A Study of Dato-DXd in Chinese Patients With Advanced Non-Small Cell Lung Cancer, Triple-negative Breast Cancer and Other Solid Tumors (TROPION-PanTumor02)

Study Overview
=================
Brief Summary
-----------------
Researchers are looking for a better way to treat advanced Triple-Negative Breast Cancer (TNBC) and Non-Small-Cell Lung Cancer (NSCLC). Advanced usually means that the cancer keeps growing even with treatment. The cancer may also be metastatic, which means that it has spread to other parts of the body or the surrounding tissue. The study drug, Datopotamab deruxtecan, is designed to work by attaching to the tumor cells and stopping the tumor growth. Datopotamab deruxtecan is also known as Dato-DXd. In this study, the researchers want to find out how well Dato-DXd works to stop tumors from growing in Chinese participants with NCSLC or TNBC. This is the first time Dato-DXd is being studied in Chinese population. Participants in this study will get Dato-DXd through a needle as an injection. They will get 1 dose of Dato-DXd every 3 weeks until their cancer gets worse or they leave the study for another reason. Participants will visit their study sites at least once every 3 weeks for as long as they are in the study. The study doctors will take blood samples every 3 weeks and take images of the participants' tumors every 6 weeks until the participant leaves the study.

Detailed Description
-----------------
This is a Phase 1/Phase 2, multicentre, open-label, multiple-cohort study, which is designed to evaluate the efficacy, safety, Pharmacokinetic, and immunogenicity of Dato-DXd in adult Chinese participants with advanced or metastatic solid tumours. It is a single-arm study with no blinding. This study is divided into different cohorts. Participants of the same cohort are with the same tumour type. The starting cohorts are Cohort 1 (NSCLC) and Cohort 2 (TNBC). Future cohorts will consist of other advanced or metastatic solid tumour types, including, but not limited to, advanced/unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma or urothelial carcinoma that is refractory or intolerant to SoC therapy or for which no Standard of Care therapy is available. Cohort 1 and Cohort 2 will be prioritised for immediate enrolment and the protocol will be amended as needed for the future cohorts. Cohort 1: The target population of Cohort 1 is adult Chinese participants with advanced or metastatic NSCLC with or without actionable genomic alterations(AGAs) (ie, alterations in genes with approved therapies, such as EGFR, ALK, or other known AGAs). Eligible participants without AGAs will have been previously treated with platinum-based chemotherapy and anti-PD-1/anti-PD-L1 monoclonal antibody either in combination or sequentially. Participants without AGAs who received anti-PD-1/anti-PD-L1 monoclonal antibody as frontline therapy may have received the combination of platinum-based chemotherapy and anti-PD-1/anti-PD-L1 monoclonal antibody in the second-line setting. Eligible participants with AGAs will have been previously treated with one or two prior lines of applicable targeted therapy that is approved for the participant's genomic alteration and platinum-based chemotherapy as the only prior line of cytotoxic therapy. Participants with AGAs may have received up to one anti-PD-1/anti-PD-L1 monoclonal antibody treatment alone or in combination with chemotherapy. A total of approximately 40 eligible participants in China will be enrolled in this cohort, including approximately 6 participants with AGAs. Cohort 2: The target population of Cohort 2 is adult Chinese participants with inoperable locally advanced or metastatic TNBC who have received at least 2 prior chemotherapy regimens for advanced breast cancer, counting the (neo)adjuvant therapy as a prior chemotherapy regimen if progression occurred within 12 months after completion of the therapy (DFI ≤ 12 months). A total of approximately 78 eligible participants in China will be enrolled in this cohort. Cohort 2 will enroll at most around 20% (approximately N=15) of enrolled participants with a DFI ≤ 12 months. Enrolled participants will be treated with Dato-DXd at 6.0 mg/kg via an IV infusion on Day 1,every 3 weeks. The primary objective of the study is to estimate the effectiveness of Dato-DXd by assessment of confirmed ORR by independent central review.

Official Title
-----------------
Phase 1/2, Multicentre, Open-label, Multiple-cohort Study of Dato-DXd in Chinese Patients With Advanced Non-small-cell Lung Cancer, Triple-negative Breast Cancer, Gastric/Gastroesophageal Junction Cancer, Urothelial Cancer, and Other Solid Tumours (TROPION-PanTumor02)

Conditions
-----------------
Carcinoma, Non-Small-Cell Lung, Triple Negative Breast Cancer

Intervention / Treatment
-----------------
* Drug: Datopotamab Deruxtecan (Dato-DXd)


