臨床研究等提出・公開システム

A Phease1, Multicenter, Open-Label, Single Sequence Crossover Study to Evaluate Drug-Drug Interaction Potential of OATP1B/CYP3A Inhibitor on The Pharmacokinetics of DS-8201a in Subjects with HER2-Expressing Advanced Solid Malignant Tumors

Phase 1 study of DS-8201a in subject with Advanced Solid Malignant Tumors

40

The median age of subjects in the Safety Analysis Set was 57.0 years (range: 31 to 80). Most of the subjects were less than 65 years old (70.0% [n = 28]). Females represented 55.0% of the subjects (n = 22), while males accounted for 45.0% (n = 18). All subjects were Asian. The most common type of cancer observed was breast cancer in 17 subjects (42.5%), followed by salivary gland cancer in 9 subjects (22.5%). Of subjects who had IHC data available, the majority (45.0% [n = 18]) were IHC 3+.

Forty subjects (Cohort1 [ritonavir]: 17, Cohort2 [itraconazole]: 23) were enrolled and received at least 1 dose of DS-8201a, and all subjects had discontinued the study. All 40 enrolled subjects were included in the Safety Analysis Set and the Efficacy Analysis Set.The primary PK analysis was conducted after all subjects had either discontinued the study or completed at least 3 cycles of DS-8201a. The PK Analysis Set included 26 subjects (Cohort1: 12, Cohort2: 14).

- The median treatment duration was 265.5 (range: 21 to 1935) days. - Thirty-nine subjects (97.5%) experienced at least 1 TEAE. At the system organ class level, TEAEs were most frequently reported in the category of gastrointestinal disorders (37 subjects [92.5%]), followed by investigations (31 subjects [77.5%]). The most frequently reported preferred terms (>= 30% overall) were nausea (33 subjects [82.5%]), decreased appetite (24 subjects [60.0%]), constipation and neutrophil count decreased (16 subjects [40.0%] each), diarrhoea, alopecia, platelet count decreased, and white blood cell count decreased (14 subjects [35.0%] each), and anaemia, fatigue, and aspartate aminotransferase increased (12 subjects [30.0%] each). - Thirty-eight subjects (95.0%) experienced TEAEs related to DS-8201a. The most frequently reported TEAEs related to DS-8201a (>= 30% overall) were nausea (33 subjects [82.5%]), decreased appetite (23 subjects [57.5%]), neutrophil count decreased (16 subjects [40.0%]), alopecia and white blood cell count decreased (14 subjects [35.0%] each), platelet count decreased (13 subjects [32.5%]), and aspartate aminotransferase increased (12 subjects [30.0%]). - Twenty-four subjects (60.0%) experienced TEAEs of >= Grade 3. - One subject (2.5%) experienced Grade 5 disease progression. This event was not considered to be related to DS-8201a. There were no other subjects who experienced TEAEs leading to death besides this subject. - Nine subjects (22.5%) experienced treatment-emergent SAEs (TESAEs). The event of pyrexia, reported in 2 subjects (5.0%), was the only TESAE reported in more than 1 subject. Treatment-emergent SAEs related to DS-8201a included pneumonitis, diarrhoea, nausea, vomiting, and malaise. - A total of 8 subjects (20.0%) experienced potential ILD/pneumonitis events, all of which were adjudicated as drug related ILD by the ILD Adjudication Committee (AC). All of these events were either Grade 1 (5 subjects [12.5%]) or Grade 2 (3 subjects [7.5%]). Five of these 8 events led to drug withdrawal. Of the 8 events, 1 event (Grade 2) was considered serious due to hospitalization and led to drug withdrawal. - One subject (2.5%) experienced an LV dysfunction on Day 255. This non serious, Grade 1 event of ejection fraction decreased was considered related to DS-8201a and it remained unresolved.

Pharmacokinetic results: The AUC17d ratio (90% CI) of DS-8201a in Cohort1 (ritonavir) and Cohort 2 (itraconazole) was determined to be 1.1921 (1.1404-1.2461) and 1.1095 (1.0732-1.1470) within the range for 0.8-1.25, respectively. It was also determined that for DS-8201a (Intact), concomitant use of ritonavir and itraconazole would not affect the exposure of DS-8201a. The AUC17d ratio (90% CI) of MAAA-1181a in Cohort1 (ritonavir) and Cohort 2 (itraconazole) was determined to be 1. 2151 (1.078-1.3696) and 1.1778 (1.1081-1.2519). These investigations concluded that for MAAA-1181a, concomitant use of ritonavir (dual inhibitor of OATP1B/CYP3A) and itraconazole (strong CYP3A inhibitor) resulted in a minimal increase on exposure of MAAA-1181a. The ratios of the payload are similar to those of DS-8201. In summary, DDIs did not cause clinically meaningful increase in exposure of MAAA-1181a.

