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A phase 2, multicenter, open-label, single-arm study of Valemetostat Tosylate (DS-3201b) in patients with relapsed or refractory adult T-cell leukemia/lymphoma

Valemetostat Tosylate (DS-3201b) Phase 2 study in relapsed or refractory adult T-cell leukemia/lymphoma

25

The median age of the subjects at the informed consent was 69 .0 years (range: 59 to 84)and 24 of 25 subjects (96 .0%) were >=65 years of age. Twelve subjects (48 .0%) were male and all of them were Asian, enrolled in Japan. The most common Adult T-cell Leukemia/lymphoma (ATL) subtype was acute (16 of 25 subjects, 64 .0%), followed by lymphomatous (6 of 25 subjects, 24 .0%) and unfavorable chronic (3 of 25 subjects, 12 .0%). The median number of prior ATL regimens was 3.0 (range: 1 to 8). Twenty-four subjects (96 .0%) had prior treatment with mogamulizumab and eight subjects (32 .0%) had prior treatment with lenalidomide.

A total of 25 subjects with relapsed or refractory ATL who met all inclusion and no exclusion criteria were received the study drug and were included in the primary efficacy analysis set and safety analysis set.

- All the 25 subjects experienced TEAEs. Overall the most frequently reported TEAEs (>=20%) were as follows: platelet count decreased (21 subjects [84.0%]), anaemia (12 subjects [48.0%]), neutrophil count decreased (7 subjects [28.0%]), lymphocyte count decreased (6 subjects [24.0%]), white blood cell count decreased (5 subjects [20.0%]), alopecia (10 subjects [40.0%]), dysgeusia(9 subjects [36.0%]), pyrexia, decreased appetite, muscle spasm, and dry skin (5 subjects [20.0%] each). - Almost all subjects (24 subjects, 96.0%) experienced drug-related TEAEs. The most common (>=10%) drug-related TEAEs were platelet count decreased (21 subjects [84.0%]), anaemia (11 subjects [44.0%]), alopecia (10 subjects [40.0%]), dysgeusia (9 subjects [36.0%]), lymphocyte count decreased, neutrophil count decreased, and white blood cell count decreased (5 subjects [20.0%] each), decreased appetite (4 subjects [16.0%]), malaise, and stomatitis (3 subjects [12.0%] each). - Grade >=3 TEAEs occurred in 17 subjects overall (68.0%). The most common (>=10%) TEAEs with Grade >=3 were anaemia, platelet count decreased (8 subjects [32.0%] each), lymphocyte count decreased, neutrophil count decreased, and white blood cell count decreased (4 subjects [16.0%] each). - There were no reports of Grade 5 TEAEs or TEAEs associated with death outcome. - Eight subjects (32.0%) experienced serious TEAEs. The reported serious TEAEs were all singular events (1 subject [4.0 %] each) with no obvious trends. Serious drug-related TEAEs occurred in 8 subjects (32.0%). The events were acute kidney injury, cardiac failure, COVID-19, cytomegalovirus chorioretinitis, cytomegalovirus infection reactivation, febrile neutropenia, hepatic function abnormal, lower gastrointestinal haemorrhage, platelet count decreased, pneumonia, and venous thrombosis limb (1 subject [4.0%] each). All but cytomegalovirus chorioretinitis (recovered/resolved with sequelae) were resolved or resolving. - TEAEs associated with study treatment discontinuation occurred in 2 subjects; 1 subject each discontinued due to cardiac failure and platelet count decreased. The event of platelet count decreased was non-serious and unresolved while the cardiac failure event was serious and resolving. - TEAEs associated with study treatment dose reduction occurred in 2 of the 25 subjects (8.0%). The events were acute kidney injury, hepatic function abnormal, and decreased appetite (1 subject [4.0%] each). The events of hepatic dysfunction and acute renal failure in the same subject were serious and both resolved. - TEAEs associated with study treatment dose interruption occurred in 7 of the 25 subjects (28.0%). The events were febrile neutropenia, platelet count decreased, COVID-19 (2 subjects [8.0%] each), anaemia, cytomegalovirus chorioretinitis, lower gastrointestinal haemorrhage, neutrophil count decreased, photosensitivity reaction, and pulmonary haemorrhage (1 subject [4.0%] each). The events of COVID-19, lower gastrointestinal haemorrhage, febrile neutropenia, platelet count decreased, and cytomegalovirus chorioretinitis (1 subject [4.0%] each) were serious and all but cytomegalovirus chorioretinitis (recovered/resolved with sequelae) were resolved.

