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

• Sponsor: Ipsen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01770353
• Collaborator: (none)
• Enrollment: 45
• Locations: 7
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors; ER/PR Positive Breast Cancer; Triple Negative Breast Cancer; Metastatic Breast Cancer With Active Brain Metastasis	Drug: Ferumoxytol; Drug: MM-398	Phase 1

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• 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 Start Date: Nov 1, 2012
• Actual Primary Completion Date: Oct 2, 2018
• Actual Study Completion Date: Oct 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pilot Phase: Ferumoxytol followed by MM-398 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	Drug: Ferumoxytol; Ferumoxytol 5 mg/kg IV as a single bolus injection, given once.; Drug: MM-398; MM-398 IV over 90 min every 2 weeks, until progressive disease or intolerable toxicity
Experimental: Expansion Phase: Ferumoxytol followed by MM-398 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	Drug: Ferumoxytol; Ferumoxytol 5 mg/kg IV as a single bolus injection, given once.; Drug: MM-398; MM-398 IV over 90 min every 2 weeks, until progressive disease or intolerable toxicity

Outcome Measures

Primary Outcome Measures

1. Pilot Phase: Tumour Levels of Irinotecan and SN-38 at Cycle 1 Day 4 [At Cycle 1 Day 4 in the Pilot phase.]

   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.

2. Expansion Phase: Impact of the Quality of MRI Scan on Tumour Evaluation [Expansion phase Cycle 1: Pre FMX dose, 1-4 hours post FMX dose, 16-24 hours post FMX dose, 2 weeks Post FMX dose.]

   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.

3. Expansion Phase: Best Overall Tumour Response (BOR) by Tumour FMX Uptake Classification at 16 - 24 Hours Post-FMX Dose [Expansion phase: C1D2 FMX phase, and every 8 weeks for RECIST assessments from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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

1. Pilot Phase + Expansion Phase: Median Progression-free Survival (PFS) (Non-CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

2. Expansion Phase: Median PFS for Cohort 3 (CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

3. Pilot Phase + Expansion Phase: BOR (Non-CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

4. Expansion Phase: BOR for Cohort 3 (CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

5. Pilot Phase + Expansion Phase: Objective Response Rate (ORR) (Non-CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

6. Expansion Phase: ORR for Cohort 3 (CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

7. Pilot Phase + Expansion Phase: Median Duration of Objective Response (DOR) (Non-CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

8. Expansion Phase: Median DOR for Cohort 3 (CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

9. Pilot Phase + Expansion Phase: Clinical Benefit Response (CBR) (Non-CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

   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.

10. Expansion Phase: CBR for Cohort 3 (CNS Assessment) [Baseline and every 8 weeks from C1D1 until disease progression, unacceptable toxicity or withdrawal of consent.]

    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.

11. Pilot Phase + Expansion Phase: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) Related to MM-398 [From MM-398 treatment start up to 30 days after last dose.]

    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.

12. Pilot Phase: Time to Reach Maximum Plasma Concentration of Irinotecan and SN-38 (Tmax) [Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.]

    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.

13. Expansion Phase: Irinotecan and SN-38 Tmax [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.]

    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.

14. Pilot Phase: Maximum Observed Plasma Concentration of Irinotecan (Cmax) [Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.]

    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.

15. Pilot Phase: SN-38 Cmax [Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.]

    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.

16. Expansion Phase: Irinotecan Cmax [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.]

    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.

17. Expansion Phase: SN-38 Cmax [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.]

    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.

18. Pilot Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) for Irinotecan [Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.]

    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.

19. Pilot Phase: SN-38 AUC(0-tlast) [Pilot phase: C1D1 pre-MM-398 infusion, end of infusion, post-infusion (2, 72, 168 hours); C1D15 pre-infusion; 30 days follow-up visit.]

    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.

20. Expansion Phase: Irinotecan AUC(0-tlast) [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.]

    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.

