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A Phase 1, 2-Part, Multicenter, First-In-Human Dose-Escalation and Dose-Expansion Study of DS-1103a Combination Therapy in Subjects With Advanced Solid Tumors

A Study of DS-1103a Combination Therapy in Participants With Advanced Solid Tumors

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

Recruiting

July. 01, 2026

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

- Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures
- Adults >=18 years of age at the time the ICF is signed (please follow local regulatory requirements if the legal age of consent for study participation is >18 years old)
- Pathologically documented HER2-expressing or HER2-mutated (activating mutation) solid tumor that is unresectable or metastatic
- Is willing and able to provide tumor tissue
- Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator assessment
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- Has a left ventricular ejection fraction (LVEF) >=50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
- Has adequate organ and bone marrow function within 14 days before the start of study treatment
Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to Cycle 1 Day 1
- A woman of childbearing potential (WOCBP) is eligible to participate if she is not pregnant as confirmed by highly sensitive pregnancy test and agrees to adhere to a contraceptive method that is highly effective during the Treatment Period and for at least the time needed to eliminate each study drug after the last dose
- A male participant capable of producing sperm is eligible to participate if he agrees to adhere to the contraception methods as specified in the protocol and avoids donating sperm during the Treatment Period and for at least the time needed to eliminate each study drug
- Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions

Dose-escalation Phase:
- Has progressed or was non-responsive to available therapies and for which no standard or available anticancer therapy exists
- Has a pathologically documented HER2-expressing or HER2-mutated solid tumor

Dose-expansion Phase:
- Has pathologically documented specific HER2 altered advanced solid tumor type
- Has received prior therapy as specified in the protocol

- Has had prior treatment with an anti-CD47 or anti-signal regulatory protein alpha (SIRP alpha) therapy
- Has an inadequate treatment washout period prior to start of study treatment as specified in the protocol
- Medical history of myocardial infarction (MI) within 6 months before study enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II to IV)
- Has a QT interval corrected with Fridericia's formula (QTcF) prolongation to >470 ms (females) or >450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)
- Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
- Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
- Has multiple primary malignancies within 3 years. Exceptions are specified in the protocol
- Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products or other monoclonal antibodies
- Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
- Is requiring concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications during the study
- Has received a live, attenuated vaccine (messenger ribonucleic acid [mRNA] and replication-deficient adenoviral vaccines are not considered live, attenuated vaccines) within 30 days prior to first exposure to study drug(s)
- Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the participant's participation in the clinical study or evaluation of the clinical study results
- Has active or uncontrolled human immunodeficiency virus (HIV) infection. Subjects with a positive/reactive HIV antibody and/or known HIV infection at Screening must be tested for HIV RNA viral load and CD4+ T-cell count during the Screening Period (if acceptable by local regulations or IRBs/IECs) and are eligible if certain criteria are met as specified in the protocol
- Has active or uncontrolled HBV or HCV. Hepatitis B and C screening testing is required. Participants are eligible only if they meet criteria as specified in the protocol
- Has unresolved toxicities from previous anticancer therapy
- Female who is pregnant, breastfeeding, or planning to become pregnant
- Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder
- Any autoimmune, connective tissue or inflammatory disorders
- Prior complete pneumonectomy
- Any of the following within 6 months of enrollment: Cerebrovascular accident, transient ischemic attack, or other arterial thromboembolism event
- Psychological, social, familial, or geographical factors that would prevent regular follow-up
- Any active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy
- Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) and/or severe arrhythmia within 28 days before enrollment

Dose Expansion
- Has had prior treatment with antibody-drug conjugate that consists of an exatecan derivative that is a topoisomerase I inhibitor including prior participation in a study involving an antibody-drug conjugate produced by Daiichi Sankyo and/or AstraZeneca

