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A Phase 1/1b Study of ASP2074 in Participants with Metastatic or Locally Advanced Solid Tumors

A study of ASP2074 in adults with solid tumors

23

In part A for the dose escalation part of the study (part 1), the majority of participants were male (71.4%), not Hispanic or Latino (92.3%) and either Asian or White (50.0% and 42.9%, respectively), with a mean (standard deviation) age of 58.6 (9.8) years (range 43 to 73 years). The majority of participants (71.4%) were between 18 and 64 years of age. The primary diagnoses for participants were colorectal adenocarcinoma (7 participants) and pancreatic adenocarcinoma (7 participants). In part B for part 1, approximately half of the participants were male (55.6%) and White (57.1%), and the majority were not Hispanic or Latino (87.5%), with a mean (standard deviation) age of 56.6 (9.5) years (range 44 to 77 years). The majority of participants (88.9%) were between 18 and 64 years of age. The primary diagnoses for participants were colorectal adenocarcinoma (5 participants) and pancreatic adenocarcinoma (4 participants).

Approximately 54 participants were planned to be enrolled in part 1, and approximately 139 participants were planned to be enrolled in the dose expansion part of the study (part 2). Due to the study being terminated early, the dose expansion part of the study was not performed. In part 1, a total of 31 participants signed informed consent, of which 8 were discontinued before being allocated to treatment. Of the remaining 23 participants, 14 participants were allocated to ASP2074 in part A and 9 participants were allocated to ASP2074 in part B. In part A, participants received ASP2074 at doses of 0.7 mg (n = 1), 2.2 mg (n = 1), 4 mg (n = 7), and 7 mg (n = 5). All 14 participants who received ASP2074 in part A discontinued study intervention. Progressive disease was the most frequent reason for discontinuing study intervention (8 [57.1%] participants). Overall, all participants reached the 30-day and 90-day safety follow-up; 6 (42.9%) participants completed the 30-day follow-up and 4 (28.6%) participants completed the 90-day follow-up. In part B, participants received ASP2074 at a run-in dose of 2.2 mg plus ASP2074 at doses of 4 mg (n = 4) and 7 mg (n = 5). All 9 participants who received ASP2074 in part B discontinued study intervention. Progressive disease was the most frequent reason for discontinuing study intervention (6 [66.7%] participants). Overall, all participants reached the 30-day and 90-day safety follow-up; 6 (66.7%) participants completed the 30-day follow-up and 2 (22.2%) participants completed the 90-day follow-up.

