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Phase 1, Multicenter, Open-Label, Multiple-Dose Study of DS-8201a to Assess the Effect on the QT Interval, and Pharmacokinetics in Subjects with HER2-Expressing Metastatic and/or Unresectable Breast Cancer

Phase 1 Study to Evaluate the Effect of DS-8201a on the QT/QTc Interval in HER2-Expressing Breast Cancer

51

51 subjects were enrolled and treated. All subjects were female and Asian; the median age at signature of informed consent was 56.0 years (range: 31 to 79). All subjects had Stage IV BC and most (47 of 51) had low HER2-expression (defined as HER2 IHC 1+ or 2+, without positive ISH), with 72.5% (37 of 51) of subjects with HER2 IHC1+ tumors; the remaining 4 of 51 subjects were HER2 positive. Subjects were heavily pretreated and 66.7% had received more than 5 lines of therapy for advanced BC.

Subject Enrolled: n = 51 Subject Treated: n = 51 <Primary Endpoint> Pharmacokinetic Analysis set (Pharmacokinetic Results): n = 51 Cardiac Safety Analysis set (Analysis of QTcF Interval): n = 49 <Secondary Endpoint> Efficacy Analysis set (Efficacy Results): n = 51 Safety Analysis set (Safety Results): n = 51

All patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or 4 drug-related events occurred in 41 (80.4%) patients. The most common (>50%) any-grade drug-related TEAEs included nausea (n = 42, 82.4%), neutrophil count decreased (n = 36, 70.6%), white blood cell count decreased (n = 33, 64.7%), and anemia (n = 31, 60.8%). The most common grades >=3 drug-related TEAEs (>10%) were neutrophil count decreased (n = 26, 51.0%), white blood cell count decreased (n = 16, 31.4%), anemia (n = 7, 13.7%), and lymphocyte count decreased (n = 7, 13.7%). SAEs occurred in 8 (15.7%) patients. The 4 (7.8%) drug-related SAEs were nausea (n = 2, 3.9%), ILD (n = 1, 2.0%), and pneumonitis (n = 1, 2.0%). Out of 51 patients, dose interruption, dose reduction, or study withdrawal due to AEs were required in 35 (68.6%), 7 (13.7%), and 14 (27.5%) patients, respectively. There were no TEAEs resulting in death. Five (9.8%) patients experienced grade 1 QT prolongation (450 to <480 ms), but all recovered and continued in the study. There were no SAEs, no patients required medication, and no action was taken with T-DXd because of QT prolongation. One patient had a treatment-related grade 2 decreased ejection fraction, and the patient was withdrawn from the study because of the event. There were 13 subjects (25.5%) who had ILD/pneumonitis events adjudicated as drug-related by an independent ILD Adjudication Committee. Most (11/13; 84.6%) ILD/pneumonitis events were grade 1 or 2; two (15.4%) events were grade 3.