The ORR assessed by the Efficacy Assessment Committee was 52.0% (90% CI: 34.1, 69.5; nominal p < 0.0001) in the final analysis. Based on the assessment by the Efficacy Assessment Committee, 5 of 25 subjects (20.0%) achieved CR and 8 subjects (32.0%) achieved PR.

Results of the secondary efficacy endpoints are based on the assessment by the Efficacy Assessment Committee, except for the ORR assessed by the investigator or subinvestigator and the OS. - The ORR as assessed by the investigator or subinvestigator was 56.0% (90% CI: 37.9, 73.0; nominal p < 0.0001). Based on the assessment by the investigator or subinvestigator, 6 of 25 subjects (24.0%) achieved CR, 1 (4.0%) achieved CRu, and 7 (28.0%) achieved PR. - The ORR by disease site as assessed by the Efficacy Assessment Committee was 50.0% for 20 subjects with disease in target lesions (nodal or extranodal lesions), 100.0% for 9 subjects with disease in peripheral blood, and 42.9% for 7 subjects with disease in skin lesions. - The CR rate as assessed by the Efficacy Assessment Committee was 20.0% (95% CI:6.8, 40.7), and the TCR as assessed by the Efficacy Assessment Committee was 88.0% (95% CI: 68.8,97.5). The median TTR as assessed by the Efficacy Assessment Committee was 8.00 weeks (4.1 to 92.1). - The median DOR as assessed by the Efficacy Assessment Committee was 26.86 weeks (95% CI: 8.14, 62.43). Of the 13 responders, 9 subjects (69.2%) had experienced RD/PD or death in the final analysis and 4 subjects (30.8%) were censored on the day of the last available tumor response assessment. The reasons for censoring were "new anticancer therapy" for 3 subjects and "other" for 1 subject. - The median PFS as assessed by the Efficacy Assessment Committee was 31.14 weeks (95% CI: 13.14, 40.29). A total of 18 subjects (72.0%) experienced RD/PD or death in the final analysis and 7 subjects (28.0%) were censored on the day of the last available tumor response assessment. The reasons for censoring were "new anticancer therapy" for 6 subjects and "other" for 1 subject. - The median OS was 71.43 weeks (95% CI: 31.29, 126.86). Of 25 subjects, 23 (92.0%) died by in the final analysis and 2 subjects (8.0%) were censored on the day of the last survival confirmation. Both reasons for censoring were "alive".

The final analysis showed valemetostat tosylate exerted a high response rate and with a potentially durable antitumor effect. Safety results of the final analysis continued to demonstrate that the most common TEAEs of valemetostat tosylate were mainly cytopenic in nature including platelet count decreased, which was manageable with monitoring and dose modification, and tolerable through the study.

Mar. 09, 2023

https://ashpublications.org/blood/article/141/10/1159/486703/An-open-label-single-arm-phase-2-trial-of

Yes

De-identified individual participant data (IPD) on completed studies 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 Information: -Study Protocol -Statistical Analysis Plan (SAP) -Informed Consent Form (ICF) Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and 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 on completed 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/

Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

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

dsclinicaltrial_jp@daiichisankyo.com

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

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

+81-3-6225-1111

dsclinicaltrial_jp@daiichisankyo.com

completed

Nov. 05, 2019

Interventional

Non-randomized, No control group, Multicenter, Open-label, PhaseII study

treatment purpose

2

- Patients with relapsed or refractory ATL who have history of treatment with mogamulizumab or are mogamulizumab intolerant, contraindication after treatment with at least 1 medication regimen.
- Aged >=20 years or older at the time of signing the informed consent.
- Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of 0-2.
- At least 1 evaluable lesion
- Subject who has defined laboratory criteria
- Life expectancy >= 3 months.

- A presence of central nervous system involvement at the time of screening tests.
- Have poorly controlled complication (ex. Chronic congestive heart failure, unstable angina)
- >= Grade 3 neuropathy.
- QTcF >470 ms
- Has an uncontrolled infection.
- Subject who use of corticosteroids over 10 mg/day
- Receipt of allogeneic hematopoietic stem cell transplantation.
- History of, or concurrent, malignant tumors.

Both

Adult T-cell leukemia/lymphoma: ATL

investigational material(s)
Generic name etc : Valemetostat tosylate
INN of investigational material : Valemetostat tosylate
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Once a day, 200 mg, oral administration

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

efficacy
ORR assessed by central evaluation organization

safety
efficacy
pharmacokinetics
pharmacodynamics
pharmacogenomics
other
- ORR assessed by investigator/sub-investigator
- Best response per tumor lesions
- CR rate
- TCR
- TTR
- DOR
- PFS
- OS
- Safety
- Pharmacokinetics
- Pharmacodynamics

Oct. 18, 2019