Safety results: The median treatment duration was 265.5 (range: 21 to 1935) days. Thirty-nine subjects (97.5%) experienced at least 1 TEAE and thirty-eight subjects (95.0%) experienced TEAEs related to DS-8201a. The details are described in the summary of Adverse Events. Efficacy results: The median study duration was 9.49 (range: 0.1 to 63.8) months. The evaluation of tumor response included only subjects with measurable tumors at baseline. Among the 36 subjects in both cohorts with measurable tumors at baseline, 1 subject (2.8%) had CR, 19 subjects (52.8%) had PR, 15 subjects (41.7%) had SD, and 1 subject (2.8%) had PD as the best response. The ORR was 55.6% (95% CI: 38.1, 72.1), the DCR was 97.2% (95% CI: 85.5, 99.9), and the CBR was 75.0% (95% CI: 57.8, 87.9). The confirmed ORR, defined as a confirmed response of CR or PR according to RECIST version 1.1 criteria, was 52.8% (95% CI: 35.5, 69.6). Among all responding subjects with CR or PR, the median DoR was 376.0 days (95% CI: 209.0, not estimated) and the median TTR was 46.0 days (95% CI: 42.0, 85.0). The median duration of SD was 381.0 days (95% CI: 138.0, not estimated). The median PFS was 419.0 days (95% CI: 260.0, 596.0). Responses were observed across a variety of tumor types.

The concomitant use of ritonavir (a dual inhibitor of OATP1B/CYP3A) and itraconazole (a strong CYP3A inhibitor) would not affect clinically meaningful increase in exposure of DS-8201a and MAAA-1181a. Furthermore, the results from the final analysis continued to support an acceptable and generally manageable safety profile and antitumor activity of DS-8201a in subjects with HER2 expressing advanced solid malignant tumors.

Nov. 01, 2021

https://aacrjournals.org/clincancerres/article/27/21/5771/671782/Pharmacokinetics-Safety-and-Efficacy-of

Yes

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Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

completed

Jan. 24, 2018

Interventional

multi center, open-label

treatment purpose

1

1.Has a pathologically documented unresectable or metastatic solid malignant tumors with HER2 expression (determined by immunohistochemistry [IHC]/in situ hybridization [ISH] [IHC 3+, IHC 2+, IHC 1+, and/or ISH +], Next Generation Sequencing, or other analysis techniques as appropriate) that is refractory to or intolerable with at least 1 prior systemic chemotherapy regimen, or for which no standard treatment is available.
2. LVEF >= 50% .
3. Has an ECOG PS 0 or 1.

1. Has a contraindication for receiving ritonavir or itraconazole according to the prescribing information.
2. Has a medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure.
3. Has complications of ventricular arrhythmia

Both

Advanced Solid Malignant Tumors

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, 5.4 mg/kg)

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

pharmacokinetics
- PK parameters of DS-8201a and MAAA-1181a (with/without ritonavir)
- PK parameters of DS-8201a and MAAA-1181a (with/without itraconazole)

- PK parameters (Cmax and AUC0-17d) of DS-8201a and MAAA-1181a (with/without ritonavir)
- PK parameters (Cmax and AUC0-17d) of DS-8201a and MAAA-1181a (with/without itraconazole)

safety
efficacy
pharmacogenomics
- Serious adverse events (SAEs)
- Treatment emergent adverse event
- Discontinuation due to AE
- Discontinuation due to adverse events of special interest (AESIs)
- Physical examination findings (including Eastern Cooperative Oncology Group Performance Status [ECOG PS])
- Vital sign measurements
- Standard clinical laboratory parameters
- 12-lead ECG parameters
- ECHO or MUGA findings
- Ophthalmologic findings
- Anti-drug antibodies

Follow the Clinical Study Protocol

+81-53-435-2850

Dec. 14, 2017