Part A Dose Escalation: o Three (30.0%) participants in the dose-limiting toxicity (DLT) evaluable analysis set (DEAS) experienced 4 DLTs.The DLTs were diarrhoea, enterocolitis, hepatic function abnormal, and hypertension (each reported by 1 participant). o All 14 (100%) participants who received ASP2074 reported at least 1 treatment-emergent adverse event (TEAE). The most common TEAE was diarrhoea (78.6%). o Attribution of TEAE relationship to study intervention was assessed by the investigator. Overall, all 14 (100%) participants had 1 or more TEAE considered by the investigator to be related to ASP2074. The most common study intervention-related TEAEs were cytokine release syndrome (CRS) and diarrhoea (64.3% each). o Eleven (78.6%) participants experienced a TEAE with maximum National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade >/= 3. o There were 4 (28.6%) participants that had TEAEs leading to death. All 4 participants died due to malignant neoplasm progression. None of the deaths were considered by the investigator to be related to ASP2074. o Treatment-emergent serious adverse events (SAEs) were reported in 10 (71.4%) participants, and SAEs considered by the investigator to be related to ASP2074 were reported in 4 (28.6%) participants. The treatment-related SAEs were CRS (2 participants) and colitis, diarrhoea, enterocolitis, and hepatic function abnormal (each reported by 1 participant). o Two (14.3%) participants had TEAEs that resulted in permanent discontinuation of study intervention. TEAEs leading to discontinuation of study intervention considered by the investigator to be related to ASP2074 were reported in 1 (7.1%) participant. The related TEAEs leading to discontinuation were diarrhoea, nausea and decreased appetite. o Ten (71.4%) participants experienced immune-related TEAEs. Of these, 3 (21.4%) participants experienced 4 serious immune-related TEAEs: colitis, CRS, diarrhoea, and enterocolitis. o Two (14.3%) participants experienced infusion-related TEAEs. No infusion-related TEAEs were reported as serious. o There were no clinically meaningful findings in the clinical laboratory values, vital signs measurements, electrocardiogram (ECG) and physical examination assessments or other observations related to safety in this study. Part B Dose Escalation: o One (12.5%) participant in the DEAS experienced 3 DLTs. This participant was in the run-in 2.2 mg + 7 mg treatment group. The DLTs were suspected drug-induced liver injury, alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased. o All 9 (100%) participants who received ASP2074 reported at least 1 TEAE. The most common TEAE was diarrhoea (88.9%). o Attribution of TEAE relationship to study intervention was assessed by the investigator. Overall, 8 (88.9%) participants had 1 or more TEAE considered by the investigator to be related to ASP2074. The most common study intervention-related TEAE was diarrhoea (66.7%). o Eight (88.9%) participants experienced a TEAE with maximum NCI-CTCAE Grade >/= 3. o There were 3 (33.3%) participants that had TEAEs leading to death. The TEAEs leading to death were malignant neoplasm progression (2 participants) and biliary sepsis. None of the deaths were considered by the investigator to be related to ASP2074. o Treatment-emergent SAEs were reported in 7 (77.8%) participants, and SAEs considered by the investigator to be related to ASP2074 were reported in 3 (33.3%) participants. The treatment-related SAEs were diarrhoea (2 participants) and colitis and suspected drug-induced liver injury (each reported by 1 participant). o One (11.1%) participant had a TEAE that resulted in permanent discontinuation of study intervention. This participant had suspected drug-induced liver injury which was considered by the investigator to be related to ASP2074. o Seven (77.8%) participants experienced immune-related TEAEs. Of these, 4 (44.4%) participants experienced 7 serious immune-related TEAEs: biliary sepsis, colitis, diarrhoea, encephalopathy, nausea, suspected drug-induced liver injury, and vomiting. The serious immune-related TEAE of biliary sepsis led to the death of the participant. o Three (33.3%) participants experienced infusion-related TEAEs. No infusion-related TEAEs were reported as serious. o There were no clinically meaningful findings in the clinical laboratory values, vital signs measurements, ECG and physical examination assessments, or other observations related to safety in this study.

Primary Endpoint: o See Adverse Events section. Secondary Endpoint: o No participants in the dose escalation part of the study had a best overall response of confirmed complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. The objective response rate (ORR) was 0% (95% CI: 0, 30.8) in part A and 0% (95% CI: 0, 41.0) in part B. o Because no participants had confirmed CR or PR, duration of response (DOR) could not be analyzed. o In part A, 2 (20.0%) participants had confirmed stable disease (SD) using RECIST 1.1 (1 participant each in the 4 mg and 7 mg treatment groups); therefore, the disease control rate (DCR) (CR + PR + SD) was 20.0%. In part B, 4 (57.1%) participants had confirmed SD using RECIST 1.1 (2 participants each in the 2.2 mg run-in + 4 mg and the 2.2 mg run-in + 7 mg treatment groups); therefore, the DCR (CR + PR + SD) was 57.1%. o The same results were observed using Immunotherapy Response Evaluation Criteria in Solid Tumours (iRECIST). o Serum CA19-9 data, in a limited number of participants with pancreatic adenocarcinoma, did not show any apparent decrease after treatment. o In part A, ASP2074 exposure (Cmax and area under the concentration-time curve [AUC]) appeared to be dose-proportional between dose levels from 0.7 to 7 mg after single dose administration. o In part A, the median terminal elimination half-life (t1/2) ranged from 2.5 to 6.2 days following single-dose administration of ASP2074 0.7 to 7 mg, and the median time of the maximum concentration (tmax) ranged from 0.09 to 0.17 days. o In part B, ASP2074 exposure seemed to be higher than that observed in part A at the same cohort dose level (e.g., part B versus part A at 4 mg and 7 mg), indicating the impact of run-in doses.