Both

Advanced Solid Tumor

Experimental: Dose Escalation: DS-1103a + T-DXd
Participants with HER2-expressing or HER2-mutated advanced metastatic solid tumors who will receive an escalating intravenous (IV) infusion of DS-1103a (starting dose of 100 mg) every 3 weeks (Q3W) starting on Cycle 1 Day 1. Starting on Cycle 2 Day 1 and on Day 1 of each subsequent cycle, participants will also receive T-DXd IV Q3W.
Drug: DS-1103a
One IV infusion Q3W on Day 1 of each 21-day cycle
Drug: T-DXd
One IV infusion Q3W on Day 1 of each 21-day cycle

Experimental: Dose Expansion (Cohort 1): DS-1103a + T-DXd
Participants with a specific HER2-altered advanced solid tumor type who will receive an IV infusion of DS-1103a at the recommended dose for expansion (RDE) in combination with T-DXd IV Q3W starting on Cycle 1 Day 1.
Drug: DS-1103a
One IV infusion Q3W on Day 1 of each 21-day cycle
Drug: T-DXd
One IV infusion Q3W on Day 1 of each 21-day cycle

Experimental: Dose Expansion (Cohort 2): DS-1103a + T-DXd
Participants with a specific HER2-altered advanced solid tumor type who will receive an IV infusion of DS-1103a at the recommended dose for expansion (RDE) in combination with T-DXd IV Q3W starting on Cycle 1 Day 1.
Drug: DS-1103a
One IV infusion Q3W on Day 1 of each 21-day cycle
Drug: T-DXd
One IV infusion Q3W on Day 1 of each 21-day cycle

Experimental: Dose Expansion (Cohort 3): DS-1103a + T-DXd
Participants with a specific HER2-altered advanced solid tumor type who will receive an IV infusion of DS-1103a at the recommended dose for expansion (RDE) in combination with T-DXd IV Q3W starting on Cycle 1 Day 1.
Drug: DS-1103a
One IV infusion Q3W on Day 1 of each 21-day cycle
Drug: T-DXd
One IV infusion Q3W on Day 1 of each 21-day cycle

1. Number of Participants with Dose-limiting Toxicities (Dose Escalation)
[Time Frame: From Cycle 1 Day 1 to Cycle 2 Day 21 (each cycle is 21 days)]

2. Objective Response Rate Assessed by Blinded Independent Central Review Following DS-1103a Combination Therapy (Dose Expansion)
Objective response rate (ORR) is defined as the proportion of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria In Solid Tumors v1.1.
[Time Frame: Baseline (Dose Expansion) up until documented progressive disease, unacceptable toxicity, death, lost to follow-up, or withdrawal by the participant, up to approximately 5 years 11 months]

3. Number of Participants with Dose-limiting Toxicities Following DS-1103a Combination Therapy (Dose Expansion; Cohort 2 Safety Run In and Japanese Population Tolerability Assessments)
[Time Frame: From Cycle 1 Day 1 to Cycle 1 Day 21 (each cycle is 21 days)]

4. Overall Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events (Dose Escalation and Expansion; Cohort 2 Safety Run In and Japanese Population Tolerability Assessments)
[Time Frame: Screening through long-term follow up, up to approximately 91 months]

1. Overall Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events (Dose Expansion)
[Time Frame: Screening through long-term follow up, up to approximately 5 years 11 months]

2. Objective Response Rate Assessed by Investigator (Dose Escalation and Dose Expansion)
Objective response rate (ORR) is defined as the proportion of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the Investigator per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.
[Time Frame: Baseline up until documented progressive disease, unacceptable toxicity, death, lost to follow-up, or withdrawal by the participant, up to approximately 91 months]

3. Disease Control Rate Assessed by Investigator (Dose Escalation and Dose Expansion) and Blinded Independent Central Review (Dose Expansion)
Disease control rate is defined as the proportion of participants with a best overall response of confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) as assessed by the Investigator (Dose Escalation and Dose Expansion) and Blinded independent Central Review (BICR)(Dose Expansion) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.
[Time Frame: Baseline up until documented progressive disease, unacceptable toxicity, death, lost to follow-up, or withdrawal by the participant, up to approximately 91 months]

