Study of MT-5111 in HER2-positive Solid Tumors

Study Overview
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Brief Summary
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This will be a Phase 1b, first in human, open-label, dose escalation and expansion study of MT-5111 (a recombinant fusion protein) given as monotherapy in subjects with HER2-positive solid tumors

Detailed Description
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This study will be conducted in two parts: Part A (Dose Escalation): The purpose of Part A is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D). Part A will include any type of HER2-positive solid cancer. Part B (Dose Expansion): The purpose of Part B is to confirm the safety and tolerability of MT-5111 doses selected from those explored in Part A including the MTD or RP2D. Part B will include 3 types of HER2-positive solid cancers in the following 3 expansion groups: Group B1: Breast cancer; Group B2: gastric or gastroesophageal adenocarcinomas (GEA); and Group B3: Other HER2-positive solid cancers. The Breast Cancer cohort will start enrolling in parallel to Part A. Up to 178 eligible subjects will be identified and treated through competitive enrollment at multiple study centers globally In Parts A and B of the study, a subject may participate for the following four periods: Screening (up to 28 days before first dose of MT-5111) Treatment period (active period where a subject will receive three weekly doses of MT-5111 over a 21-day treatment cycle) Short-term Follow-up (30 days after last dose of MT-5111) Long-term follow-up (up to 24 months after the last dose of MT-5111) MT-5111 will be given as an intravenous (IV) infusion over about 30 minutes on the same day every week (i.e., on day 1, day 8 and day 15 of each cycle, a cycle being defined as 21 days). A subject can continue receiving MT-5111 as long as it is well-tolerated, their disease has not worsened, or until the subject decides they no longer want to participate in the study.

Official Title
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A Phase 1 Open-label, Multicenter Dose Escalation and Expansion Study of MT-5111 in Subjects With Previously Treated Advanced HER2-positive Solid Tumors

Conditions
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HER2-positive Solid Cancers

Intervention / Treatment
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* Drug: MT-5111 (experimental study drug)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, unresectable, locally advanced or metastatic solid cancers: Part A (Dose-Escalation): All HER2-positive solid cancers are eligible Part B (Dose-Expansion): Any type of HER2-positive solid cancer, including breast cancer, and gastric or gastroesophageal adenocarcinomas (GEA). HER2-positive in the latest tumor sample tested for HER2 (testing to be done on a metastatic lesion in cases of metastatic cancers). Relapsed or refractory to or intolerant of existing therapy(ies) At least 1 measurable or evaluable lesion according to RECIST 1.1 (Subjects with evaluable disease only may be included in the dose escalation phase) ECOG performance score of ≤ 1 Adequate Bone marrow function as determined by: Absolute neutrophil count (ANC) ≥ 1,000/mm3 Platelet count ≥ 75,000 mm³ and Hemoglobin ≥ 8.0 g/dL Red blood cell transfusion within 2 weeks of study treatment start is allowed if hemoglobin levels remain stable Kidney function: Creatinine clearance (CLcr) ≥ 50 mL/min either measured or estimated using the Cockcroft-Gault formula Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 55% on the echocardiogram (ECHO) assessment (preferred), or multigated acquisition (MUGA) scan, and QTcF ≤ 480 ms for women and QTcF ≤ 450 ms for men [average from three QTcF values on the triplicate 12-lead electrocardiogram (ECG)] at baseline Hepatic function: Total bilirubin ≤ 1.5 x ULN, or ≤ 3 x ULN for subjects with Gilbert's Syndrome and AST ≤ 3 x ULN (or ≤ 5 x ULN if liver metastasis) and ALT ≤ 3 x ULN (or ≤ 5 x ULN if liver metastasis) Exclusion Criteria: History or current evidence of another tumor that is histologically distinct from the tumor under study Current evidence of new or growing CNS metastases during screening Subjects with known CNS metastases will be eligible if they meet protocol specified criteria Evidence of CTCAE Grade >1 toxicity before the start of treatment, except for hair loss and those Grade 2 toxicities listed as permitted in other eligibility criteria History or evidence of significant cardiovascular disease Current evidence of active, uncontrolled hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV) (evidenced by detectable viral load by PCR) or acquired immunodeficiency syndrome (AIDS) related illness Current evidence of ≥ grade 2 underlying pulmonary disease Certain exclusionary prior treatments

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Interventional Model Description: MT-5111 (active drug)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A- Dose Escalation<br>Part A- Dose Escalation in patients with previously treated advanced HER2-positive solid tumors. The assigned dose level of MT-5111 will be given as an intravenous (IV) infusion over about 30 minutes on the same day every week (i.e., on day 1, day 8 and day 15 of each cycle). | Drug: MT-5111 (experimental study drug)<br>* Experimental treatment with MT-5111<br>|
| Experimental: Part B- Dose Expansion<br>Part B - Dose Expansion in previously treated HER2-positive breast, GEA and other HER2-positive solid cancers Part B will include 3 expansion groups: Group B1 (Breast Cancer) will begin enrolling while Part A is being conducted following the completion of Cohort 7 and Subsequent cohort of subjects in group B1 may enroll into higher doses that are tolerated in Part A. Group B2 (GEA) and Group B3 (Other HER-2 positive solid cancer groups) will begin enrollment after the MTD or RP2D is determined in Part A. The assigned dose level of MT-5111 will be given as an intravenous (IV) infusion over about 30 minutes on the same day every week (i.e., on day 1, day 8 and day 15 of each cycle). | Drug: MT-5111 (experimental study drug)<br>* Experimental treatment with MT-5111<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate safety and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) | Evaluation of safety of MT-5111 as measured by number of subjects with adverse events using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 | 21 day cycle | 
| To evaluate tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) | Evaluation of tolerability of MT-5111 as measured by number of subjects with dose limiting toxicities (DLTs) | 21 day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK as measured by concentrations of free MT-5111 (Maximum Plasma Concentration [Cmax]) | Evaluation of the pharmacokinetic profile of MT-5111 | Day 1, Day 8, and Day 15 in Each 21-Day cycle | 
| PK as measured by concentrations of free MT-5111 (Time to reach maximum concentration after drug administration [Tmax]) | Evaluation of the pharmacokinetic profile of MT-5111 | Day 1, Day 8, and Day 15 in Each 21-Day cycle | 
| PK as measured by concentrations of free MT-5111 (Area Under the Curve [AUC]) | Evaluation of the pharmacokinetic profile of MT-5111 | Day 1, Day 8, and Day 15 in Each 21-Day cycle | 
| To evaluate the tumor response to MT-5111 | Objective response rate (ORR) defined as the proportion of subjects with either a complete response or a partial response as determined by investigator assessment | Screening, approximately every 6 weeks, at End of Treatment and 30 days after the last dose | 
| To evaluate the immunogenicity of MT-5111 | Immunogenicity as measured by MT-5111 (anti-drug antibody [ADA] titer) | Screening (baseline), Day 1 of each 21 day cycle, at the End of Treatment and the Follow-up Visit | 
| To evaluate the immunogenicity of MT-5111 | Immunogenicity as measured by MT-5111 (neutralizing antibody [NAb]) | Screening (baseline), Day 1 of each 21 day cycle, at the End of Treatment and the Follow-up Visit |