)
PFS was defined as the time in months from first dose of MM-398 to the date of radiologic disease progression by RECIST per Investigator assessment or death due to any cause, whichever occurred first.
The date of progression is defined as the earliest date that an overall tumour response of PD or death was recorded. For subjects who did not have a qualifying progressive disease or death, the date of censoring for PFS was the date when the last valid tumour assessment determined a lack of progression. The PFS assessed by the Investigator was analysed using the Kaplan-Meier method, and the median PFS based on non-CNS assessment is presented.
Expansion Phase: Median PFS for Cohort 3 (CNS Assessment)
PFS was defined as the time in months from first dose of MM-398 to the date of radiologic disease progression by modified RECIST (mRECIST) criteria (CNS disease; Cohort 3) per Investigator assessment or death due to any cause, whichever occurred first.
The date of progression is defined as the earliest date that an overall tumour response of PD or death was recorded. For subjects who did not have a qualifying progressive disease or death, the date of censoring for PFS was the date when the last valid tumour assessment determined a lack of progression. The PFS assessed by the Investigator was analysed using the Kaplan-Meier method, and the median PFS based on CNS mRECIST assessment is provided for Cohort 3.
Pilot Phase + Expansion Phase: BOR (Non-CNS Assessment)
BOR was defined as the best response by RECIST version 1.1 (Non-CNS assessments) criteria per Investigator assessment, recorded from the first dose of MM-398 until disease progression or the start of new anti-cancer therapy and/or surgery.
Tumour response was classified as CR, PR, SD or PD. Classification of SD required at least 1 assessment of SD at least 4 weeks after starting treatment. Subjects were categorised as not evaluable if there was insufficient data for response classification. The BOR is presented for non-CNS assessments for the Pilot phase and Cohorts 1 - 3.
Expansion Phase: BOR for Cohort 3 (CNS Assessment)
BOR was defined as the best response by mRECIST criteria (CNS disease; Cohort 3) criteria per Investigator assessment, recorded from the first dose of MM-398 until disease progression or the start of new anti-cancer therapy and/or surgery.
Tumour response was classified as CR, PR, SD or PD. Classification of SD required at least 1 assessment of SD at least 4 weeks after starting treatment. Subjects were categorised as not evaluable if there was insufficient data for response classification. The BOR is presented for CNS assessments for Cohort 3.
Pilot Phase + Expansion Phase: Objective Response Rate (ORR) (Non-CNS Assessment)
The ORR was defined as the percentage of subjects with a BOR of either a CR or PR relative to the total number of evaluable subjects. Subjects with insufficient data for response classification were classified as non-responders for objective response. The ORR is presented for non-CNS assessments for the Pilot phase and Cohorts 1 - 3.
Expansion Phase: ORR for Cohort 3 (CNS Assessment)
The ORR was defined as the percentage of subjects with a BOR of either a CR or PR relative to the total number of evaluable subjects. Subjects with insufficient data for response classification were classified as non-responders for objective response. The ORR is presented for CNS assessments for Cohort 3.
Pilot Phase + Expansion Phase: Median Duration of Objective Response (DOR) (Non-CNS Assessment)
DOR was defined as the time from first documentation of response (CR or PR whichever occurred first, based on Investigator assessment using RECIST criteria) to the date of disease progression or to death due to any cause, whichever occurred first. DOR was computed for subjects who had CR or PR as the BOR. For subjects who did not have a qualifying progressive disease or death, the date of censoring was the date when the last valid tumour assessment determined a lack of progression. The median DOR is presented for non-CNS assessments for the Pilot phase and Cohorts 1-3.
Expansion Phase: Median DOR for Cohort 3 (CNS Assessment)
DOR was defined as the time from first documentation of response (CR or PR whichever occurred first, based on Investigator assessment using mRECIST criteria) to the date of disease progression or to death due to any cause, whichever occurred first. DOR was computed for subjects who had CR or PR as the BOR. For subjects who did not have a qualifying progressive disease or death, the date of censoring was the date when the last valid tumour assessment determined a lack of progression. The median DOR is presented for CNS assessments for Cohort 3.