21. Expansion Phase: SN-38 AUC(0-tlast) [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.]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85159-5499
2	HonorHealth	Scottsdale	Arizona	United States	85258
3	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
4	Moffitt Cancer Center	Tampa	Florida	United States	33607
5	University of Michighan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
6	Washington University	Saint Louis	Missouri	United States	63110
7	UNC- Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• Ipsen

Investigators

• Study Director: Ipsen Medical Director, Ipsen

Study Documents (Full-Text)

• Statistical Analysis Plan - Feb 28, 2019
• Study Protocol - Apr 3, 2017

More Information

Publications

None provided.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT01770353
• Other Study ID Numbers: MM-398-01-01-02
• First Posted: Jan 17, 2013
• Last Update Posted: Nov 27, 2019
• Last Verified: Nov 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Ipsen: 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
• Additional relevant MeSH terms: Breast Neoplasms; Brain Neoplasms; Triple Negative Breast Neoplasms; Ferrosoferric Oxide

Study Results

Participant Flow

Recruitment Details	Six study centres in the United States recruited subjects into this Phase 1, 2-phase, non-comparative, open-label study. Each phase consisted of 4 stages: screening, ferumoxytol (FMX) treatment, irinotecan liposome injection (MM-398) treatment and follow-up (30 days after last dose).
Pre-assignment Detail	Subjects with solid tumours were recruited to the Pilot phase. Subjects with locally advanced or metastatic breast cancer (BC) were recruited to the Expansion phase which consisted of 3 cohorts dependent on BC tumour sub-types and the presence of active brain metastases. Data was combined into 1 arm for the Expansion Phase as all subjects had BC.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus intravenous (IV) injection of 5 milligrams per kilogram (mg/kg) FMX (up to 510 mg) on Day 1. Subjects underwent FMX magnetic resonance imaging (MRI) scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 milligrams per square metre (mg/m^2) MM-398 free base equivalent (FBE) (Cycle 1 Day 1 [C1D1]) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: Oestrogen receptor (ER) and/or progesterone receptor (PR)-positive BC and human epidermal growth factor receptor 2 (HER-2) negative BC. Cohort 2: Triple negative BC (TNBC). Cohort 3: BC with active brain metastasis.
Period Title: Overall Study
STARTED	15	30
Received FMX	15	30
Received FMX and MM-398	13	29
COMPLETED	9	18
NOT COMPLETED	6	12

Baseline Characteristics

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: FMX Then MM-398	Total
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.	Total of all reporting groups
Overall Participants	15	30	45
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 60%	25 83.3%	34 75.6%
>=65 years	6 40%	5 16.7%	11 24.4%
Sex: Female, Male (Count of Participants)
Female	11 73.3%	30 100%	41 91.1%
Male	4 26.7%	0 0%	4 8.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.7%	2 6.7%	3 6.7%
Not Hispanic or Latino	13 86.7%	27 90%	40 88.9%
Unknown or Not Reported	1 6.7%	1 3.3%	2 4.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 6.7%	0 0%	1 2.2%
Asian	0 0%	2 6.7%	2 4.4%
Native Hawaiian or Other Pacific Islander	0 0%	1 3.3%	1 2.2%
Black or African American	0 0%	2 6.7%	2 4.4%
White	14 93.3%	23 76.7%	37 82.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 6.7%	2 4.4%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398.

Arm/Group Title	Pilot Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13
Irinotecan	4253 (3600)
SN-38	38.1 (91.5)

2. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

The pharmacodynamic evaluable population included all subjects who received at least 1 dose of MM-398 and who had pre-treatment FMX-MRI scan(s) and radiological scans at 8 weeks.

Arm/Group Title	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	7	5	6
Measure Scans	7	5	11
Pre-FMX Dose (1): adequate	4	3	7
Pre-FMX Dose (1): suboptimal	3	2	4
Pre-FMX Dose (2): adequate	0	1
Pre-FMX Dose (2): suboptimal	1	1
1-4 hours Post FMX: adequate	4	1	5
1-4 hours Post FMX: suboptimal	2	1	2
16-24 hours Post FMX (1): adequate	4	3	6
16-24 hours Post FMX (1): suboptimal	3	2	4
16-24 hours Post FMX (2): adequate	0
16-24 hours Post FMX (2): suboptimal	1
Post FMX Day 15: adequate	0	2
Post FMX Day 15: suboptimal	1	1

3. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

The pharmacodynamic evaluable population included all subjects who received at least 1 dose of MM-398 and who had pre-treatment FMX-MRI scan(s) and radiological scans at 8 weeks.

