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FIRST-IN-HUMAN STUDY OF DS-1471A IN SUBJECTS WITH ADVANCED SOLID TUMORS

FIRST-IN-HUMAN STUDY OF DS-1471A IN SUBJECTS WITH ADVANCED SOLID TUMORS

17

Baseline demographics of the overall study population (safety Analysis Set, which was identical to full analysis set [FAS]) were as follows: median age 62.0 years (range: 48 to 75 years); Asian (100.0%); 14 males (87.5%) and 2 females (12.5%).

The dose-escalation phase of the study was conducted in 17 participants (the study was terminated before the initiation of dose-expansion). Of the 17 enrolled participants, 16 participants received the study treatment. DS-1471a was administered to 6 cohorts as follows: Cohort 1 (1 mg/kg): 1 participant; Cohort 2 (3 mg/kg): 3 participants; Cohort 3 (6 mg/kg): 3 participants; Cohort 4 (12 mg/kg): 3 participants; Cohort 5 (24 mg/kg): 3 participants; Cohort 6 (40 mg/kg): 3 participants. A total of 16 participants were included in the Safety Analysis Set and Full Analysis Set.

-13 of the 16 participants (81.3%) experienced treatment-emergent adverse events (TEAEs). The most common TEAE was pyrexia (8 participants [50.0%]). TEAEs which were experienced by 2 or more participants were as follows: decreased appetite (3 participants [18.8%]), biliary tract infection, headache, nausea, and malaise (2 participants [12.5%] each). - 9 participants (56.3%) experienced drug-related TEAEs. Drug-related TEAEs which were experienced by 2 or more participants were as follows: pyrexia (7 participants [43.8%]), headache (2 participants [12.5%]). - No TEAEs associated with an outcome of death were reported. - Two participants (12.5%) experienced serious TEAEs: biliary tract infection (1 participant in Cohort 3 [6 mg/kg]) and cerebrovascular accident (1 participant in Cohort 5 [24 mg/kg]). Biliary tract infection resolved; cerebrovascular accident did not resolve. Both serious TEAEs were assessed as not related to the study drug, but due to progressive disease. - No TEAEs associated with study drug discontinuation or study drug dose reduction were reported. - TEAEs associated with study drug interruption occurred in 1 of the 16 participants (6.3%). The event was infusion-related reaction (IRR) (Grade 2), which was not serious and resolved with study drug interruption and medication. - One participant experienced TEAEs associated with study drug delay. The event was viral upper respiratory tract infection. Viral upper respiratory tract infection was reported in Cohort 5 (24 mg/kg), not serious (Grade 2) and resolved with study drug delay. The event was assessed as not related to the study drug. - There was no report of TEAEs classified as DLTs.

The collected data for safety and tolerability as Primary Outcome measure was reported in the Adverse events section. Efficacy Results: There was no antitumor activity of DS-1471a that meets a response defined by RECIST v1.1 in this study. The efficacy results are presented below. - There were no participants whose decrease in sum of diameters (SoDs) from baseline in target lesions was over 30%. - No participants continued study treatment beyond 12th week scan for tumor assessment due to early disease progression. - In the results of best overall response (BOR) assessed by the investigator, 5 of 16 participants showed stable disease (SD), and 11 of 16 participants experienced progressive disease (PD). Pharmacokinetic (PK) results: An S-shaped PK profile at high doses and more than dose-proportional increase in area under the plasma concentration-time curve (AUC) across 1 to 40 mg/kg suggested target-mediated drug disposition and non-linear PK. Immunogenicity results: No participant was positive for antidrug antibody (ADA) at baseline. Treatment-induced ADA was observed in 1 participant in Cohort 6 (40 mg/kg). No apparent effect of ADA on PK was observed.

The most common TEAE and related TEAE was pyrexia. Two of 16 participants experienced serious TEAEs, neither was considered related to the study drug. There were no TEAEs that resulted in death or study drug discontinuation. No antitumor activity of DS-1471a was observed up to 40 mg/kg based on the SoDs from baseline in target lesions and the results of BOR assessed by the investigator.