Pilot Phase + Expansion Phase: Clinical Benefit Response (CBR) (Non-CNS Assessment)
CBR was defined as the percentage of subjects with a BOR characterised as a CR at any time, PR at any time, or SD ≥ 24 weeks relative to the total number of evaluable subjects. The CBR is presented for non-CNS assessments.
Expansion Phase: CBR for Cohort 3 (CNS Assessment)
CBR was defined as the percentage of subjects with a BOR characterised as a CR at any time, PR at any time, or SD ≥ 24 weeks relative to the total number of evaluable subjects. The CBR is presented for CNS assessment for Cohort 3.
Pilot Phase + Expansion Phase: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) Related to MM-398
The number of subjects who experienced a TEAE reported to be related to MM-398 by the Investigator are presented for the Pilot and Expansion phases. An AE was considered treatment emergent if it began on or after the first administration of MM-398, started prior to dosing with MM-398 and increased in severity or seriousness after dosing, or started prior to dosing of MM-398 but the causality changed to 'related' after dosing.
Pilot Phase: Time to Reach Maximum Plasma Concentration of Irinotecan and SN-38 (Tmax)
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) and SN-38 (metabolite) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 salt-base equivalent [SBE]). The pharmacokinetic (PK) analysis was based on non-compartmental analysis. Any plasma concentrations below the lower limit of quantification (LLOQ) were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 micrograms per millilitre (mcg/mL), and for SN-38 the LLOQ for the Pilot phase was 0.441 nanograms per millilitre (ng/mL). The median tmax is presented for the Pilot phase.
Expansion Phase: Irinotecan and SN-38 Tmax
For the Expansion phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) and SN-38 (metabolite) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL and for SN-38 the LLOQ for the Expansion phase was 0.600 ng/mL. The median tmax is presented for dose levels in the Expansion phase for which data was collected. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Pilot Phase: Maximum Observed Plasma Concentration of Irinotecan (Cmax)
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean Cmax is presented for the Pilot phase.
Pilot Phase: SN-38 Cmax
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Pilot phase was 0.441 ng/mL. The mean Cmax is presented for the Pilot phase.
Expansion Phase: Irinotecan Cmax
For the Expansion phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean Cmax is presented for the Expansion phase. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Expansion Phase: SN-38 Cmax
For the Expansion phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Expansion phase was 0.600 ng/mL. The mean Cmax is presented for dose levels in the Expansion phase for which data was collected. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Pilot Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) for Irinotecan
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean AUC(0-tlast) is presented for the Pilot phase.
Pilot Phase: SN-38 AUC(0-tlast)
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Pilot phase was 0.441 ng/mL. The mean AUC(0-tlast) is presented for the Pilot phase.
Expansion Phase: Irinotecan AUC(0-tlast)
For the Expansion phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean AUC(0-tlast) is presented for the Expansion phase. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Expansion Phase: SN-38 AUC(0-tlast)
For the Expansion phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Expansion phase was 0.600 ng/mL. The mean AUC(0-tlast) is presented for dose levels in the Expansion phase for which data was collected. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01770353
Brief Title
MM-398 (Nanoliposomal Irinotecan, Nal-IRI) to Determine Tumor Drug Levels and to Evaluate the Feasibility of Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated Macrophages and to Predict Patient Response to Treatment
Official Title
A Phase I Study in Patients Treated With MM-398 (Nanoliposomal Irinotecan, Nal-IRI) to Determine Tumor Drug Levels and to Evaluate the Feasibility of Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated Macrophages and to Predict Patient Response to Treatment
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
November 2012 (undefined)
Primary Completion Date
October 2, 2018 (Actual)
Study Completion Date
October 2, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ipsen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a Phase I study to understand the biodistribution of MM-398 and to determine the feasibility of using Ferumoxytol as a tumor imaging agent.
Detailed Description
This study is conducted over two phases.
