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Phase 1, Open-Label, First-in-Human Study of DS-6157a in Subjects with Advanced Gastrointestinal Stromal Tumor

Phase 1, Open-Label, First-in-Human Study of DS-6157a in Subjects with Advanced Gastrointestinal Stromal Tumor

34

The majority of patients participating in this study were either Asian (16 patients, 47.1%) or White (16 patients, 47.1%), and there were more male patients (19 patients, 55.9%) than female patients (15 patients, 44.1%). The median age of patients was 60.5 (range: 29 to 81 years) years, with 67.6% of patients being between 18 to 64 years, and 32.4% of patients 65 or older. All patients enrolled in the study had advanced, metastatic GIST. The most frequent site for primary tumor location was the stomach (13 patients, 38.2%), followed by “other” (9 patients, 26.5%).

No. of subjects screened (signed ICF)　47 No. of subjects who met eligibility criteria and received study drug after signed ICF 34 No. of subjects used in the analysis of the primary endpoint 34

All 34 patients received at least one dose of DS-6157a. The median duration of treatment was 9.9 weeks (range: 3 to 65 weeks). Thirty-two patients (94.1%) experienced TEAEs considered related to DS-6157a by the Investigator. The most frequently reported TEAEs assessed as related to study drug were nausea (27 patients, 79.4%) and decreased appetite (17 patients, 50.0%). A total of 9 patients (26.5%) experienced at least one treatment-emergent serious adverse event (TESAE). The most frequently reported TESAEs by Preferred Term (PT) were abdominal pain, hepatic function abnormal, and platelet count decreased (2 patients each, 5.9%). One patient (2.9%) experienced a Grade 5 TEAE of hepatic function abnormal which was considered related to DS-6157a per Investigator assessment. Adverse events of special interest (AESIs) for this study included interstitial lung disease (ILD) and infusion-related reactions (IRR). One patient (2.9%) in the 6.4 mg/kg dose level experienced Grade 1 ILD. The study drug was withdrawn due to this event. The event was considered related to DS-6157a by the investigator. The conclusion of the ILD Adjudication Committee was that this was a non-ILD event. Four patients (11.8%) experienced IRRs during the study. None of the IRR events were serious TEAEs. No action was taken with the study drug for any of the events, with the exception of the Grade 3 event (study drug was withdrawn; the event was upgraded to a Grade 1 and eventually resolved). All of the IRR events were considered related to DS-6157a

In this Phase I study, although DS-6157a was generally well tolerated, GI toxicity was common. Myelosuppression was observed in patients and likely related to payload. TESAEs, including Grade 5 abnormal liver function were observed.

- There were no patients that achieved a complete response. One patient (2.9%) achieved a partial response (PR) and 17 patients (50.0%) had stable disease (SD).The median progression-free survival (PFS) was 4.2 months (95% confidence interval [CI] 1.6, 6.9). - In general, the systemic exposures (Cmax and AUCtau) of intact DS-6157a, total anti-GPR20 antibody, and MAAA-1181a increased in a dose-dependent manner.

Thirty-four patients were enrolled and treated in the Dose-Escalation part (Part 1) of this study. The Dose-Expansion part (Part 2) of this study was not conducted. Of the 34 patients who received DS-6157a, the majority (18 patients, 52.9%) discontinued study treatment due to progressive disease, followed by physician decision (6 patients, 17.6%). Two patients (5.9%) died on treatment, of which 1 patient (2.9%) died due to disease progression and 1 patient (2.9%) died due to an adverse event (AE). The MTD was determined to be 6.4 mg/kg. Seventeen patients (50.0%) and four patients (11.8%) experienced CTCAE Grade >=3 TEAEs and serious adverse events related to DS-6157a, respectvely. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response.

June. 06, 2023

No

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

May. 31, 2020

Interventional

multi center, open-label

treatment purpose

1

1. - Dose Escalation (Part 1): subjects should meet one of the following criteria:
a. (For US sites only) Subjects with GIST who have progressed on, or are intolerant to, imatinib (IM) and at least one post-IM treatment, or who are not candidates for post-IM standard of care treatment
b. (For Japan sites only) Subjects with GIST who have received all the existing standard of care treatments or who are not candidates for one or more available post-IM standard of care treatments
c. Subjects with GIST who are not candidates for IM or curative intent surgical treatment
- Dose Expansion (Part 2) Cohort 1: subjects with GIST who have progressed on or are intolerant to IM and at least one post-IM treatment
- Dose Expansion (Part 2) Cohort 2: subjects with GIST who have progressed on IM and had not received a post-IM treatment (2nd line)
2. LVEF >= 50% .
3. Has an ECOG PS 0-1.
4. Is aged >=20 years old in Japan or >=18 years old in other countries

1. Has a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety, efficacy, or any other assessments of the investigational regimen
2. Has a documented history of myocardial infarction or unstable angina within 6 months before study treatment
3. Has clinically significant pulmonary compromise or requirement for supplemental oxygen

Both

Advanced gastrointestinal stromal tumor (GIST)

investigational material(s)
Generic name etc : DS-6157a
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Dose Escalation Part : IV solution (Once every 3 weeks, initial dose 1.6 mg /kg)
Dose Expansion Part : IV solution (Once every 3 weeks, recommended dose for expansion part)


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

safety
efficacy
Dose Escalation Part: To evaluate the safety and tolerability and to determine the maximum tolerated dose and the recommended dose for expansion of DS-6157a.
Dose Expansion Part: To investigate the safety, tolerability and efficacy of DS-6157a.

efficacy
pharmacokinetics
other
1. To characterize the pharmacokinetic (PK) properties of DS-6157a, total anti- GPR20 antibody and drug component (MAAA-1181a)
2. To evaluate the efficacy of DS-6157a (Part 1 only)
3. To assess the incidence of anti-drug antibodies (ADAs) against DS-6157a

April. 08, 2020