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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.

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)

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.

DS-8201a (DP1)

DS-8201a is to be administered via intravenous (IV) dose. DS-8201a (DP2) was used only used for Dose Expansion Part 2e.

DS-8201a (DP2)

DS-8201a (DP) is to be administered via intravenous (IV) dose.

DS-8201a (DP)

Global Clinical Leader

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.

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

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

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

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.

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.

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.

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.

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.

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.

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.

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.

The serum PK parameters Maximum (peak) Observed serum concentration of DS-8201a and its analytes were estimated using standard non-compartmental method.

The serum PK parameters of Time of maximum plasma concentration (Tmax) for DS-8201a and its analytes were estimated using standard non-compartmental methods.

The serum PK parameters of Terminal elimination half-life for DS-8201a and its analytes was estimated using standard non-compartmental methods.

Treatment-emergent adverse events were graded by Common Terminology Criteria for Adverse Events, v4.03.

Daiichi Sankyo

AstraZeneca

Daiichi Sankyo Co., Ltd.

TEAEs were AEs that occur, having been absent before the first dose of study drug, or has worsened in severity or seriousness after the first dose until 28 days after the last dose. Serious adverse events with an onset or worsening ≥29 days after the last dose, if related to the study treatment, are also TEAEs. TEAEs from other HER2-expressing solid tumors other than breast or gastric were combined as prespecified in the protocol (excluding 1 patient with gastric cancer who received 5.4 mg/kg).

Participants in Cohort 1 received an intravenous 0.8 mg/kg dose of DS-8201a (FL-DP1).

Dose Escalation: Cohort 1, 0.8 mg/kg

Participants in Cohort 2 received an intravenous 1.6 mg/kg dose of DS-8201a (FL-DP1).

Dose Escalation: Cohort 2, 1.6 mg/kg

Participants in Cohort 3 received an intravenous 3.2 mg/kg dose of DS-8201a (FL-DP1).

Dose Escalation: Cohort 3, 3.2 mg/kg

Participants in Cohort 4 received an intravenous 5.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Escalation: Cohort 4, 5.4 mg/kg

Participants in Cohort 5 received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Escalation: Cohort 5, 6.4 mg/kg

Participants in Cohort 6 received an intravenous 8.0 mg/kg dose of DS-8201a (FL-DP1).

Dose Escalation: Cohort 6, 8.0 mg/kg

Participants with HER2-overexpressing breast cancer received an intravenous 5.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-positive Breast Cancer, 5.4 mg/kg

Participants with HER2-overexpressing breast cancer received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-positive Breast Cancer, 6.4 mg/kg

Participants with HER2-low expressing breast cancer received an intravenous 5.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-low Expressing Breast Cancer, 5.4 mg/kg

Participants with HER2-low expressing breast cancer received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-low Expressing Breast Cancer, 6.4 mg/kg

Participants with HER2-overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-overexpressing Gastric or GEJ, 5.4 mg/kg

Dose Expansion: HER2-overexpressing Gastric or GEJ, 6.4 mg/kg

Participants with any other HER2-expressing solid tumor other than breast or gastric or any tumor with HER2 mutation received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-expressing Other Solid Tumors

Participants with HER2-overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma received an intravenous 5.4 mg/kg dose of DS-8201a (FL-DP1).

Participants with HER2-expressing NSCLC tumors received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-expressing NSCLC Tumors

Participants with HER2-expressing colorectal tumors received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP1).

Dose Expansion: HER2-expressing Colorectal Tumors

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Japan

Region of Enrollment

Demographic and baseline characteristics were assessed in the Enrolled Analysis Set (Dose Escalation, n=27; Dose Expansion, n=265).

Contact for Clinical Trial Information

ORR was assessed among participants in the Intent-to-Treat Analysis Set.

Objective Response Rate (ORR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Escalation and Dose Expansion Phases)

DCR was assessed in the Intent-to-Treat Analysis Set.

Disease Control Rate (DCR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Escalation and Dose Expansion Phases)

Complete response

Partial response

Stable disease

Progressive disease

Non-evaluable

Best overall response was assessed in the Intent-to-Treat Analysis Set.

Best Overall Response Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Escalation and Dose Expansion Phases)

DoR was assessed among participants who achieved a CR or PR in the Intent-to-Treat Analysis Set.

Duration of Response (DoR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases)

Time to response was assessed among participants who achieved CR or PR in the Intent-to-Treat Analysis Set.

Time to Response (TTR) Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases)

PFS was assessed in the Intent-to-Treat Analysis Set.

Progression-free Survival Following Treatment With DS-8201a in Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases)

OS was assessed in the Intent-to-Treat Analysis Set.

Overall Survival Among Participants With Advanced Solid Malignant Tumors (Dose Expansion Phases)

AUClast

AUCinfinity

Japan only: Participants with HER2-expressing breast cancer received an intravenous 6.4 mg/kg dose of DS-8201a (FL-DP2).

Dose Expansion: HER2-expressing Breast Cancer

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.

Pharmacokinetic (PK) Analysis: Area Under the Concentration Versus Time Curve (AUC) of Serum DS-8201a Following First Dose

Pharmacokinetic Analysis: Maximum (Peak) Observed Serum Concentration (Cmax) of Serum DS-8201a Following First Dose

Pharmacokinetic Analysis: Time of Maximum Plasma Concentration (Tmax) of Serum DS-8201a Following First Dose

Pharmacokinetic Analysis: Terminal Elimination Half-life (t1/2) of Serum DS-8201a Following First Dose

Treatment-emergent adverse events (TEAEs)

Drug-related TEAEs

TEAEs ≥Grade 3

Drug-related TEAEs ≥Grade 3

Serious TEAEs (including AEs ending in death)

Drug-related serious TEAEs

TEAEs associated with death

Drug-related TEAEs associated with death

TEAEs associated with discontinuation of drug

Related TEAEs associated with drug discontinuation

TEAEs associated with dose reduction

Drug-related TEAEs associated with dose reduction

TEAEs associated with dose interruption

Related TEAEs associated with dose interruption

Safety events were assessed in the Safety Analysis Set. It was prespecified in the protocol that single patients with unique tumor types would be combined into 1 group for the safety analysis. For the safety overview, TEAEs for HER2-expressing NSCLC, Colorectal, and Other Solid Tumors (excluding 1 HER2-low gastric cancer subject who received 5.4 mg/kg) were combined and reported together.

Spots Global Cancer Trial Database for Study of DS-8201a in Subjects With Advanced Solid Malignant Tumors

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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