Pilot Phase: This study will enroll approximately 12 patients, up to 20 in total in the Pilot Phase and 30 patients in the Expansion Phase. The first three patients that are enrolled in the Pilot Phase can have any solid tumor type; however subsequent patients must have Non-small cell lung cancer (NSCLC), Colorectal cancer (CRC), Triple negative breast cancer (TNBC), Estrogen Receptor/Progesterone Receptor (ER/PR) positive breast cancer, pancreatic cancer, ovarian cancer, gastric cancer, gastro-oesophageal junction adenocarcinoma or head and neck cancer. No more than three patients with ER/PR positive breast cancer can be enrolled in the Pilot Phase and similar restrictions may be placed on other tumor types to ensure a heterogeneous population.
Expansion Phase: The expansion will enroll patients with advanced metastatic breast cancer into three cohorts of 10 patients each depending on sub-type of breast cancer:
Cohort 1: ER and/or PR-positive breast cancer Cohort 2: TNBC Cohort 3: BC with active brain metastasis
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumors, ER/PR Positive Breast Cancer, Triple Negative Breast Cancer, Metastatic Breast Cancer With Active Brain Metastasis
Keywords
solid tumors, Triple Negative Breast Cancer, Colorectal Cancer, MM-398, nanoliposomal irinotecan, Ferumoxytol, ER/PR positive Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer, Gastro-Esophageal Junction Adenocarcinoma, Head and Neck Cancer, TNBC
7. Study Design
Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pilot Phase: Ferumoxytol followed by MM-398
Arm Type
Experimental
Arm Description
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min on Days 1 and 15 of every 4 week cycle
Arm Title
Expansion Phase: Ferumoxytol followed by MM-398
Arm Type
Experimental
Arm Description
Ferumoxytol 5 mg/kg IV at the rate of 1 mL/sec, given once on Day 1. MM-398 IV over 90 min dose 1 on Days 1 and 15 of every 4 week cycle Cohort 1: ER and/or PR-positive BC Cohort 2: TNBC Cohort 3: BC with active brain metastasis
Intervention Type
Drug
Intervention Name(s)
Ferumoxytol
Intervention Description
Ferumoxytol 5 mg/kg IV as a single bolus injection, given once.
Intervention Type
Drug
Intervention Name(s)
MM-398
Intervention Description
MM-398 IV over 90 min every 2 weeks, until progressive disease or intolerable toxicity
Primary Outcome Measure Information:
Title
Pilot Phase: Tumour Levels of Irinotecan and SN-38 at Cycle 1 Day 4
Description
Two tumour biopsies were collected 72 hours after the first MM-398 IV infusion during Cycle 1 of the MM-398 Treatment phase of the Pilot phase for determination of tumour levels of irinotecan and SN-38 (an active metabolite). The lesions selected for biopsy were based on the results of the FMX-MRI obtained on Days 1, 2 and 4 of the FMX phase, and were collected from a previously non-biopsied lesion. The first core biopsy was taken in the region of the tumour that showed the greatest signal change on either the T2 or T1 sequences, based on FMX-MRI. The second core biopsy was taken from the region that showed the least signal change based on FMX-MRI, avoiding areas of necrosis.
Time Frame
At Cycle 1 Day 4 in the Pilot phase.
Title
Expansion Phase: Impact of the Quality of MRI Scan on Tumour Evaluation
Description
Feasibility of FMX quantitation in tumour lesion was assessed through the acquisition of baseline (pre-FMX dose) and follow-up (post FMX dose) scans of sufficient quality to enable quantitative analysis to be performed. Quality was assessed by summarising scans as adequate for tumour evaluation or suboptimal but for which evaluation was completed for evaluation. Two FMX-MRI scans were taken on Day 1 (pre-FMX dosing) and on Day 2 (16-24 hours post dose) of the FMX phase. One MRI scan was also taken at 1-4 hours post FMX dose (Day 1 of FMX phase) and at 2 weeks post FMX dose (Day 15 of the MM-398 phase). It was possible for a subject to have 2 FMX-MRI scans for the same visit and timepoint corresponding to a scan target location. The number of MRI scan results that were assessed to be adequate or suboptimal at each timepoint are presented.
Time Frame
Expansion phase Cycle 1: Pre FMX dose, 1-4 hours post FMX dose, 16-24 hours post FMX dose, 2 weeks Post FMX dose.