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/

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230234

Akihiro Inoguchi

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

Complete

July. 31, 2023

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

The clinical sites will screen for the full inclusion criteria per protocol.
1. Sign and date the informed consent form (ICF)
2. Adults >=18 years at the time the ICF is signed
3. Has a histologically or cytologically documented, locally advanced, metastatic, or unresectable solid tumor that is refractory to or intolerable with standard treatment, or for which no standard treatment is available
4. Has at least 1 measurable lesion according to RECIST v1.1 on computed tomography (CT) or magnetic resonance imaging (MRI)
5. Is willing and able to provide tumor tissue (newly obtained or archival)
6. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1
7. Life expectancy >=3 months
8. Has a left ventricular ejection fraction (LVEF) >=50% within 28 days prior to Cycle 1 Day 1
9. Required baseline local laboratory data (within 7 days prior to Cycle 1 Day 1) as prespecified in the protocol
10. If the participant is a female of childbearing potential, she must have a negative highly sensitive pregnancy test within 7 days prior to study drug administration (Cycle 1 Day 1) and must be willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 7 months following the last dose of study drug
11. If male, the participant must avoid donating sperm and willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 4 months following the last dose of study drug
12. Is willing and able to comply with scheduled visits, study drug administration plan, laboratory tests, other study procedures, and study restrictions

Patients with liver cirrhosis and/or hepatocellular carcinoma (HCC) may be eligible to participate if they meet additional protocol specified criteria.

1. Has an inadequate treatment washout period prior to start of study treatment (Cycle 1 Day1) as prespecified in the protocol
2. Has history of or current presence of untreated central nervous system (CNS) metastases
3. Has a history of leptomeningeal carcinomatosis
4. Has a history of (non-infectious) interstitial lung disease (ILD) other than radiation pneumonitis, currently has ILD, or when suspected ILD cannot be ruled out by imaging at screening
5. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
6. Has any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, arterial thromboembolic event, or pulmonary embolism
7. Has uncontrolled or clinically significant cardiovascular disease
8. Is requiring chronic steroid treatment (>10 mg daily prednisone equivalents)
9. Has multiple primary malignancies, except adequately resected nonmelanoma skin cancer, curatively treated in situ disease, superficial cancer in the gastrointestinal tract curatively resected by endoscopic surgery, or any other solid tumors curatively treated with no evidence of recurrent disease for >=3 years
10. Has unresolved toxicities from previous anticancer treatment, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCICTCAE) Version (v)5.0, Grade <=1 or baseline
11. Exposure to another investigational medical product within 4 weeks prior to Cycle 1 Day 1 or current participation in other therapeutic investigational procedures
12. Has any known contraindication to treatment with, including hypersensitivity to the study drug substances or inactive ingredients in the study drug product
13. Has an active, known, or suspected autoimmune disease
14. Has evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
15. Has an active hepatitis or uncontrolled hepatitis B or C infection, except for participants with hepatitis B infection that is controlled by antiviral therapy
16. Has human immunodeficiency virus (HIV) infection with exceptions per protocol for participants in Dose Expansion
17. Has received a live, attenuated vaccine (messenger RNA [mRNA] and replication-deficient adenoviral vaccines are not considered live, attenuated vaccines) within 30 days prior to first exposure to study drug (Cycle 1 Day 1)
18. Female who is pregnant or breastfeeding
19. Has psychological, social, familial, or geographical factors that would prevent regular follow-up
20. Has prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results

Patients with hepatocellular carcinoma (HCC) may be eligible to participate if they meet additional protocol specified criteria.

Both

Locally advanced or metastatic solid tumors

Generic name etc : DS-1471a
Dosage and Administration for Investigational material : Dose Escalation Part : IV solution (Once every 4 weeks, initial dose 1 mg /kg), Dose Expansion Phase : IV solution (Once every 4 weeks, recommended dose for expansion phase)

Safety
Dose Escalation Part: To evaluate thesafety and tolerabilityof DS-1471a anddetermine the MTDand/or RDE(s)
Dose Expansion Phase: To evaluate theoverall safety of DS-1471a at the RDE(s)

+81-3-3542-2511

July. 14, 2023

United States/Spain/France/Belgium