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Phase III Clinical Study of ME3208 in Patients with Steroid-Dependent/Resistant Chronic Graft Versus Host Disease

Phase III Clinigal Study of ME3208 in Patients with cGVHD

21

All the 21 subjects who received the study drug were included in the analysis sets. The median age was 50.0 years. The age was < 18 years in 1 subject (4.8%), >= 18 to < 65 years in 15 subjects (71.4%), and >= 65 years in 5 subjects (23.8%). As for gender, 7 subjects (33.3%) were female and 14 subjects (66.7%) were male. The median time from the last transplantation to the first diagnosis was 8.00 months, and the median duration of chronic GVHD was 23.70 months. Eighteen subjects (85.7%) were steroid-dependent, 1 subject (4.8%) was steroid-resistant, and 2 subjects (9.5%) were both steroid-dependent and resistant. Chronic GVHD was moderate in 12 subjects (57.1%) and severe in 9 subjects (42.9%). The median number of prior treatments for chronic GVHD was 2.0, and 3 subjects (14.3%) had a history of the use of ibrutinib. No subjects had the history of the use of ruxolitinib. The median dose of corticosteroids at baseline was 0.220 mg/kg/day. Five subjects (23.8%) had lesions in 4 or more organs. Common organs with lesions were the oral cavity (18 subjects), eyes (15 subjects) and skin (11 subjects).

Twenty-five subjects who gave consent were screened, and 21 eligible subjects were enrolled in the treatment period and received the study drug. Of these, 13 subjects were switched to post-marketing clinical study, and 8 subjects discontinued the study treatment. The reasons for discontinuation of the study treatment were progression of chronic GVHD (2 subjects), physician's judgment (2 subjects), progression or recurrence of malignancy (2 subjects), deviation regarding restricted concomitant medications (1 subject), and withdrawal by subject (1 subject). Of the 8 subjects who discontinued the study treatment, 3 subjects completed the follow-up and 5 subjects terminated the study. The reasons for discontinuation of the study were death (3 subjects), physician's judgment (1 subject) and withdrawal by subject (1 subject).

- AEs occurred in 19 of 21 subjects (90.5%) and were assessed as ADRs in 10 of these subjects (47.6%). - The AEs that occurred in 2 or more subjects were Cataract in 6 subjects (28.6%), COVID-19 in 5 subjects (23.8%), Diarrhoea in 4 subjects (19.0%), Herpes zoster, Back pain, Muscle spasms and Hypokalaemia in 3 subjects each (14.3%), Pneumonia, Sepsis, Constipation, Gastrooesophageal reflux disease, Large intestine polyp, Keratitis, Chillblains, Rash, Urticaria, Diabetes mellitus, Upper respiratory tract inflammation, Headache, Oedema, and Insomnia in 2 subjects each (9.5%). The ADRs that occurred in 2 or more subjects were Herpes zoster, COVID-19, Muscle spasms and Headache in 2 subjects each (9.5%). - Grade >= 3 AEs occurred in 10 of 21 subjects (47.6%). Of these, Grade 3 AEs were Cataract in 3 subjects (14.3%), COVID-19 and Pneumonia in 2 subjects each (9.5%) and Bronchitis, Bronchopulmonary aspergillosis, Skin infection, Pleural infection, Gastrointestinal polyp, Glaucoma, Pulmonary embolism, Headache, Hypopharyngeal cancer, Oesophageal carcinoma and Malignant mediastinal neoplasm in 1 subject each (4.8%). Grade 4 AEs were Sepsis in 2 subjects (9.5%) and Brain abscess, Pneumonia aspiration, Ileus, Cataract and Cardiac failure in 1 subject each (4.8%). Grade 5 AE was Acute myeloid leukaemia recurrent in 1 subject (4.8%). Grade >= 3 ADRs occurred in 2 of 21 subjects (9.5%) and were Grade 3 Pneumonia and Headache in 1 subject each (4.8%). - The incidence of AEs and ADRs did not tend to increase over time with continued treatment, regardless of the timing of treatment. - The incidence of AEs did not differ greatly by age (< 18 years/ >= 18 to < 65 years/ >= 65 years) and gender (male/female). - Three subjects died during the study. Two subjects died during the follow-up period because of Acute myeloid leukaemia. Another subject died during the post-treatment observation period because of the recurrence of Acute myeloid leukaemia, the malignancy treated by transplantation. The relationship of this event to the study drug was ruled out. - Serious AEs occurred in 10 of 21 subjects (47.6%). These events were cataract in 4 subjects (19.0%), Pneumonia, Sepsis and COVID-19 in 2 subjects each (9.5%) and Brain abscess, Bronchitis, Bronchopulmonary aspergillosis, Pneumonia aspiration, Skin infection, Pleural infection, Glaucoma, Ileus, Gastrointestinal polyp, Hypopharyngeal cancer, Oesophageal carcinoma, Acute myeloid leukaemia recurrent, Malignant mediastinal neoplasm, Cardiac failure, Headache and Pulmonary embolism in 1 subject each (4.8%). Of these, it was considered that a relationship with the study drug could not be ruled out for Pneumonia and Headache in 1 subject each (4.8%), however, both events resolved with treatment and the study treatment was continued. - AEs leading to discontinuation of treatment occurred in 2 of 21 subjects (9.5%). One of these subjects had Skin infection and the other subject experienced Acute myeloid leukaemia recurrent and Malignant mediastinal neoplasm, and treatment with the study drug was discontinued. Neither event was considered related to the study drug. - Most subjects showed no clinically significant changes in laboratory values, vital signs, and body weight. No Grade >= 3 AEs related to laboratory values, vital signs, or body weight were observed, and no serious events were observed. - One subject had QTcF > 500 msec and increase by > 60 msec from baseline at the time of discontinuation of the study drug, but except for this subject, no subjects had QTcF of > 480 msec or increase by > 60 msec from baseline during the treatment with the study drug.