Title
Expansion Phase: Best Overall Tumour Response (BOR) by Tumour FMX Uptake Classification at 16 - 24 Hours Post-FMX Dose
Description
FMX tumour uptake was classified as 'low tumour uptake' or 'high tumour uptake', and was determined for 16 to 24-hours post-FMX dosing. The FMX uptake in a subject's lesions was classified using the median of the baseline-corrected FMX values at that timepoint across all subjects. The best radiological overall tumour response to MM-398 from the beginning to the end of the study was assessed using both the Investigator and imaging results per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (Non-central nervous system [CNS] assessments; Cohorts 1, 2 and 3). Tumour response was classified as a Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). BOR is presented by tumour uptake classification at 16-24 hours post-FMX dose by cohort for the non-CNS RECIST assessment.
Time Frame
Expansion phase: C1D2 FMX phase, and every 8 weeks for RECIST assessments from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Secondary Outcome Measure Information:
Title
Pilot Phase + Expansion Phase: Median Progression-free Survival (PFS) (Non-CNS Assessment)
Description
PFS was defined as the time in months from first dose of MM-398 to the date of radiologic disease progression by RECIST per Investigator assessment or death due to any cause, whichever occurred first.
The date of progression is defined as the earliest date that an overall tumour response of PD or death was recorded. For subjects who did not have a qualifying progressive disease or death, the date of censoring for PFS was the date when the last valid tumour assessment determined a lack of progression. The PFS assessed by the Investigator was analysed using the Kaplan-Meier method, and the median PFS based on non-CNS assessment is presented.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Expansion Phase: Median PFS for Cohort 3 (CNS Assessment)
Description
PFS was defined as the time in months from first dose of MM-398 to the date of radiologic disease progression by modified RECIST (mRECIST) criteria (CNS disease; Cohort 3) per Investigator assessment or death due to any cause, whichever occurred first.
The date of progression is defined as the earliest date that an overall tumour response of PD or death was recorded. For subjects who did not have a qualifying progressive disease or death, the date of censoring for PFS was the date when the last valid tumour assessment determined a lack of progression. The PFS assessed by the Investigator was analysed using the Kaplan-Meier method, and the median PFS based on CNS mRECIST assessment is provided for Cohort 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Pilot Phase + Expansion Phase: BOR (Non-CNS Assessment)
Description
BOR was defined as the best response by RECIST version 1.1 (Non-CNS assessments) criteria per Investigator assessment, recorded from the first dose of MM-398 until disease progression or the start of new anti-cancer therapy and/or surgery.
Tumour response was classified as CR, PR, SD or PD. Classification of SD required at least 1 assessment of SD at least 4 weeks after starting treatment. Subjects were categorised as not evaluable if there was insufficient data for response classification. The BOR is presented for non-CNS assessments for the Pilot phase and Cohorts 1 - 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Expansion Phase: BOR for Cohort 3 (CNS Assessment)
Description
BOR was defined as the best response by mRECIST criteria (CNS disease; Cohort 3) criteria per Investigator assessment, recorded from the first dose of MM-398 until disease progression or the start of new anti-cancer therapy and/or surgery.
