A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations

Study Overview
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Brief Summary
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This is an open-label, multi-center, single arm, Phase II study to evaluate the efficacy and safety of T-DXd for the treatment of unresectable and/or metastatic solid tumors harboring specific HER2 activating mutations regardless of tumor histology. The target population are patients who have progressed following prior treatment or who have no satisfactory alternative treatment options, including approved second line therapies in the specific tumor type. Pre-specified HER2 mutations will be locally assessed using NGS tests or alternative methods. Prior HER2 targeting therapy is permitted.

Official Title
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A Phase II, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) for the Treatment of Unresectable and/or Metastatic Solid Tumors Harboring HER2 Activating Mutations Regardless of Tumor Histology

Conditions
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Advanced Solid Tumors With HER2 Mutation,eg:Colorectal,Urothelial,Gastric, Hepatobiliary,Endometrial,Melanoma,Ovarian,Cervical,Salivary Gland,Pancreatic,Breast

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥18 years old. Other age restrictions may apply as per local regulations. Unresectable and/or metastatic solid tumors with pre-specified HER2 mutations (S310F, S310Y, G660D, R678Q, D769Y, D769H, V777L, Y772_A775dup / A775_G776insYVMA, L755S, G778_P780dup / P780_Y781insGSP, T862A, and V842I locally determined by NGS or a validated nucleic acid-based methodology (eg, qPCR, digital PCR) on tumor tissue, who have progressed following prior treatment or who have no satisfactory alternative treatment options. Prior HER2 targeted therapy is permitted. All patients must provide an FFPE tumor sample for retrospective central HER2 testing. LVEF ≥50% ECOG 0-1 All patients have measurable target disease assessed by the Investigator based on RECIST v1.1 Exclusion Criteria: HER2 overexpressing (IHC3+ or IHC2+/ISH+) breast, gastric or gastroesophageal junction adenocarcinoma. HER2 mutant NSCLC. Medical history of myocardial infarction within 6 months before randomization/enrolment, symptomatic CHF, unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD cannot be ruled out by imaging at screening Corrected QT interval by Fridericia's formula (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG. Lung-specific intercurrent clinically significant severe illnesses. History of active primary immunodeficiency, known HIV, active HBV or HCV infection Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). Has spinal cord compression or clinically active central nervous system metastases.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: T-DXd<br>T-DXd monotherapy | Drug: Trastuzumab deruxtecan<br>* Trastuzumab deruxtecan (T-DXd) by intravenous infusion<br>* Other names: DS-8201a (T-DXd);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed objective response rate by RECIST 1.1 based on independent central review (ICR). | Confirmed ORR per RECIST 1.1 is the proportion of patients with Complete Response or Partial Response that is subsequently confirmed, based on ICR. | An average of approximately 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DoR) based on ICR and Investigator assessment. | DOR is defined as the time from the date of first documented response until the date of documented progression or death, based on ICR and Investigator assessment. | An average of approximately 12 months. | 
| Disease control rate (DCR) based on ICR and Investigator assessment. | DCR is the proportion of patients who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD), based on ICR and Investigator assessment. | An average of approximately 12 months. | 
| Progression free survival (PFS) based on ICR and Investigator assessment. | PFS is the time from first dose of study treatment until the date of objective disease progression or death, based on ICR and Investigator assessment. | An average of approximately 12 months. | 
| Proportion of patients alive and progression-free. | Proportion of patients who are alive and progression-free based on ICR and Investigator assessment. | At 6 and 12 months. | 
| Confirmed Objective Response Rate (ORR) based on investigator assessment. | Confirmed ORR per RECIST 1.1 is the proportion of patients with Complete Response or Partial Response that is subsequently confirmed, based on investigator assessment | An average of approximately 12 months. | 
| Overall survival (OS). | OS is the time form the date of first dose of study treatment until death due to any cause. | An average of approximately 20 months. | 
| Occurrence of adverse events (AEs) and serious adverse events (SAEs). | Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0. | An average of approximately 14 months. | 
| Serum concentration of T-DXd. | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd. | An average of approximately 14 months. | 
| Serum concentration of total anti-HER2 antibody. | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for total anti-HER2 antibody. | An average of approximately 14 months. | 
| Serum concentration of MAAA-1181a. | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for MAAA-1181a. | An average of approximately 14 months. | 
| The immunogenicity of T-DXd assessed by the presence of ADAs for T-DXd. | Individual participant data and descriptive statistics will be provided for data at each time point. | An avarage of approximately 14 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T-DXd, HER2, DS-8201a, Trastuzumab Deruxtecan, Metastatic, Solid Tumors, Histology Agnostic