Pharmacokinetic Results: DS-8201a mean maximum serum concentration (Cmax) was 179 ug/mL at Cycle 1 and 154 ug/mL at Cycle 3. DS-8201a mean area under the serum concentration-time curve during the dosing interval (AUCtau) was 677 ug*d/mL at Cycle 1 and 905 ug*d/mL at Cycle 3. The concentration profile of the total anti-HER2 antibody was similar to that of DS-8201a: Total anti-HER2 antibody mean Cmax was 165 ug/mL at Cycle 1 and 142 ug/mL at Cycle 3; the mean total anti-HER2 antibody AUCtau was 752 ug*d/mL at Cycle 1 and 1030 ug*d/mL at Cycle 3. MAAA-1181a exposure was low compared to exposures of DS-8201a and total anti-HER2 antibody: The mean MAAA-1181a Cmax was 12.6 ng/mL at Cycle 1 and 9.60 ng/mL at Cycle 3, and the mean MAAA-1181a AUCtau was 39.0 ng*d/mL at Cycle 1 and 41.5 ng*d/mL at Cycle 3. The mean accumulation ratio (AR) for AUCtau at Cycle 3 was 1.35 for DS-8201a, 1.36 for total anti-HER2 antibody, 1.09 for MAAA-1181a, which was consistent with the observed terminal elimination half-life of DS-8201a. Analysis of QTcF Interval: DS-8201a 6.4 mg/kg administration was not associated with a clinically meaningful (change from baseline >10 milliseconds) QTcF prolongation. A slight increase in the mean QTcF interval was observed for up to 7 hours post-dose at both Cycles 1 and 3. However, no prolongation of the mean change from baseline in QTcF was observed on Cycle 1 and Cycle 3 Day 8 and Day 15 (The difference of QTcF <0 milliseconds). The upper bound of the 90% CI was under 10 milliseconds at all time points. There was a slightly positive trend towards increase in the difference of QTcF with increase in concentrations of DS-8201a and MAAA-1181a. However, the upper bound of the 90% CI for the difference of QTcF at the observed mean Cmax for each analyte in the linear model of concentration versus change from baseline in mean QTcF was under 10 milliseconds for Cycle 1 and Cycle 3. Additionally, almost all observations of change of QTcF around the median time to maximum serum concentration (Tmax) for DS-8201a were below 10 milliseconds.

Efficacy Results: Of 51 subjects, 22 (43.1%) had a BOR (confirmed) of partial response (PR); no subjects had complete response (CR). The investigator-assessed ORR (confirmed) was 43.1% (95% CI: 29.3, 57.8). The median DoR was 8.54 (95% CI: 5.13, 15.38) months. The median TTR for responders was 2.99 (95% CI: 2.63, 4.14) months. The DCR was 84.3% (95% CI: 71.4, 93.0). The median best percent change from baseline in SLD of tumor lesions for subjects with measurable tumors was -34.67% (range: -77.1 to 18.3). PFS events occurred in 34 subjects (66.7%), all of which were due to PD. The median PFS was 8.08 (95% CI: 5.59, 10.22) months, and no subject died. The median OS was 27.07 (95% CI: 20.53, -) months. Safety Results: The median duration of treatment was 7.0 months (range: 0.7 to 26.5). The median relative dose intensity was 94%. For the details of the adverse events, please see the above section " adverse events".

This study characterized the PK profile of DS-8201a after multiple dosing and demonstrated that DS-8201a has no clinically meaningful impact on the QTc interval. Furthermore, the results of this study support a manageable safety profile and antitumor activity of DS-8201a in patients with HER2-expressing metastatic and/or unresectable BC.

Yes

Plan Description: 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/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Dec. 26, 2017

Interventional

multi center, open-label

treatment purpose

1

1. Has a pathologically documented unresectable or metastatic breast cancer with HER2 expression (immunohistochemistry [IHC] 3+, IHC 2+, IHC 1+ and/or in situ hybridization [ISH]* +) that is refractory to or intolerable with standard treatment, or for which no standard treatment is available.
2. LVEF >= 50% .
3. Has an ECOG PS 0 or 1.

1. Has a medical history of myocardial infarction within 6 months before enrollment.
2. Has a medical history of ventricular arrhythmias, other than rare, occasional premature ventricular contractions.
3. Has uncontrolled or significant cardiovascular disease,

Both

Breast Cancer

investigational material(s)
Generic name etc : DS-8201a
INN of investigational material : trastuzumab deruxtecan
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : IV solution (Once every 3 weeks, 6.4 mg/kg)

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

pharmacokinetics
other
-To assess the effect of DS-8201a on the QTc interval
-To assess PK after multiple dosing of DS-8201a

Baseline-adjusted QTcF interval, serum concentration and PK parameters of DS-8201a, total anti-HER2 antibody, and MAAA-1181a.

safety
efficacy
-Concentration-QT,
-Objective response rate (ORR)
-Disease control rate (DCR)

RECIST Version 1.1

Nov. 15, 2017