- The best ORR (95% CI) at 24 weeks after enrollment of the last subject, which was the primary endpoint, was 85.7% (63.66, 96.95). The lower limit of 95% CI exceeded the predetermined threshold of 25% for efficacy assessment. Thus, the primary objective of this study was achieved. All responders showed PR. - The median primary DOR was not applicable (NA), and Kaplan-Meier estimates were 0.77 and 0.58 at 24 and 48 weeks, respectively. Secondary DOR was similar to that of Primary DOR. The median Quaternary DOR was NA, and Kaplan-Meier estimates were 0.83 and 0.76 at 24 and 48 weeks, respectively. - Responses were observed in organs of interest with lesions other than the lower gastrointestinal tract, with CR in all organs. No subjects with lesions in the liver were enrolled. The best ORR by organ including GSR of GVHD was 100.0% (1/1) for the upper gastrointestinal tract, 80.0% (4/5) for joint/fascia, 72.2% (13/18) for oral cavity, and 54.5% (6/11) for skin.

When ME3208 Tablet 200 mg was administered once daily to patients with steroid-dependent/resistant cGVHD, the best ORR (95% CI) was 85.7% (63.66, 96.95). Thus, the primary objective of this study was achieved. The median primary DOR was NA, and Kaplan-Meier estimates were 0.83 and 0.76 at 24 and 48 weeks, respectively, demonstrating the persistence of efficacy. No AEs specific to Japanese were observed, and there was no new concern regarding the safety of ME3208.

Mar. 25, 2025

June. 15, 2024

https://onlinelibrary.wiley.com/doi/10.1002/ajh.27424

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2011210041

Kijima Koji

Meiji Seika Pharma Co.,Ltd.

2-4-16, Kyobashi, Chuo-ku, Tokyo

clinical-trials@meiji.com

Kijima Koji

Meiji Seika Pharma Co.,Ltd.

2-4-16, Kyobashi, Chuo-ku, Tokyo

+81-3-3273-3746

clinical-trials@meiji.com

Complete

Nov. 01, 2021

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Patients who are able to provide written informed consent
2) Patients who received allogeneic hematopoietic cell transplantation (aHCT)
3) Patients diagnosed with moderate to severe chronic GVHD
4) Patients defined as steroid-dependent/refractory chronic GVHD at any time point after aHCT
5) Patients with the performance scale of 60 or more at baseline

1) Patients with active acute GVHD
2) Patients with post-transplant lymphoproliferative disease
3) Patients with a severe past history or complications (malabsorption syndrome, poorly controlled psychiatric disease, coronary artery disease, etc.) that may affect the evaluation of this study as judged by the principal investigator or subinvestigator
4) Patients who cannot maintain medication adherence as judged by the principal investigator or subinvestigator
5) Patients for whom the principal investigator or subinvestigator judged that the implementation of this study is inappropriate

Both

Chronic graft versus host disease

ME3208 tablets are administered orally once daily. Subjects will visit the study site until the treatment discontinuation criteria are met or the study treatment is completed. The designated examination, observation, and investigation will be conducted at each visit.

Efficacy: best overall response rate (best ORR) [Percentage of participants who achieve complete response (CR) or partial response (PR)]
Safety: The safety are assessed by subjective symptoms, objective findings, physiological and clinical examinations.

The efficacy of ME3208 are evaluated using duration of response (DOR), best ORR by organ and time point, time to response (TTR) , etc. as secondary outcomes.
Evaluate the pharmacokinetics after administration of ME3208.

+81-11-706-7061

Oct. 19, 2021

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