Arm/Group Title	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	7	5	6
High tumour uptake and CR	1 6.7%	0 0%	0 0%
High tumour uptake and PR	1 6.7%	3 10%	0 0%
High tumour uptake and SD	0 0%	2 6.7%	0 0%
High tumour uptake and Non-CR/Non-PD	0 0%	0 0%	0 0%
High tumour uptake and PD	2 13.3%	0 0%	0 0%
Low tumour uptake and CR	1 6.7%	0 0%	1 2.2%
Low tumour uptake and PR	1 6.7%	0 0%	2 4.4%
Low tumour uptake and SD	1 6.7%	0 0%	2 4.4%
Low tumour uptake and Non-CR/Non-PD	0 0%	0 0%	0 0%
Low tumour uptake and PD	0 0%	0 0%	1 2.2%

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population consists of all subjects who received at least 1 dose of MM-398.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13	10	9	10
Median (95% Confidence Interval) [months]	1.8	1.9	4.3	3.2

5. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population consists of all subjects who received at least 1 dose of MM-398. Data is presented for Cohort 3 only which included subjects with brain metastasis, and who underwent CNS assessment using mRECIST criteria.

Arm/Group Title	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	10
Median (95% Confidence Interval) [months]	3.6

6. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13	10	9	10
CR	0 0%	0 0%	0 0%	0 NaN
PR	1 6.7%	4 13.3%	3 6.7%	3 NaN
SD	5 33.3%	0 0%	3 6.7%	2 NaN
Non-CR/Non-PD	0 0%	0 0%	0 0%	0 NaN
PD	5 33.3%	5 16.7%	2 4.4%	3 NaN
Not evaluable	2 13.3%	1 3.3%	1 2.2%	2 NaN

7. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Data is presented for Cohort 3 only which included subjects with brain metastasis, and who underwent CNS assessment using mRECIST criteria.

Arm/Group Title	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	10
CR	0 0%
PR	3 20%
SD	3 20%
Non-CR/Non-PD	0 0%
PD	2 13.3%
Not evaluable	2 13.3%

8. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Percentages are based on the number of subjects in the efficacy evaluable population in the corresponding phase/cohort.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13	10	9	10
Number (95% Confidence Interval) [percentage of participants]	7.7 51.3%	40.0 133.3%	33.3 74%	30.0 NaN

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Percentages are based on the number of subjects in the efficacy evaluable population in the corresponding phase/cohort. Data is presented for Cohort 3 which included subjects with brain metastasis, and who underwent CNS assessment using mRECIST criteria.

Arm/Group Title	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	10
Number (95% Confidence Interval) [percentage of participants]	30.0 200%

10. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Data is presented for the number of subjects who had a BOR classification of CR or PR.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	1	4	3	3
Median (Full Range) [months]	3.84	7.46	5.62	4.14

11. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Data is presented for the number of subjects who had a BOR classification of CR or PR. Data is presented for Cohort 3 only which included subjects with brain metastasis, and who underwent CNS assessment using mRECIST criteria.

Arm/Group Title	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	3
Median (Full Range) [months]	1.84

12. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Percentages are based on the number of subjects in the efficacy evaluable population in the corresponding phase/cohort.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: Cohort 1	Expansion Phase: Cohort 2	Expansion Phase: Cohort 3
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with ER and/or PR-positive BC and HER-2 negative BC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with TNBC. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13	10	9	10
Number (95% Confidence Interval) [percentage of participants]	15.4 102.7%	40.0 133.3%	33.3 74%	30.0 NaN

13. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy evaluable population included all subjects who received at least 1 dose of MM-398. Percentages are based on the number of subjects in the efficacy evaluable population in the corresponding phase/cohort. Data is presented for Cohort 3 which included subjects with brain metastasis, and who underwent CNS assessment using mRECIST criteria.

