Phase 1, Two-Part, Multicenter, Open-Label, Multiple Dose, First-in-Human Study of DS-1062a in Subjects with Advanced Solid Tumors

This study is one single group of participants with non-small cell lung cancer (NSCLC) who
have not been cured by other treatments. It is the first time the drug has been used in
humans. There will be two parts and a sub-study.

The primary purpose of the parts are:

- Dose Escalation: To investigate the safety and tolerability and to determine the maximum
tolerated dose (MTD) and the recommended dose for expansion (RDE) of DS-1062a

- Dose Expansion: To investigate the safety and tolerability of DS-1062a in additional
solid tumors

This study is expected to last approximately 6 years from the time the first participant is
enrolled to the time the last subject is off the study. Study sites are located in both the
United States and Japan.

The number of treatment cycles is not fixed in this study. Participants who continue to
benefit from the study treatment may continue, unless:

- they withdraw

- their disease gets worse

- they experience unacceptable side effects.

The primary purpose of the sub-study is to compare the effectiveness of steroid versus
non-steroid mouthwash as prophylaxis against oral mucositis/stomatitis in participants
receiving DS-1062a.

The sub-study is a randomized study that will include approximately 76 participants enrolling
into the Dose Expansion part.

Inclusion Criteria

All Participants:

- Has relapsed or progressed following local standard treatments or for which no
standard treatment is available.

- Consents to provide mandatory pre-treatment tumor tissue samples for the measurement
of TROP2 and other biomarkers. There is no minimum TROP2 expression level required for
inclusion.

- Consents to undergo mandatory on-treatment biopsy if clinically feasible and not
contraindicated at the time of on-treatment biopsy, and consents to provide the tumor
tissue samples from on-treatment biopsy for the measurement of TROP2 level and other
biomarkers.

- Is aged ≥18 years old.

- Has an Eastern Cooperative Oncology Group performance status 0-1.

- Has a left ventricular ejection fraction (LVEF) ≥50% by either an ECHO or MUGA within
28 days before enrollment.

- Has measurable disease based on RECIST version1.1.

- Has adequate bone marrow reserve and organ function within 7 days before Cycle 1, Day
1.

- Has an adequate treatment washout period prior to Cycle 1, Day 1.

- If of reproductive/childbearing potential, agrees to use a highly effective from of
contraception or avoid intercourse during and upon completion of the study and for at
least 7 months for females and 4 months for males after the last dose of study drug,
and agrees not to retrieve, freeze or donate sperm or ova starting at Screening and
throughout the study period, and at least 7 months for males and 4 months for males
after the final study drug administration.

- After being fully informed about their illness and the investigative nature of the
protocol (including foreseeable risks and possible toxicities), is willing and able
comply with the protocol and to provide written, ethics committee-approved informed
consent form before performance of any study-specific procedures or examinations.

- Has a life expectancy of ≥3 months.

- Has no prior treatment with antibody drug conjugate with deruxtecan (including
trastuzumab deruxtecan [T-DXd; DS-8201a], and/or patritumab deruxtecan [HER3-DXd;
U3-1402]) and/or ifinatamab deruxtecan [I-DXd; DS-7300]. (Note: Participants in the
new HR-positive HER2-low breast cancer cohort is required to have prior treatment with
T-DXd and must not have been treated with any other deruxtecan ADC besides T-DXd.)

- Has no prior treatment with trophoblast cell surface antigen 2 (TROP2)-targeted
therapy.

Additional Inclusion Criteria for NSCLC participants:

- Has a pathologically documented unresectable advanced NSCLC disease not amenable to
curative therapy.

Additional Inclusion Criteria for TNBC participants:

- Has a pathologically documented advanced/unresectable or metastatic breast cancer with
HR- (estrogen and progesterone receptor) negative disease and HER2 negative expression
according to the American Society of Clinical Oncology - College of American
Pathologists guidelines (ASCO-CAP).