Tumour response was classified as CR, PR, SD or PD. Classification of SD required at least 1 assessment of SD at least 4 weeks after starting treatment. Subjects were categorised as not evaluable if there was insufficient data for response classification. The BOR is presented for CNS assessments for Cohort 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Pilot Phase + Expansion Phase: Objective Response Rate (ORR) (Non-CNS Assessment)
Description
The ORR was defined as the percentage of subjects with a BOR of either a CR or PR relative to the total number of evaluable subjects. Subjects with insufficient data for response classification were classified as non-responders for objective response. The ORR is presented for non-CNS assessments for the Pilot phase and Cohorts 1 - 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Expansion Phase: ORR for Cohort 3 (CNS Assessment)
Description
The ORR was defined as the percentage of subjects with a BOR of either a CR or PR relative to the total number of evaluable subjects. Subjects with insufficient data for response classification were classified as non-responders for objective response. The ORR is presented for CNS assessments for Cohort 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Pilot Phase + Expansion Phase: Median Duration of Objective Response (DOR) (Non-CNS Assessment)
Description
DOR was defined as the time from first documentation of response (CR or PR whichever occurred first, based on Investigator assessment using RECIST criteria) to the date of disease progression or to death due to any cause, whichever occurred first. DOR was computed for subjects who had CR or PR as the BOR. For subjects who did not have a qualifying progressive disease or death, the date of censoring was the date when the last valid tumour assessment determined a lack of progression. The median DOR is presented for non-CNS assessments for the Pilot phase and Cohorts 1-3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Expansion Phase: Median DOR for Cohort 3 (CNS Assessment)
Description
DOR was defined as the time from first documentation of response (CR or PR whichever occurred first, based on Investigator assessment using mRECIST criteria) to the date of disease progression or to death due to any cause, whichever occurred first. DOR was computed for subjects who had CR or PR as the BOR. For subjects who did not have a qualifying progressive disease or death, the date of censoring was the date when the last valid tumour assessment determined a lack of progression. The median DOR is presented for CNS assessments for Cohort 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Pilot Phase + Expansion Phase: Clinical Benefit Response (CBR) (Non-CNS Assessment)
Description
CBR was defined as the percentage of subjects with a BOR characterised as a CR at any time, PR at any time, or SD ≥ 24 weeks relative to the total number of evaluable subjects. The CBR is presented for non-CNS assessments.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Expansion Phase: CBR for Cohort 3 (CNS Assessment)
Description
CBR was defined as the percentage of subjects with a BOR characterised as a CR at any time, PR at any time, or SD ≥ 24 weeks relative to the total number of evaluable subjects. The CBR is presented for CNS assessment for Cohort 3.
Time Frame
Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.
Title
Pilot Phase + Expansion Phase: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) Related to MM-398
Description
The number of subjects who experienced a TEAE reported to be related to MM-398 by the Investigator are presented for the Pilot and Expansion phases. An AE was considered treatment emergent if it began on or after the first administration of MM-398, started prior to dosing with MM-398 and increased in severity or seriousness after dosing, or started prior to dosing of MM-398 but the causality changed to 'related' after dosing.
Time Frame
From MM-398 treatment start up to 30 days after last dose.
Title
Pilot Phase: Time to Reach Maximum Plasma Concentration of Irinotecan and SN-38 (Tmax)
Description
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) and SN-38 (metabolite) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 salt-base equivalent [SBE]). The pharmacokinetic (PK) analysis was based on non-compartmental analysis. Any plasma concentrations below the lower limit of quantification (LLOQ) were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 micrograms per millilitre (mcg/mL), and for SN-38 the LLOQ for the Pilot phase was 0.441 nanograms per millilitre (ng/mL). The median tmax is presented for the Pilot phase.
Time Frame
Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.
Title
Expansion Phase: Irinotecan and SN-38 Tmax
Description
For the Expansion phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) and SN-38 (metabolite) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL and for SN-38 the LLOQ for the Expansion phase was 0.600 ng/mL. The median tmax is presented for dose levels in the Expansion phase for which data was collected. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Time Frame
Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.
Title
Pilot Phase: Maximum Observed Plasma Concentration of Irinotecan (Cmax)
Description
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean Cmax is presented for the Pilot phase.
Time Frame
Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.
Title
Pilot Phase: SN-38 Cmax
Description
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Pilot phase was 0.441 ng/mL. The mean Cmax is presented for the Pilot phase.
Time Frame
Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.
Title
Expansion Phase: Irinotecan Cmax
Description
For the Expansion phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean Cmax is presented for the Expansion phase. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Time Frame
Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.
Title
Expansion Phase: SN-38 Cmax
Description
For the Expansion phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Expansion phase was 0.600 ng/mL. The mean Cmax is presented for dose levels in the Expansion phase for which data was collected. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Time Frame
Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.
Title
Pilot Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) for Irinotecan
Description
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean AUC(0-tlast) is presented for the Pilot phase.
Time Frame
Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.
