Study of DS-8201a in Subjects With Advanced Solid Malignant Tumors

Study Overview
=================
Brief Summary
-----------------
This is an open-label, two-part, multicenter study to evaluate the safety and tolerability of DS-8201a in participants with advanced solid malignant tumors.

Official Title
-----------------
Phase 1, Two-Part, Multicenter, Non-randomized, Open-label, Multiple Dose First-In-Human Study of DS-8201A, in Subjects With Advanced Solid Malignant Tumors

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: DS-8201a (DP1)
* Drug: DS-8201a (DP2)
* Drug: DS-8201a (DP)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group performance status( PS) of 0 or 1. Left Ventricular Ejection Fraction (LVEF) ≥ 50% Part 1: Advanced/unresectable or metastatic breast cancer or gastric or gastroesophageal junction adenocarcinoma that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Part 2a: Advanced breast cancer with HER2 overexpression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Treated with ado-trastuzumab emtansine (T-DM1) Part 2b: Advanced gastric or gastroesophageal junction adenocarcinoma with HER2 overexpression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Treated with trastuzumab Part 2c: Advanced breast cancer with HER2 low expression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Part 2d: Satisfy at least one of the following criteria Advanced/unresectable or metastatic solid malignant tumor with HER2 expression other than breast cancer and gastric or gastroesophageal junction adenocarcinoma that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Advanced/unresectable or metastatic tumor with HER2 mutation that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Part 2e: Advanced breast cancer with HER2 overexpression that is refractory to or intolerable with standard treatment, or for which no standard treatment is available. Treated with ado-trastuzumab emtansine (T-DM1) (patients with HER2 overexpression only) Exclusion Criteria: Has a medical history of symptomatic Congestive Heart Failure (CHF) (NYHA classes II-IV) or serious cardiac arrhythmia. Has a medical history of myocardial infarction or unstable angina. Has a QTc prolongation to > 450 millisecond (ms) in males and > 470 ms in females. Has a medical history of clinically significant lung diseases