Arm/Group Title	Expansion Phase: Cohort 3
Arm/Group Description	Subjects with BC with active brain metastasis. FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	10
Number (95% Confidence Interval) [percentage of participants]	50.0 333.3%

14. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The MM-398 safety population consisted of all subjects who received at least 1 dose of MM-398. Data was combined into 1 arm for the Expansion Phase as all subjects had BC.

Arm/Group Title	Pilot Phase: FMX Then MM-398	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
Measure Participants	13	29
Number [participants]	13 86.7%	28 93.3%

15. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Pilot Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13
Irinotecan	1.72
SN-38	3.20

16. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
Measure Participants	21
Irinotecan: Cycle 1 40 mg/m^2 SBE	NA
Irinotecan: Cycle 1 60 mg/m^2 SBE	1.71
Irinotecan: Cycle 1 80 mg/m^2 SBE	1.73
Irinotecan: Cycle 2 40 mg/m^2 SBE	NA
Irinotecan: Cycle 2 60 mg/m^2 SBE	3.03
Irinotecan: Cycle 2 80 mg/m^2 SBE	2.12
Irinotecan: Cycle 3 40 mg/m^2 SBE	NA
Irinotecan: Cycle 3 60 mg/m^2 SBE	3.26
Irinotecan: Cycle 3 80 mg/m^2 SBE	2.47
SN-38: Cycle 1 60 mg/m^2 SBE	3.08
SN-38: Cycle 2 60 mg/m^2 SBE	25.88
SN-38: Cycle 2 80 mg/m^2 SBE	NA
SN-38: Cycle 3 60 mg/m^2 SBE	31.29
SN-38: Cycle 3 80 mg/m^2 SBE	NA

17. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Pilot Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13
Mean (Full Range) [mcg/mL]	39.0

18. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Pilot Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13
Mean (Full Range) [ng/mL]	2.40

19. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
Measure Participants	21
Cycle 1 40 mg/m^2 SBE	NA
Cycle 1 60 mg/m^2 SBE	28.1
Cycle 1 80 mg/m^2 SBE	44.4
Cycle 2 40 mg/m^2 SBE	NA
Cycle 2 60 mg/m^2 SBE	30.4
Cycle 2 80 mg/m^2 SBE	46.6
Cycle 3 40 mg/m^2 SBE	NA
Cycle 3 60 mg/m^2 SBE	30.3
Cycle 3 80 mg/m^2 SBE	45.8

20. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
Measure Participants	21
Cycle 1 60 mg/m^2 SBE	3.08
Cycle 2 60 mg/m^2 SBE	3.63
Cycle 2 80 mg/m^2 SBE	NA
Cycle 3 60 mg/m^2 SBE	2.60
Cycle 3 80 mg/m^2 SBE	NA

21. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Pilot Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13
Mean (Full Range) [mcg*hours/mL (mcg*h/mL)]	1721

22. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Pilot Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	13
Mean (Full Range) [ng*h/mL]	212

23. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
Measure Participants	21
Cycle 1 40 mg/m^2 SBE	NA
Cycle 1 60 mg/m^2 SBE	1430
Cycle 1 80 mg/m^2 SBE	1530
Cycle 2 40 mg/m^2 SBE	NA
Cycle 2 60 mg/m^2 SBE	1589
Cycle 2 80 mg/m^2 SBE	1788
Cycle 3 40 mg/m^2 SBE	NA
Cycle 3 60 mg/m^2 SBE	1700
Cycle 3 80 mg/m^2 SBE	NA

24. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK set included subjects who received at least 1 dose of MM-398, blood samples were collected at the predefined points (with no major protocol deviations affecting PK variables & sufficient number of plasma concentrations to estimate main PK parameters [Cmax, AUC]); analysis was within the sample stability period to estimate main PK parameters.

