DS-6157a in Participants With Advanced Gastrointestinal Stromal Tumor (GIST)

Inclusion Criteria:

* Written informed consent
* At least 20 years old in Japan or 18 years old in other countries at the time of signature of the informed consent form (ICF), following local regulatory requirements
* Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
* Has histopathologically documented unresectable and/or metastatic GIST meeting the criteria below:
* Dose Escalation (Part 1): Participants should meet one of the following criteria:

  1. (For US sites only) Participants with GIST who have progressed on or are intolerant to imatinib (IM) and at least one post-IM treatment or who are not candidates for post-IM standard of care treatment
  2. (For Japan sites only) Participants with GIST who have received all the existing standard of care treatments or who are not candidates for one or more available post-IM standard of care treatments
  3. Participants with GIST who are not candidates for IM or curative intent surgical treatment (i.e., participants without activating KIT or platelet-derived growth factor receptor alpha (PDGFRa) mutations, with PDGFRa D842V mutations, or are KIT negative by local results)
* Dose Expansion (Part 2) Cohort 1: Participants with GIST who have progressed on or are intolerant to IM and at least one post-IM treatment
* Dose Expansion (Part 2) Cohort 2: Participants with GIST who have progressed on IM and had not received a post-IM treatment (2nd line)
* Consents to provide fresh tumor biopsy tissue samples both before and on DS-6157a treatment for the measurement of GPR20 levels by immunohistochemistry and other biomarkers
* Has a left ventricular ejection fraction (LVEF) ≥50% by either echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 28 days before study treatment
* Has at least 1 measurable lesion based on RECIST Version 1.1 as assessed by the Investigator
* Has adequate organ function within 7 days before the start of study treatment, defined as:

  1. Platelet count ≥100,000/mm\^3
  2. Hemoglobin ≥8.5 g/dL
  3. Absolute neutrophil count ≥1,500/mm\^3
  4. Creatinine clearance ≥50 mL/min
  5. Aspartate aminotransferase ≤3 × upper limit of normal (ULN) (if liver metastases are present, ≤5 × ULN)
  6. Alanine aminotransferase ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
  7. Total bilirubin ≤1.5 × ULN or ≤3.0 × ULN for participants with documented history of Gilbert's Syndrome
* Has an adequate treatment washout period prior to start of study treatment, defined as:

  1. Major surgery: ≥4 weeks (or 2 weeks for minor surgeries)
  2. Radiation therapy: ≥3 weeks (or 2 weeks for palliative radiation excluding pelvic radiation)
  3. Systemic anti-cancer therapy (except for anti-androgen for prostate cancer and bisphosphonate, denosumab, or medroxyprogesterone acetate for bone metastases):

     * Cytotoxic chemotherapy: ≥3 weeks or 5 times the terminal elimination half-life (t½) of the chemotherapeutic agent, whichever is shorter
     * Antibody and antibody-conjugates therapy: ≥3 weeks or 5 times the t½, whichever is longer
     * Prior tyrosine kinase inhibitors (TKIs): washout period from 2 to 21 days depending on the TKI
     * Immunotherapy: ≥4 weeks.
* Male participants with female partners of childbearing potential and female participants of child-bearing potential must agree to use a highly effective form of contraception, or avoid intercourse during and upon completion of the study and for at least 4 months (for males) and for at least 7 months (for females) after the last dose of study drug.

Exclusion Criteria:

* History of an allogeneic bone marrow or solid organ transplant within 3 months before the start of study treatment
* Concomitant treatment with any medication that is classified as having a known risk of Torsades de pointes should be avoided from the start of study treatment through the end of Cycle 3
* Prophylactic administration of granulocyte colony-stimulating factor (G-CSF), filgrastim, pegfilgrastim, erythropoietin, or the transfusion of blood, red blood cells, or platelets within 14 days before the start of treatment and during Cycle 1. Chronic therapy with erythropoietin at stable dose that started at least 14 days before the first dose of DS-6157a may continue.
* Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, Grade ≤1. Participants with chronic Grade 2 toxicities may be eligible.
* Has spinal cord compression or clinically active central nervous system (CNS) metastases (including brain metastases), defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms
* Has known hypersensitivity to either the drug substances or inactive ingredients in the drug product
* Has a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety, efficacy, or any other assessments of the investigational regimen
* Has a documented history of myocardial infarction or unstable angina within 6 months before study treatment
* Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or a serious cardiac arrhythmia requiring treatment
* Has a corrected QT by Fridericia's formula (QTcF), of \>470 ms based on the average of triplicate 12-lead electrocardiogram (ECG) per local read
* Has a documented history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
* Has clinically significant pulmonary compromise or requirement for supplemental oxygen
* Has clinically significant corneal disease
* Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
* Has active human immunodeficiency virus (HIV) infection as determined by plasma HIV RNA viral load.
* Has evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, as manifest by the detectable viral load (HBV-DNA or HCV-RNA, respectively)
* Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days before study treatment
* Women who plan to become pregnant while in the study and for at least 7 months after the last administration of study treatment
* Men who plan to father a child while in the study and for at least 4 months after the last administration of study treatment
* Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, substance abuse, or other medical condition that would increase the risk of toxicity or interfere with participation of the participant or evaluation of the clinical study