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

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Dose escalation<br>Part 1 is a dose escalation to identify the Maximum Tolerated dose (MTD) or the recommended phase 2 dose of DS-8201a guided by the modified continuous reassessment method using a Bayesian logistic regression model following escalation with overdose control principal. | Drug: DS-8201a (DP1)<br>* DS-8201a to be administered via intravenous (IV) dose. DS-8201a (DP1) was used for the Dose Escalation phase and for Dose expansion Parts 2a, 2b, 2c, and 2d.<br>Drug: DS-8201a (DP)<br>* DS-8201a (DP) is to be administered via intravenous (IV) dose.<br>|
| Experimental: Part 2 Dose expansion<br>Part 2 is a dose expansion to examine the safety and efficacy of DS-8201a and it is consist of multiple cohorts: in subjects with trastuzumab emtansine (T-DM1)-treated HER2 overexpressing breast cancer (Part 2a); trastuzumab-treated HER2 overexpressing gastric or gastroesophageal junction adenocarcinoma (Part 2b); HER2 low expressing breast cancer (Part 2c), HER2 expressing other solid malignant tumor (Part 2d); HER2 expressing breast cancer (Japan only; Part 2e) | Drug: DS-8201a (DP1)<br>* DS-8201a to be administered via intravenous (IV) dose. DS-8201a (DP1) was used for the Dose Escalation phase and for Dose expansion Parts 2a, 2b, 2c, and 2d.<br>Drug: DS-8201a (DP2)<br>* DS-8201a is to be administered via intravenous (IV) dose. DS-8201a (DP2) was used only used for Dose Expansion Part 2e.<br>Drug: DS-8201a (DP)<br>* DS-8201a (DP) is to be administered via intravenous (IV) dose.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Escalation and Dose Expansion Phases) | Objective response rate (ORR) by independent central review was defined as the proportion of participants who achieve either complete response [CR] or partial response [PR] per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. HER2-positive other solid tumors included participants with salivary/submandibular/parotid gland (8 participants), breast with HER2-mutation (2 participants), endometrial (2 participants), esophageal (2 participants), Paget's disease (2 participants), cholangiocarcinoma (1 participant), extraskeletal myxoide chondrosarcoma (1 participant), gallbladder (1 participant), pancreatic (1 participant), small intestine (1 participant), uterine cervix (1 participant) and HER2-low gastric/GEJ (1 participant who received 5.4 mg/kg) cancer. | From 6 months postdose of last participant up to 3 years 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Escalation and Dose Expansion Phases) | Disease control rate (DCR) by independent central review was calculated as the proportion of participants demonstrating complete response (CR), partial response (PR), or stable disease (SD) for a minimum of 6 weeks (±1week) from the first dosing date. CR was defined as a disappearance of all target lesions, PR as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. HER2-positive other solid tumors included 8 participants with salivary/submandibular/parotid gland, 2 breast with HER2-mutation, 2 endometrial, 2 esophageal, 2 Paget's disease, 1 cholangiocarcinoma, 1 extraskeletal myxoide chondrosarcoma, 1 gallbladder, 1 pancreatic, 1 small intestine, 1 uterine cervix, and 1 participant who received 5.4 mg/kg with HER2-low gastric/GEJ cancer. | From 6 months postdose of last participant up to 3 years 5 months | 
| Best Overall Response Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Escalation and Dose Expansion Phases) | Best overall response by independent central review was defined as the proportion of participants who achieved either complete response [CR], partial response [PR], stable disease (SD), progressive disease (PD), or were non-evaluable (NE) as per RECIST v1.1. CR was defined as a disappearance of all target lesions, PR at least a 30% decrease in the sum of diameters of target lesions, and SD as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD defined as at least a 20% increase in the sum of diameters of target lesions. HER2-positive other solid tumors included 8 participants with salivary/submandibular/parotid gland, 2 breast with HER2-mutation, 2 endometrial, 2 esophageal, 2 Paget's disease, 1 cholangiocarcinoma, 1 extraskeletal myxoide chondrosarcoma, 1 gallbladder, 1 pancreatic, 1 small intestine, 1 uterine cervix, and 1 participant who received 5.4 mg/kg with HER2-low gastric/GEJ cancer. | From 6 months postdose of last participant up to 3 years 5 months | 
| Duration of Response (DoR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases) | Duration of response (DoR) by independent central review was defined as the time between the date of the first complete response (CR) or partial response (PR) until the date of the first documentation of progressive disease (PD) or death due to any cause. CR was defined as a disappearance of all target lesions, PR as at least a 30% decrease in the sum of diameters of target lesions, and PD as at least a 20% increase in the sum of diameters of target lesions. HER2-positive other solid tumors included participants with salivary/submandibular/parotid gland (8 participants), breast with HER2-mutation (2 participants), endometrial (2 participants), esophageal (2 participants), Paget's disease (2 participants), cholangiocarcinoma (1 participant), extraskeletal myxoide chondrosarcoma (1 participant), gallbladder (1 participant), pancreatic (1 participant), small intestine (1 participant), uterine cervix (1 participant) and HER2-low gastric/GEJ (1 participant who received 5.4 mg/kg) cancer. | From 6 months postdose of last participant up to 3 years 5 months | 
| Time to Response (TTR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases) | Time to response (TTR) by independent central review was defined as the time interval between the date of registration until the date at which the criteria were first met for complete response (CR) or partial response (PR). Only participants who achieved CR or PR were included in the TTR analysis. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. HER2-positive other solid tumors included participants with salivary/submandibular/parotid gland (8 participants), breast with HER2-mutation (2 participants), endometrial (2 participants), esophageal (2 participants), Paget's disease (2 participants), cholangiocarcinoma (1 participant), extraskeletal myxoide chondrosarcoma (1 participant), gallbladder (1 participant), pancreatic (1 participant), small intestine (1 participant), uterine cervix (1 participant) and HER2-low gastric/GEJ (1 participant who received 5.4 mg/kg) cancer. | From 6 months postdose of last participant up to 3 years 5 months | 
| Progression-free Survival Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases) | Progression-free survival (PFS) by independent central review was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. HER2-positive other solid tumors included participants with salivary/submandibular/parotid gland (8 participants), breast with HER2-mutation (2 participants), endometrial (2 participants), esophageal (2 participants), Paget's disease (2 participants), cholangiocarcinoma (1 participant), extraskeletal myxoide chondrosarcoma (1 participant), gallbladder (1 participant), pancreatic (1 participant), small intestine (1 participant), uterine cervix (1 participant) and HER2-low gastric/GEJ (1 participant who received 5.4 mg/kg) cancer. | From 6 months postdose of last participant up to 3 years 5 months | 
| Overall Survival Among Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases) | Overall survival (OS) by independent central review was defined as the time interval from the date of enrollment to the date of death from any cause. HER2-positive other solid tumors included participants with salivary/submandibular/parotid gland (8 participants), breast with HER2-mutation (2 participants), endometrial (2 participants), esophageal (2 participants), Paget's disease (2 participants), cholangiocarcinoma (1 participant), extraskeletal myxoide chondrosarcoma (1 participant), gallbladder (1 participant), pancreatic (1 participant), small intestine (1 participant), uterine cervix (1 participant) and HER2-low gastric/GEJ (1 participant who received 5.4 mg/kg) cancer. | From 6 months postdose of last participant up to 3 years 5 months | 
| Pharmacokinetic (PK) Analysis: Area Under the Concentration Versus Time Curve (AUC) of Serum DS-8201a Following First Dose | The serum PK parameters of DS-8201a and its analytes for area under the concentration-versus-time curve from time 0 to the last quantifiable concentration as calculated by the linear-up log-down trapezoidal method (AUClast) and AUC from time 0 to infinity (AUCinf) elimination rate constant associated with the terminal phase were estimated using standard non-compartmental methods. | Post first dose up to Day 147 | 
| Pharmacokinetic Analysis: Maximum (Peak) Observed Serum Concentration (Cmax) of Serum DS-8201a Following First Dose | The serum PK parameters Maximum (peak) Observed serum concentration of DS-8201a and its analytes were estimated using standard non-compartmental method. | Post first dose up to Day 147 | 
| Pharmacokinetic Analysis: Time of Maximum Plasma Concentration (Tmax) of Serum DS-8201a Following First Dose | The serum PK parameters of Time of maximum plasma concentration (Tmax) for DS-8201a and its analytes were estimated using standard non-compartmental methods. | Post first dose up to Day 147 | 
| Pharmacokinetic Analysis: Terminal Elimination Half-life (t1/2) of Serum DS-8201a Following First Dose | The serum PK parameters of Terminal elimination half-life for DS-8201a and its analytes was estimated using standard non-compartmental methods. | Post first dose up to Day 147 | 
| Overview of Treatment-emergent Adverse Events | Treatment-emergent adverse events were graded by Common Terminology Criteria for Adverse Events, v4.03. | Baseline up to 28 days after the last dose of study drug, up to 3 years 5 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Advanced solid tumors, phase 1, oncology, HER2, Antibody drug conjugate (ADC)