Arm/Group Title	Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
Measure Participants	21
Cycle 1 60 mg/m^2 SBE	237
Cycle 2 60 mg/m^2 SBE	NA
Cycle 2 80 mg/m^2 SBE	NA
Cycle 3 60 mg/m^2 SBE	214
Cycle 3 80 mg/m^2 SBE	NA

Adverse Events

Time Frame	TEAEs were collected from MM-398 treatment start to end of study (approximately 6 years). 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.
Adverse Event Reporting Description	TEAEs are presented for the MM-398 safety population which included all subjects who received at least 1 dose of MM-398. All analyses using this population were based on the treatment actually received. All cause mortality is presented for the safety population which included all subjects who received at least 1 dose of FMX or MM-398, and the subjects affected received FMX only. Data was combined into 1 arm for the Expansion Phase as all subjects had BC.
Arm/Group Title	Pilot Phase: FMX Then MM-398		Expansion Phase: FMX Then MM-398
Arm/Group Description	FMX phase: Subjects received a single bolus IV injection of 5 mg/kg FMX (up to 510 mg) on Day 1. Subjects underwent FMX-MRI scans and pre-MM-398 treatment biopsies on Days 1 to 4. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent.		FMX phase: Subjects received an IV infusion of 5 mg/kg FMX (up to 510 mg) administered over a minimum of 15 minutes on Day 1. Subjects underwent FMX-MRI scans and a pre-MM-398 treatment biopsy on Days 1 to 2. MM-398 Treatment phase: Within 7 days of the FMX infusion, subjects received up to 70 mg/m^2 MM-398 FBE (C1D1) administered as an IV infusion over 90 minutes, repeated every 2 weeks until disease progression, unacceptable toxicity or withdrawal of consent. Cohort 1: ER and/or PR-positive BC and HER-2 negative BC. Cohort 2: TNBC. Cohort 3: BC with active brain metastasis.
All Cause Mortality
	Pilot Phase: FMX Then MM-398		Expansion Phase: FMX Then MM-398
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		1/30 (3.3%)
Serious Adverse Events
	Pilot Phase: FMX Then MM-398		Expansion Phase: FMX Then MM-398
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/13 (30.8%)		17/29 (58.6%)
Cardiac disorders
Pericardial effusion	0/13 (0%)	0	1/29 (3.4%)	1
Gastrointestinal disorders
Diarrhoea	1/13 (7.7%)	1	5/29 (17.2%)	5
Nausea	1/13 (7.7%)	1	3/29 (10.3%)	3
Abdominal pain	2/13 (15.4%)	2	1/29 (3.4%)	1
Vomiting	1/13 (7.7%)	1	1/29 (3.4%)	1
Colitis	1/13 (7.7%)	1	0/29 (0%)	0
Duodenal perforation	0/13 (0%)	0	1/29 (3.4%)	1
Enteritis	0/13 (0%)	0	1/29 (3.4%)	1
General disorders
Asthenia	0/13 (0%)	0	3/29 (10.3%)	3
Fatigue	0/13 (0%)	0	1/29 (3.4%)	1
Pyrexia	0/13 (0%)	0	1/29 (3.4%)	1
Hepatobiliary disorders
Cholecystitis acute	0/13 (0%)	0	1/29 (3.4%)	1
Infections and infestations
Pneumonia	0/13 (0%)	0	2/29 (6.9%)	2
Urinary tract infection	0/13 (0%)	0	1/29 (3.4%)	4