Title
Pilot Phase: SN-38 AUC(0-tlast)
Description
In Cycle 1 only of the Pilot phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma following a dose of 70 mg/m^2 MM-398 FBE (80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Pilot phase was 0.441 ng/mL. The mean AUC(0-tlast) is presented for the Pilot phase.
Time Frame
Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.
Title
Expansion Phase: Irinotecan AUC(0-tlast)
Description
For the Expansion phase, samples were collected to determine the levels of total irinotecan (liposomal and free drug) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for irinotecan was 0.140 mcg/mL. The mean AUC(0-tlast) is presented for the Expansion phase. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Time Frame
Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.
Title
Expansion Phase: SN-38 AUC(0-tlast)
Description
For the Expansion phase, samples were collected to determine the levels of SN-38 (metabolite) in plasma and data is presented for Cycles 1 to 3 by dose received for each cycle (depending on dose titration): 35 to 70 mg/m^2 MM-398 FBE (40 to 80 mg/m^2 MM-398 SBE). The PK analysis was based on non-compartmental analysis. Any plasma concentrations below the LLOQ were assigned as missing/zero in the data set according to predetermined rules. The LLOQ for SN-38 for the Expansion phase was 0.600 ng/mL. The mean AUC(0-tlast) is presented for dose levels in the Expansion phase for which data was collected. PK results for subjects in all cohorts of the Expansion Phase were combined for those on the same cycle and at the same dose. The total number of subjects evaluated in the PK set for the Expansion Phase was 21, with different numbers evaluated for each cycle/dose.
Time Frame
Expansion phase: Cycles 1-3 pre-MM-398 infusion, end of infusion, post-infusion (2, 48,168 hours); D15 pre-infusion; 30 days follow-up visit.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
All subjects:
Pathologically confirmed diagnosis of solid tumors
Metastatic disease
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
Adequate bone marrow, hepatic and renal function
Normal Electrocardiogram (ECG)
18 years of age or above
Able to understand and sign informed consent
Pilot study only:
- CRC, TNBC, ER/PR Breast Cancer, NSCLC, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer, Gastroesophageal Junction (GEJ) adenocarcinoma, Head and Neck Cancer
Expansion Phase Additional Criteria:
Locally advanced or metastatic breast cancer
Received at least one cytotoxic therapy in the locally advanced and metastatic setting
Received ≤ 5 prior lines of chemotherapy in the metastatic setting
Candidate for chemotherapy
Expansion Phase Cohort 3 additional inclusion criteria:
Breast cancer with active brain metastasis
Neurologically stable
Exclusion Criteria:
Active Central nervous system (CNS) metastasis (applies to pilot phase and expansion phase cohort 1 and 2 only)
Clinically significant GI disorders
Prior irinotecan or bevacizumab therapy within last 6 months and for Expansion Phase patients, have received any prior treatment with Topol inhibitor
Known hypersensitivity to MM-398 or ferumoxytol
Inability to undergo MRI
Active infection
Pregnant or breast feeding
Prior chemotherapy administered within 3 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to the first scheduled day of dosing in this study
Received radiation therapy in the last 14 days
Treated with parenteral iron in the previous 4 weeks
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ipsen Medical Director
Organizational Affiliation
Ipsen
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85159-5499
Country
United States
Facility Name
HonorHealth
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Facility Name
UCSF Helen Diller Family Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33607
Country
United States
Facility Name
University of Michighan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
UNC- Lineberger Comprehensive Cancer Center
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
33201358
Citation
Sachdev JC, Munster P, Northfelt DW, Han HS, Ma C, Maxwell F, Wang T, Belanger B, Zhang B, Moore Y, Thiagalingam A, Anders C. Phase I study of liposomal irinotecan in patients with metastatic breast cancer: findings from the expansion phase. Breast Cancer Res Treat. 2021 Feb;185(3):759-771. doi: 10.1007/s10549-020-05995-7. Epub 2020 Nov 17.
Results Reference
derived
Learn more about this trial
MM-398 (Nanoliposomal Irinotecan, Nal-IRI) to Determine Tumor Drug Levels and to Evaluate the Feasibility of Ferumoxytol Magnetic Resonance Imaging to Measure Tumor Associated Macrophages and to Predict Patient Response to Treatment
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