- Progressive disease was the most frequent reason for discontinuing study intervention. - ASP2074 exposure appeared to be dose-proportional between dose levels from 0.7 to 7 mg after single dose administration. - ASP2074 exposure seemed to be higher in cohorts with a run-in period, indicating the impact of run-in doses. - The sponsor decided to terminate study because an efficacious dose was not reached and ASP2074 was generally not well tolerated at doses up to 7 mg. Part 2 was not performed.

Oct. 15, 2025

No

Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220554

Guseva Maria

Astellas Pharma Inc.

2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo

clinicaltrialregistration@astellas.com

Medical Information Center

Astellas Pharma Inc.

2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo

+81-120-189-371

clinicaltrialregistration@astellas.com

Complete

Jan. 12, 2023

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Participant has locally-advanced (unresectable) or metastatic solid tumor malignancy (no limit to the number of prior treatment regimens) which is confirmed by available pathology records or current biopsy. For dose escalation, the participant must have colorectal, pancreatic, gastric cancer, esophageal or Gastroesophageal junction (GEJ) adenocarcinoma. For the tumor-specific expansion cohorts, the participant must have colorectal adenocarcinoma, esophageal or GEJ adenocarcinoma, or pancreatic adenocarcinoma.
2. Participant has at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
3. Participant has progressed or failed to tolerate after receiving all standard approved therapies or is no longer eligible for standard therapy (no limit to the number of prior treatment regimens).
4. Participant has an Eastern Cooperative Oncology Group (ECOG) Status of 0 or 1.
5. Participants who have received radiotherapy must have completed this therapy (including stereotactic radiosurgery) at least 2 weeks prior to study intervention administration.
6. Participant's adverse events (excluding alopecia) from prior therapy have improved to grade 1 or baseline for the participant (e.g., grade 2 hypothyroidism) within 14 days prior to the first dose of study intervention.
7. Participant has predicted life expectancy >= 12 weeks.
8. Participant must meet all of the criteria based on laboratory tests. In case of multiple laboratory data within this period, the most recent data should be used. If a participant has received a recent blood transfusion, the laboratory tests must be obtained >= 2 weeks after any blood transfusion.
9. Female participant is not pregnant confirmed by serum pregnancy test and medical evaluation by interview and at least 1 of the following conditions apply:
o Not a woman of childbearing potential (WOCBP)
o WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 90 days after final study intervention administration.
10. Female participant must agree not to breastfeed starting at screening and throughout the study period and for 90 days after final study intervention administration.
11. Female participant must not donate ova starting at first dose of study intervention and throughout the study period and for 90 days after final study intervention administration.
12. Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 90 days after final study intervention administration.
13. Male participant must not donate sperm during the treatment period and for 90 days after final study intervention administration.
14. Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 90 days after final study intervention administration.
15. Participant agrees not to participate in another interventional study while receiving study treatment in the present study.

