Safety and Tolerability of MSI-1436C in Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a Phase I, open-label, dose escalation study. MSI-1436 will be administered as a single intravenous infusion twice a week for 3 weeks on a 4-week cycle.

Detailed Description
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This is a Phase I, open-label, dose escalation study. MSI-1436 will be administered as a single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will be enrolled according to a standard Phase I Fibonacci design to receive MSI-1436. Drug infusions will last approximately 2 hours. If a subject has a dose-limiting toxicity (DLT) at any time during the study, MSI-1436 will be held and either re-started or discontinued in that subject as per the Dose Adjustments and Toxicities Guidelines.

Official Title
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A Phase I Study of the Safety and Tolerability of Single Agent MSI-1436C in Metastatic Breast Cancer Patients

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: MSI-1436C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed, witnessed, and dated Institutional Review Board (IRB) approved Informed Consent Form (ICF). Pathologically confirmed metastatic breast cancer with measurable disease. Metastatic sites must be measurable on CT, MRI, or FDG-PET/CT as per the revised RECIST v1.1 criteria or measurable disease on physical examination. A metastatic site must be biopsy proven Life expectancy ≥3 months. Patients enrolled must have received 2 or more lines of therapy and all patients with HER2 expressing tumors must have received HER2 targeted therapy. Female Age ≥18 years. Stable brain metastasis is permitted. This is not considered measurable disease. Stable brain metastasis is defined as no change on CT scan or MRI for minimum of 2 months AND no change in steroid dose for a minimum of 4 weeks A negative serum pregnancy test, if female of reproductive potential. Reproductive potential defined as age < 55 or with no menses for < 1 year Screening laboratory values as follows: Total bilirubin ≤1.5 times upper limit of normal (ULN). Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvate transaminase)≤ 2.5 times ULN. Serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥60 mL/min. Absolute neutrophil count >1,500 cells/mm3. Platelet count ≥100,000 plt/mm3. Hemoglobin ≥ 8 g/dL. Non-diabetic Exclusion Criteria: Pregnant or breast-feeding ECOG Performance Status greater than 2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSI-1436C (Trodusquemine) 20 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 20 mg/m2. Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|
| Experimental: MSI-1436C (Trodusquemine) 26 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 26 mg/m2. Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|
| Experimental: MSI-1436C (Trodusquemine) 34 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 34 mg/m2 . Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|
| Experimental: MSI-1436C (Trodusquemine) 44 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 44 mg/m2 . Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|
| Experimental: MSI-1436C (Trodusquemine) 57 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 57 mg/m2. Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|
| Experimental: MSI-1436C (Trodusquemine) 74 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 74 mg/m2 . Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|
| Experimental: MSI-1436C (Trodusquemine) 96 mg/m2 IV<br>Open label, interventional, dose escalation of MSI-1436 (Trodusquemine), single intravenous infusion twice a week for 3 weeks on a 4-week cycle. Subjects will receive MSI-1436 at a dose of 96 mg/m2 . Drug infusions will last approximately 2 hours. | Drug: MSI-1436C<br>* Dose escalation, single intravenous infusion twice a week for 3 weeks on a 4-week cycle.<br>* Other names: Trodusquemine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally Tolerated Dose (MTD) of MSI-1436 | Subjects will be enrolled according to a standard Phase I Fibonacci design to receive MSI-1436C. If a subject has a dose-limiting toxicity (DLT) at any time during the study, MSI-1436C will be held and either re-started or discontinued in that subject as per the Dose Adjustments and Toxicities Guidelines. | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) | The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of MSI-1436C. | one year | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | All adverse events and dose-limiting toxicities will be recorded and tabulated. A dose-limiting toxicity (DLT) will be defined as any grade 3 or higher NCI Common Toxicity Criteria adverse event (CTCAE) that is deemed related to the study drug MSI-1436C, any infusion reaction necessitating drug discontinuation, or any other drug related adverse event leading to the study drug discontinuation. Descriptive statistics will be used to summarize adverse events and dose-limiting toxicities. The proportion of AEs and DLTs will be calculated along with their corresponding exact 95% confidence intervals. | one year | 
| response rates | To assess the response rates of MSI-1436C in metastatic breast cancer patients the outcome variable of interest is time-to-progression. Patients who have not progressed (or who have not died) as of their last known follow-up, will be considered 'censored' for the time-to-progression analysis. Time-to-progression will be estimated using the Kaplan-Meier Product-Limit Method. Any post- hoc group comparisons will be carried out using the log-rank test. Patients who have not progressed (or who have not died) as of their last known follow-up, will be considered 'censored' for the time-to-progression analysis. | one year | 
| Peak plasma concentration of the drug after administration (cmax) | The maximum (or peak) serum concentration that MSI-1436C achieves in the plasma after the drug has been administrated and prior to the administration of a second dose. | one year | 
| Time to reach cmax | The amount of time for MSI-1436C to reach Cmax | one year | 
| Time required for the concentration of MSI-1436C to reach half of its original value, or half life (t1/2) | The time required for the concentration of MSI-1436C to reach half of its original value. | one year |