A Study of XMT-2056 in Advanced/Recurrent Solid Tumors That Express HER2

Study Overview
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Brief Summary
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A Study of XMT-2056 in advanced/recurrent solid tumors that express HER2.

Detailed Description
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The first-in-human (FIH) study of XMT-2056 is a Phase 1, open-label study of XMT-2056 in previously treated patients with advanced/recurrent solid tumors expressing HER2. The XMT-2056 monotherapy trial will consist of dose escalation (DES) and expansion (EXP) parts. DES will be the dose-finding portion of the study to assess the safety and tolerability of XMT-2056 and determine the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D). The RP2D will be determined based on the totality of the clinical data, including safety and preliminary anti-tumor effect, PK, and relevant biomarker data.

Official Title
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A Phase 1, First-in-Human, Dose Escalation and Expansion, Multicenter Study of XMT-2056 in Participants With Advanced/Recurrent Solid Tumors That Express HER2

Conditions
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HER2-positive Breast Cancer, HER2-positive Gastric Cancer, HER2-positive Non-Small Cell Lung Cancer, HER2-positive Colorectal Cancer, HER2-positive Tumors, HER2 Low Breast Cancer

Intervention / Treatment
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* Drug: XMT-2056


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has recurrent or metastatic solid tumors with HER2 expression and has disease progression after treatment, is intolerant to treatment, or is contraindicated with available anti-cancer therapies known to confer benefit, based on investigator's judgement. Note: HER2+ will be determined by institutional practice (e.g., IHC, ISH, or NGS). In the absence of institutional standards, the relevant ASCO/CAP guidelines for HER2 testing should be followed. HER2 activating mutations or HER2 gene amplification are considered as qualifying for HER2+ disease for all participants. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Participant must have measurable disease as defined by RECIST version 1.1. Participant has fresh tumor biopsy tissue available for submission to central laboratory. If obtaining fresh tumor tissue is not medically feasible, archival tumor tissue can be submitted following written approval of the request by the study Medical Monitor. Samples must be obtained after the participant's most recent HER2-targeting therapy unless determined to be medically infeasible after discussion with the medical monitor. Exclusion Criteria: Participant is receiving immunosuppressive doses of systemic medications, (doses >10 mg/day prednisone or equivalent) that cannot be discontinued for at least 2 weeks before the first dose and during study drug treatment administration. Note: physiologic hormone replacement therapy is an exception. Participant has received prior treatment targeting STING pathway. Diagnosis of additional malignancy that required active treatment (including surgery, systemic therapy, and radiation) within the last 2 years, expect for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the breast or the cervix. Participants with an additional malignancy that has a low risk for recurrence may be eligible after discussion with the study Medical Monitor. Participants have untreated CNS metastases (including new and progressive brain metastases), history of leptomeningeal metastasis, or carcinomatous meningitis. Participants are eligible if CNS metastases are adequately treated and participants are neurologically stable for at least 2 weeks prior to enrollment. In addition, participants must be either off corticosteroids, or on a stable/decreasing dose of ≤ 10 mg prednisone daily (or equivalent).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XMT-2056<br>XMT-2056 alone (monotherapy) | Drug: XMT-2056<br>* XMT-2056 will be administered through a vein in your arm or port catheter (intravenously)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of dose-limiting toxicities (DLTs) associated with XMT-2056 during the first cycle of treatment (Dose Escalation) | Determine the maximum tolerated dose (MTD) of XMT-2056 | 15 months | 
| Incidence of adverse events (Dose Escalation and Dose Expansion) | Assess the safety and tolerability of XMT-2056 by determining the number of patients with adverse events from date of first dose to 30 days post last dose. | 3 years | 
| Objective Response Rate (ORR) (Dose Expansion) | The percentage of patients with a best overall response of confirmed complete or partial response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) (Dose Escalation) | The percentage of patients with a best overall response of confirmed complete or partial response as assessed by the investigator per Resist Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | 3 years | 
| Duration of response (DOR) (Dose Escalation and Dose Expansion) | The time from when response criteria are first met until disease progression or death in participants who achieve a confirmed complete or partial response. | 3 years | 
| Disease control rate (DCR) (Dose Escalation and Dose Expansion) | The percentage of patients who achieve a complete response, partial response or stable disease as the result of study treatment | 3 years | 
| Time of maximum observed plasma concentration of XMT-2056 (Tmax) (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XMT-2056 | 3 years | 
| Maximum observed plasma concentration of XMT-2056 (Cmax) (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XMT-2056 | 3 years | 
| Area under the concentration-time curve of XMT-2056 (AUC) (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XMT-2056 | 3 years | 
| Systemic clearance of XMT-2056 (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XmT-2056 by measuring the rate at which the drug is eliminated from the body | 3 years | 
| Apparent terminal elimination of half-life of XMT-2056 (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XMT-2056 | 3 years | 
| Volume of Distribution (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XMT-2056 | 3 years | 
| Trough concentration of XMT-2056 (Ctrough) (Dose Escalation and Dose Expansion) | Assess the pharmacokinetics of XMT-2056 by measuring the lowest concentration of drug before dosing | 3 years | 
| Serum samples for analysis of XMT-2056 antidrug and neutralizing antibodies (ADA/nAb) (Dose Escalation and Dose Expansion) | Assess the development of antidrug antibodies (ADA) and neutralizing antibodies (nAB) to XMT-2056 | 3 years |