Additional Inclusion Criteria for HR positive, HER2-negative participants:

- Pathologically documented unresectable or metastatic breast cancer that is:

- HER2-negative

- Positive for estrogen receptor and/or progesterone receptor

- Is documented refractory or resistant to endocrine therapy

- Was previously treated with a minimum of 1 and a maximum of 3 prior lines of
chemotherapy in the advanced/metastatic setting

Additional Inclusion Criteria for Small-cell lung cancer (SCLC) participants:

- Pathologically documented unresectable or metastatic, and/or extensive-stage SCLC that
was previously treated with 1 to 2 prior lines of therapy including platinum-based
chemotherapy and immune checkpoint inhibitor.

- No prior exposure to topotecan and/or irinotecan.

Additional Inclusion Criteria for Endometrial cancer participants:

- Pathologically documented recurrent or persistent endometrial cancer that relapsed or
progressed after any established and/or curative therapies, including at least 1
systemic therapy.

Additional Inclusion Criteria for Pancreatic adenocarcinoma participants:

- Pathologically documented unresectable or metastatic pancreatic cancer that was
previously treated with at least 1 prior line of systemic therapy in neoadjuvant,
adjuvant, locally advanced or metastatic setting.

Additional Inclusion Criteria for HER2-negative gastroesophageal cancer participants:

- Pathologically documented unresectable or metastatic adenocarcinoma of the stomach or
esophagus, including the gastroesophagel junction (GEJ) that was previously treated
with at least 1 prior line of systemic therapy.

- No known history of HER2-positivity (defined as Immunohistochemistry IHC 3+ or IHC 2+
and in situ hybridization ISH+) as classified by ASCO-CAP at any time.

Additional Inclusion Criteria for Esophageal cancer participants:

- Pathologically documented unresectable or metastatic squamous cell carcinoma of the
esophagus that was previously treated with at least 1 prior line of therapy including
platinum-based chemotherapy.

Additional Inclusion Criteria for Head and neck squamous cell carcinoma (HNSCC)
participants:

- Pathologically documented unresectable or metastatic HNSCC that was previously treated
with 1-3 prior lines of therapy including platinum and ICI (in combination or
sequential), in the advanced or metastatic setting.

Additional Inclusion Criteria for participants with advanced-stage urothelial cancer:

- Pathologically documented unresectable, locally advanced or metastatic, urothelial
carcinoma (transitional cell and mixed transitional/non-transitional cell histologies)
of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) that
was previously treated with at least 1 prior line of therapy including an ICI.

Additional Inclusion Criteria for Colorectal cancer (CRC) participants:

- Pathologically documented unresectable or metastatic CRC that was previously treated
with, or were not considered candidates for, available therapies including
fluoropyrimidine-based chemotherapy, an anti-vascular. endothelial growth factor
therapy, and an anti-epidermal growth factor (EGFR) therapy.

- Has not progressed or relapsed within 6 months of therapy with irinotecan.

Additional Inclusion Criteria for Platinum-resistant ovarian cancer participants:

- Pathologically documented unresectable or metastatic ovarian cancer that:

- Is epithelial ovarian (including less-common histologies per National
Comprehensive Cancer Network (NCCN).

- Has relapsed or progressed within 6 months of platinum-based chemotherapy.

Additional Inclusion Criteria for Platinum-sensitive ovarian cancer participants:

- Pathologically documented unresectable or metastatic ovarian cancer that:

- Is epithelial ovarian (including less-common histologies per NCCN guidelines),
fallopian tube, or primary peritoneal presentation.

- Has relapsed or progressed at least 6 months after the most recent platinum-based
chemotherapy.

Additional Inclusion Criteria for Cervical cancer participants:

- Pathologically documented unresectable or metastatic cervical cancer that relapsed or
progressed after at least 1 prior line of systemic therapy.

Additional Inclusion Criteria for Castration-resistant prostate cancer participants:

- Pathologically documented unresectable CRPC that:

- Is adenocarcinoma of the prostate without neuroendocrine differentiation or small cell
histology.

- Is surgically or medically castrated, with testosterone levels of less than 50
nanograms per deciliter.

- Objective progression as determined by radiographic progression for participants with
measurable disease after androgen deprivation.

- Has relapsed or progressed after at least 1 of the following: abiraterone,
enzalutamide, apalutamide or darolutamide.

- Has at least 1 documented lesion on either a bone scan or a CT/MRI scan.

- CRPC subjects will be chemotherapy-naïve.