4. Clinical Benefit Rate Assessed by Investigator (Dose Escalation and Dose Expansion) and Blinded Independent Central Review (Dose Expansion)
Clinical benefit rate (CBR) is defined as the proportion of participants with a best overall response of confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) lasting >=183 days as assessed by the Investigator (Dose Escalation and Dose Expansion) and Blinded Independent Central Review (BICR) (Dose Expansion) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.
[Time Frame: Baseline up until documented progressive disease, unacceptable toxicity, death, lost to follow-up, or withdrawal by the participant, up to approximately 91 months]

5. Duration of Response Assessed by Investigator (Dose Escalation and Dose Expansion) and Blinded Independent Central Review (Dose Expansion)
Duration of response (DoR) in a responding participant is defined as the time from the date of the first documentation of objective response (confirmed complete response [CR] or confirmed partial response [PR]) to the date of the first radiographic disease (as assessed by the Investigator [Dose Escalation and Dose Expansion] and Blinded Independent Central Review (BICR) [Dose Expansion]) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first.
[Time Frame: Baseline up until documented progressive disease, unacceptable toxicity, death, lost to follow-up, or withdrawal by the participant, up to approximately 91 months]

6. Pharmacokinetic Parameter Area Under the Plasma Concentration Curve for DS-1103a (Dose Escalation and Dose Expansion)
Area under the plasma concentration-time curve up to the last quantifiable time (AUClast) and Area under the plasma concentration-time curve during dosing interval (AUCtau) will be assessed using non-compartmental methods.
[Time Frame: Dose Escalation: Cycles 1,2, and 4: Days 1,2,4,8,15; Cycle 3 Days 1,8,15; Cycle 6 and 8 Day 1; Dose Expansion: Cycles 1 and 3: Days 1,2,4,8,15; Cycle 2 Days 1,8,15; Cycle 4,6, and 8 Day 1 (each cycle is 21 days)]

7. Pharmacokinetic Parameter Maximum Plasma Concentration for DS-1103a (Dose Escalation and Dose Expansion)
Maximum plasma concentration (Cmax) will be assessed using non-compartmental methods.
[Time Frame: Dose Escalation: Cycles 1,2, and 4: Days 1,2,4,8,15; Cycle 3 Days 1,8,15; Cycle 6 and 8 Day 1; Dose Expansion: Cycles 1 and 3: Days 1,2,4,8,15; Cycle 2 Days 1,8,15; Cycle 4,6, and 8 Day 1 (each cycle is 21 days)]

8. Pharmacokinetic Parameter Time to Maximum Plasma Concentration for DS-1103a (Dose Escalation and Dose Expansion)
Time to maximum plasma concentration (Tmax) will be assessed using non-compartmental methods.
[Time Frame: Dose Escalation: Cycles 1,2, and 4: Days 1,2,4,8,15; Cycle 3 Days 1,8,15; Cycle 6 and 8 Day 1; Dose Expansion: Cycles 1 and 3: Days 1,2,4,8,15; Cycle 2 Days 1,8,15; Cycle 4,6, and 8 Day 1 (each cycle is 21 days)]

9. Pharmacokinetic Parameter Minimum Plasma Concentration for DS-1103a (Dose Escalation and Dose Expansion)
Minimum plasma concentration (Cmin) will be assessed using non-compartmental methods.
[Time Frame: Dose Escalation: Cycles 1,2, and 4: Days 1,2,4,8,15; Cycle 3 Days 1,8,15; Cycle 6 and 8 Day 1; Dose Expansion: Cycles 1 and 3: Days 1,2,4,8,15; Cycle 2 Days 1,8,15; Cycle 4,6, and 8 Day 1 (each cycle is 21 days)]

10. Number of Participants With Treatment-emergent Anti-drug Antibodies (ADAs) (Dose Escalation and Dose Expansion)
[Time Frame: Cycle 1 (D1, D15), Cycle 2 (D1, D15 [Dose Escalation only]), Cycles 3 and 4 (D1), thereafter every 2 cycles (D1), EOT, 40-day and 3-month (mth) follow-up (FU).]

July. 07, 2026

Yes

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