Coccidioidomycosis	0/13 (0%)	0	1/29 (3.4%)	1
Influenza	0/13 (0%)	0	1/29 (3.4%)	1
Sepsis	0/13 (0%)	0	1/29 (3.4%)	1
Urinary tract infection staphylococcal	0/13 (0%)	0	1/29 (3.4%)	1
Injury, poisoning and procedural complications
Femur fracture	0/13 (0%)	0	1/29 (3.4%)	1
Investigations
Alanine aminotransferase increased	0/13 (0%)	0	1/29 (3.4%)	1
Aspartate aminotransferase increased	0/13 (0%)	0	1/29 (3.4%)	1
Troponin increased	0/13 (0%)	0	1/29 (3.4%)	1
Metabolism and nutrition disorders
Hypokalaemia	0/13 (0%)	0	1/29 (3.4%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/13 (0%)	0	1/29 (3.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to meninges	1/13 (7.7%)	1	0/29 (0%)	0
Nervous system disorders
Aphasia	0/13 (0%)	0	1/29 (3.4%)	1
Dizziness	0/13 (0%)	0	1/29 (3.4%)	1
Dysaesthesia	0/13 (0%)	0	1/29 (3.4%)	1
Headache	0/13 (0%)	0	1/29 (3.4%)	1
Hydrocephalus	0/13 (0%)	0	1/29 (3.4%)	1
Lethargy	0/13 (0%)	0	1/29 (3.4%)	1
Psychiatric disorders
Confusional state	0/13 (0%)	0	1/29 (3.4%)	1
Mental status changes	0/13 (0%)	0	1/29 (3.4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/13 (0%)	0	1/29 (3.4%)	1
Hypoxia	0/13 (0%)	0	1/29 (3.4%)	1
Pulmonary haemorrhage	0/13 (0%)	0	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Pilot Phase: FMX Then MM-398		Expansion Phase: FMX Then MM-398
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		29/29 (100%)
Blood and lymphatic system disorders
Anaemia	5/13 (38.5%)		7/29 (24.1%)
Neutropenia	4/13 (30.8%)		2/29 (6.9%)
Thrombocytopenia	3/13 (23.1%)		0/29 (0%)
Eye disorders
Blepharospasm	0/13 (0%)		2/29 (6.9%)
Vision blurred	0/13 (0%)		2/29 (6.9%)
Gastrointestinal disorders
Diarrhoea	9/13 (69.2%)		25/29 (86.2%)
Nausea	9/13 (69.2%)		15/29 (51.7%)
Vomiting	7/13 (53.8%)		11/29 (37.9%)
Constipation	5/13 (38.5%)		5/29 (17.2%)
Abdominal pain	2/13 (15.4%)		6/29 (20.7%)
Dyspepsia	2/13 (15.4%)		2/29 (6.9%)
Flatulence	1/13 (7.7%)		3/29 (10.3%)
Stomatitis	1/13 (7.7%)		2/29 (6.9%)
Abdominal distension	1/13 (7.7%)		2/29 (6.9%)
Oral pain	0/13 (0%)		3/29 (10.3%)
Ascites	1/13 (7.7%)		1/29 (3.4%)
Abdominal pain upper	0/13 (0%)		2/29 (6.9%)
Colitis	1/13 (7.7%)		0/29 (0%)
Gastrooesophageal reflux disease	1/13 (7.7%)		1/29 (3.4%)
Faecaloma	1/13 (7.7%)		0/29 (0%)
Oesophageal stenosis	1/13 (7.7%)		0/29 (0%)
General disorders
Fatigue	3/13 (23.1%)		17/29 (58.6%)
Asthenia	0/13 (0%)		3/29 (10.3%)
Oedema peripheral	1/13 (7.7%)		3/29 (10.3%)
Chills	1/13 (7.7%)		1/29 (3.4%)
Mucosal inflammation	1/13 (7.7%)		0/29 (0%)
Non-cardiac chest pain	1/13 (7.7%)		0/29 (0%)
Infections and infestations
Urinary tract infection	3/13 (23.1%)		4/29 (13.8%)
Pneumonia	2/13 (15.4%)		0/29 (0%)
Bronchitis	1/13 (7.7%)		2/29 (6.9%)
Upper respiratory tract infection	0/13 (0%)		2/29 (6.9%)
Enterocolitis infection	1/13 (7.7%)		0/29 (0%)
Lymphangitis	1/13 (7.7%)		0/29 (0%)