Additional inclusion criteria for HR-positive HER2-low breast cancer subjects previously
treated with T-DXd

- Pathologically documented unresectable or metastatic breast cancer that is:

- HER2-low, defined as IHC 1+ or IHC 2+ / ISH-negative as classified by ASCO-CAP.

- Positive for estrogen receptor and/or progesterone receptor

- Was previously treated with T-DXd in the advanced or metastatic setting

Additional Inclusion Criteria for Sub-study:

- Is competent and able to comprehend, sign, and date both the main study and the oral
mucositis/stomatitis addendum informed consent forms (ICFs) prior to the start of any
sub-study procedure or assessment

- Is willing to comply with the procedures of the sub-study, including keeping a daily
questionnaire on oral hygiene and oral mucositis/stomatitis-related symptoms

Exclusion Criteria:

- Has a history of malignancy, other than a tumor type specified in the Inclusion
Criteria, except (a) adequately resected non-melanoma skin cancer, (b) curatively
treated in situ disease, or (c) other solid tumors curatively treated, with no
evidence of disease for ≥3 years.

- Uncontrolled or significant cardiac disease including myocardial infarction or
uncontrolled/unstable angina within 6 months prior to Cycle 1 Day 1.

- History of congestive heart failure (New York Heart Association classes II-IV) or
uncontrolled or significant cardiac arrhythmia, uncontrolled hypertension(resting
systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg).

- Has a mean corrected QT interval (QTcF) prolongation to >470 ms based on of the
screening triplicate 12-lead ECGs.

- 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 clinically significant corneal disease.

- Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
Has active human immunodeficiency virus (HIV) infection that is not well controlled.
All of the following criteria are required to define an HIV infection that is well
controlled: undetectable viral RNA load, CD4+ count >350, no history of AIDS-defining
opportunistic infection within the past 12 months, and stable for at least 4 weeks on
the same anti-HIV medications. If an HIV infection meets the above criteria,
monitoring of viral RNA load and CD4+ count is recommended. Subjects/participants must
be tested for HIV during the Screening Period if acceptable by local regulations or an
IRB/IEC.

- Has an active or uncontrolled hepatitis B and/or hepatitis C infection.

- Has spinal cord compression or clinically active brain metastases, defined as
untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to
control associated symptoms. Participants with clinically inactive brain metastases
may be included in the study. A minimum of 2 weeks must have elapsed between the end
of whole brain radiotherapy and study enrollment. Participants with treated brain
metastases that are no longer symptomatic and who require no treatment with steroids
may be included in the study if they have recovered from the acute toxic effect of
radiotherapy.

- Is lactating or pregnant as confirmed by pregnancy tests performed within 7 days
before enrollment.

- Has unresolved toxicities from previous anticancer therapy.

- Has a concomitant medical condition that would increase the risk of toxicity, in the
opinion of the Investigator.

- Has a history of severe hypersensitivity reactions to either the drug substances or
inactive ingredients of DS-1062a. Has a history of severe hypersensitivity reaction to
other monoclonal antibodies.

- Has any other medical conditions, including cardiac disease or psychological
disorders, and/or substance abuse that would increase the safety risk to the
participant or interfere with participation of the participant or evaluation of the
clinical study in the opinion of the Investigator.

- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
including, but not limited to, any underlying pulmonary disorder, or any autoimmune,
connective tissue or inflammatory disorders with pulmonary involvement, or prior
pneumonectomy.

- Has leptomeningeal carcinomatosis.

- 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.

- Psychological, social, familial, or geographical factors that would prevent regular
follow-up. Adults under guardianship, curatorship, safeguard of justice, or family
empowerment measure are not eligible.

- Otherwise considered inappropriate for the study by the investigator.

Additional Exclusion Criteria for Sub-study:

- Has had any prior oral mucositis/stomatitis that did not resolve within 3 months of
signing the ICFs

- Requires oral steroid or steroid nasal spray or inhaler for asthma, chronic
obstructive pulmonary disease, or any other reason at the time of randomization

- Requires immunosuppressive drugs at the time of randomization

- Has oral inflammation or infections, including candidiasis (thrush) at the time of
randomization

- Has a history of severe hypersensitivity reactions or any other contraindication to
steroids or other active principles or excipients of the mouthwash