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Capable of giving signed informed consent. Participant must be ≥ 18 years at the time of screening. Eastern Cooperative Oncology Group performance status of 0 or 1. At least one lesion not previously irradiated that qualifies as a RECIST 1.1 target lesion at baseline and can be accurately measured at baseline and is suitable for accurate repeated measurements. Additional Inclusion Criteria for Cohort 1 (NSCLC): - Histologically or cytologically documented Stage IIIB or IIIC NSCLC disease not amenable for surgical resection or definitive chemoradiation or Stage IV NSCLC disease at the beginning of study intervention. For the subset of participants without AGAs: Documented negative test results for EGFR and ALK genomic alterations. If test results for EGFR and ALK are not available, participants are required to undergo testing performed locally for these genomic alterations. Participants must meet one of the required prior therapy requirements for advanced or metastatic NSCLC. For the subset of participants with AGAs: - Documented positive test results for one or more actionable genomic alteration: EGFR, ALK, ROS1, METex14 skipping, RET or other AGAs with approved therapies - Received one or two prior lines of applicable targeted therapy for the participant's genomic alteration at the time of screening. Additional Inclusion Criteria for Cohort 2 (TNBC) Pathologically documented oestrogen and progesterone receptor-negative and HER2-negative expression. Inoperable locally advanced or metastatic breast cancer. Received at least 2 prior chemotherapy regimens for locally advanced or metastatic breast cancer and previously treated with a taxane in any setting. Key Exclusion Criteria: Has leptomeningeal carcinomatosis or metastasis Has clinically significant corneal disease Has known active hepatitis or uncontrolled hepatitis B or C infection Has a history of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Prior exposure to specific therapies without an adequate treatment washout period prior to enrolment. Additional Exclusion Criteria for Cohort 1 (NSCLC): - Has mixed SCLC and NSCLC histology.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase 1/Phase 2, multicentre, open-label, multiple-cohort study, which is designed to evaluate the efficacy, safety, PK, and immunogenicity of Dato-DXd in adult Chinese participants with advanced or metastatic solid tumours.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dato-DXd Arm<br>This single-arm study consists of multiple cohorts, divided by indication. | Drug: Datopotamab Deruxtecan (Dato-DXd)<br>* Dato-DXd is an antibody-drug conjugate (ADC) that binds to TROP2.<br>* Other names: DS-1062a;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate(ORR) assessed by independent central review(ICR). | Confirmed ORR assessed by ICR is defined as the proportion of participants in each cohort who have a confirmed complete response(CR) or confirmed partial response(PR), as assessed by ICR per RECIST 1.1. The measure of interest is the estimate of confirmed ORR. | Up to approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate(ORR) assessed by investigator | Confirmed ORR assessed by investigator is defined as the proportion of participants in each cohort who have a confirmed CR or confirmed PR, as determined by investigator assessment per RECIST 1.1. | Up to approximately 36months | 
| Duration of Response (DoR) | Duration of response is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression per RECIST 1.1, as assessed by ICR and by investigator, or death due to any cause. | Up to approximately 36 months | 
| Disease Control Rate (DCR) | Disease control rate is defined as the percentage of participants who have a confirmed CR or PR or who have stable disease (SD) per RECIST 1.1, as assessed by ICR and by investigator. | Up to approximately 36 months | 
| Best Overall Response (BoR) | Best overall response is defined as participant's best confirmed response during their participation in the study, but prior to starting any subsequent anticancer therapy, up until RECIST 1.1-defined PD or the last evaluable assessment in the absence of RECIST 1.1-defined progression. Best overall response will be assessed by ICR and by investigator per RECIST 1.1. | Up to approximately 36 months | 
| Time To Response (TTR) | Time to response is defined as the time from the date of the first dose of study intervention until the date of first documented objective response, which is subsequently confirmed per RECIST 1.1, as assessed by ICR and by investigator. | Up to approximately 36 months | 
| Progression-Free Survival (PFS) | Progression-free survival is defined as time from the date of the first dose of study intervention until progression per RECIST 1.1, as assessed by ICR and by investigator, or death due to any cause. | Up to approximately 36 months | 
| Overall Survival (OS) | Overall survival is defined as the time from the date of the first dose of study intervention to the date of death due to any cause. | Up to approximately 36 months | 
| Number of participants with treatment-emergent adverse event(TEAE), adverse event of special interest (AESI) as assessed by CTCAE version 5.0 | Evaluated from first dose to safety follow up visit. | Up to approximately 36 months | 
| Pharmacokinetic Parameter: Time to maximum plasma concentration (Tmax) |  | Cycle 1, Day 1: predose and 30 minutes, 3 hours, 5 hours, and 7 hours postdose and Days 2, 4, 8, and 15; Cycles 2 Day 1:predose Cycle 4 and 8, Day 1: predose and 1 hour postdose (each cycle is 21 days) | 
| Immunogenicity of Dato-DXd | The presence of ADAs against Dato-DXd will be evaluated. Titre will be determined when ADA is positive. | Up to approximately 36 months | 
| Pharmacokinetic Parameter: Area under the plasma concentration- time curve (AUC) |  | Cycle 1, Day 1: predose and 30 minutes, 3 hours, 5 hours, and 7 hours postdose and Days 2, 4, 8, and 15; Cycles 2 Day 1 predose; Cycle 4 and 8, Day 1: predose and 1 hour postdose (each cycle is 21 days) | 
| Pharmacokinetic Parameter: Maximum plasma concentration (Cmax) |  | Cycle 1, Day 1: predose and 30 minutes, 3 hours, 5 hours, and 7 hours postdose and Days 2, 4, 8, and 15; Cycles 2 Day 1:predose Cycle 4 and 8, Day 1: predose and 1 hour postdose (each cycle is 21 days) | 
| Percentage of participants with TEAEs, AESIs as assessed by CTCAE version 5.0 | Evaluated from first dose to safety follow up visit. | Up to approximately 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-small-cell Lung Cancer, Triple-negative Breast Cancer, Dato-DXd, DS-1062a