Sinusitis	1/13 (7.7%)		0/29 (0%)
Skin candida	1/13 (7.7%)		0/29 (0%)
Urinary tract infection enterococcal	1/13 (7.7%)		0/29 (0%)
Injury, poisoning and procedural complications
Contusion	0/13 (0%)		2/29 (6.9%)
Fall	0/13 (0%)		2/29 (6.9%)
Investigations
Alanine aminotransferase increased	0/13 (0%)		6/29 (20.7%)
Neutrophil count decreased	0/13 (0%)		5/29 (17.2%)
Aspartate aminotransferase increased	0/13 (0%)		4/29 (13.8%)
Weight decreased	0/13 (0%)		4/29 (13.8%)
Blood alkaline phosphatase increased	0/13 (0%)		3/29 (10.3%)
White blood cell count decreased	0/13 (0%)		3/29 (10.3%)
Lymphocyte count decreased	0/13 (0%)		3/29 (10.3%)
Blood phosphorous decreased	0/13 (0%)		2/29 (6.9%)
Transaminases increased	1/13 (7.7%)		1/29 (3.4%)
Metabolism and nutrition disorders
Hypokalaemia	8/13 (61.5%)		11/29 (37.9%)
Decreased appetite	3/13 (23.1%)		9/29 (31%)
Hypomagnesaemia	3/13 (23.1%)		4/29 (13.8%)
Hypocalcaemia	0/13 (0%)		6/29 (20.7%)
Dehydration	2/13 (15.4%)		4/29 (13.8%)
Hypophosphataemia	2/13 (15.4%)		3/29 (10.3%)
Hypoalbuminaemia	0/13 (0%)		4/29 (13.8%)
Hyperglycaemia	1/13 (7.7%)		2/29 (6.9%)
Hyponatraemia	2/13 (15.4%)		1/29 (3.4%)
Hypercalcaemia	1/13 (7.7%)		1/29 (3.4%)
Malnutrition	0/13 (0%)		2/29 (6.9%)
Iron deficiency	1/13 (7.7%)		0/29 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/13 (7.7%)		7/29 (24.1%)
Muscle spasms	2/13 (15.4%)		4/29 (13.8%)
Arthralgia	0/13 (0%)		4/29 (13.8%)
Neck pain	1/13 (7.7%)		3/29 (10.3%)
Bone pain	1/13 (7.7%)		2/29 (6.9%)
Flank pain	0/13 (0%)		2/29 (6.9%)
Muscular weakness	0/13 (0%)		2/29 (6.9%)
Musculoskeletal pain	0/13 (0%)		2/29 (6.9%)
Myalgia	0/13 (0%)		2/29 (6.9%)
Nervous system disorders
Headache	3/13 (23.1%)		6/29 (20.7%)
Dizziness	2/13 (15.4%)		2/29 (6.9%)
Dysgeusia	2/13 (15.4%)		1/29 (3.4%)
Neuropathy peripheral	0/13 (0%)		3/29 (10.3%)
Psychiatric disorders
Anxiety	1/13 (7.7%)		4/29 (13.8%)
Insomnia	0/13 (0%)		3/29 (10.3%)
Depression	0/13 (0%)		2/29 (6.9%)
Renal and urinary disorders
Dysuria	1/13 (7.7%)		1/29 (3.4%)
Respiratory, thoracic and mediastinal disorders
Cough	1/13 (7.7%)		6/29 (20.7%)
Dyspnoea	0/13 (0%)		5/29 (17.2%)
Oropharyngeal pain	1/13 (7.7%)		1/29 (3.4%)
Pleural effusion	0/13 (0%)		2/29 (6.9%)
Rhinorrhoea	0/13 (0%)		2/29 (6.9%)
Skin and subcutaneous tissue disorders
Alopecia	2/13 (15.4%)		6/29 (20.7%)
Palmar-plantar erythrodysaesthesia syndrome	0/13 (0%)		2/29 (6.9%)
Rash	0/13 (0%)		2/29 (6.9%)
Ecchymosis	1/13 (7.7%)		0/29 (0%)
Erythema	1/13 (7.7%)		0/29 (0%)
Vascular disorders
Hypotension	0/13 (0%)		3/29 (10.3%)
Hypertension	1/13 (7.7%)		0/29 (0%)

Limitations/Caveats

Data for the subjects in the 3 Expansion Phase cohorts were combined when presenting results for the overall Expansion Phase because all cohorts were defined in the protocol to contain subjects with BC.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.