1. Participant has received other investigational agents or devices concurrently or within 21 days or 5 half-lives, whichever is shorter, prior to first dose of study intervention administration.
2. Participant has any condition which makes the participant unsuitable for study participation.
3. Participant has a known or suspected hypersensitivity to ASP2074 or any components of the formulation used.
4. Participants with squamous cell colorectal carcinoma; gastrointestinal stromal tumor and neuroendocrine carcinomas.
5. Participant weighs < 40 kg.
6. Participant requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to study intervention administration. Participants using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day prednisone), receiving a single dose of systemic corticosteroids, or receiving systemic corticosteroids as premedication for radiologic imaging contrast use is eligible.
7. Participant has symptomatic central nervous system (CNS) metastases or participant has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Participants with previously treated CNS metastases are eligible, if they are clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study treatment and are not requiring immunosuppressive doses of systemic steroids (> 30 mg per day of hydrocortisone or > 10 mg per day of prednisone or equivalent) for longer than 2 weeks.
8. Participant has an active autoimmune disease. Participants with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy, or skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment are allowed.
9. Participant was discontinued from prior immunomodulatory therapy due to a grade >= 3 toxicity that was mechanistically related (e.g., immune related) to the agent.
10. Participant is known to have human immunodeficiency virus (HIV) infection. However, participants with HIV infection with CD4+ T-cell counts >= 350 cells/microL and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 6 months are eligible. NOTE: Screening for HIV infection should be conducted per local requirements.
11. Participant is known to have active hepatitis B (positive hepatitis B surface antigen (HBsAg)) or hepatitis C infection. NOTE: Screening for these infections should be conducted per local requirements.
o For participant who is negative for HBsAg, but hepatitis B core antibody (HBcAb) positive, a hepatitis B virus (HBV) DNA test will be performed and if positive the participant will be excluded.
o Participant with positive hepatitis C virus (HCV) serology, but negative HCV RNA test results are eligible.
o Participant treated for HCV with undetectable viral load results are eligible
12. Participant has received a live vaccine against infectious diseases within 28 days prior to initiation of study treatment.
13. Participant with a history of interstitial lung disease (ILD) or non-infectious pneumonitis, or currently has ILD/pneumonitis.
14. Participant has an infection requiring systemic therapy within 14 days prior to study drug treatment.
15. Participant has received a prior allogeneic bone marrow or solid organ transplant.
16. Participant is expected to require another form of antineoplastic therapy while on study treatment.
17. Participant with a history of the following significant cardiovascular disease will be excluded:
o Participant has inadequately controlled hypertension on antihypertensive medications.
o Participant has a history of myocardial infarction or unstable angina within 6 months prior to day 1.
o Participant has New York Heart Association Class II or greater Congestive heart failure (CHF).
o History of cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months prior to study treatment.
o Participant has significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study treatment.
o Participant has cardiac arrhythmia, complete left bundle branch block, obligate use of a cardiac pacemaker, long time from the start of the Q wave to the end of the T wave (QT) syndrome or right bundle branch block with left anterior hemiblock (bifascicular block).
o Participant has a corrected QT interval (single ECG) using Fridericia's formula (QTcF) > 450 msec during screening. A single 12-lead ECG will be performed during screening.
18. Participant has had psychiatric illness/social situations that would limit compliance with study requirements.
19. Participant has a prior malignancy, other than the current malignancy for which the participant is seeking treatment, active (i.e., requiring treatment of intervention) within the previous 2 years except for locally curable malignancies that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast.
20. Participant has had major surgery within 28 days prior to the start of study treatment.

Both

Metastatic or locally advanced solid tumors

This study will be in 2 parts.
1. ASP2074 Dose Escalation (Part 1)
Participants will be assigned to sequentially or in parallel escalating dose/regimen cohorts of ASP2074 in three parts (Part A, B and C). Part B and Part C will be opened sequentially based upon sponsor review of emerging data.
2. ASP2074 Dose Expansion (Part 2)
Colorectal Adenocarcinoma, Esophageal or Gastroesophageal junction (GEJ) Adenocarcinoma, Pancreatic Adenocarcinoma
Participants will receive ASP2074 with dose/regimen selected from dose escalation (Part 1).

ASP2074 will be given as an infusion on the first day of each treatment cycle. The participants in this study will have treatment cycles until: they have medical problems from the treatment; their cancer gets worse; they start other cancer treatment; they ask to stop treatment; or they do not come back for treatment.

- Dose Limiting Toxicities (DLTs)
- Adverse Events (AEs)
- Serious Adverse Events (SAEs)
- Clinical laboratory values
- Vital sign
- Routine 12-lead electrocardiogram

- Objective Response Rate (ORR) per Immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) and RECIST v1.1
- Duration of Response (DOR) per iRECIST and RECIST v1.1
- Disease Control Rate (DCR) per iRECIST and RECIST v1.1
- Serum CA19-9 levels in participants with pancreatic cancer
- Selected Pharmacokinetic (PK) parameters of ASP2074 in serum: Area under the concentration-time curve from time zero to 336 hours post dose (AUC[0-336h]), Maximum concentration (Cmax), Concentration immediately prior to dosing at multiple dosing (Ctrough), Time of maximum concentration (tmax)
- Changes in target antigen expression and CD8 infiltration/ activation in tumor

+81-3-3542-2511

Jan. 18, 2023

United States