An Open-label, Dose Escalation and Expansion, Phase 1/ 2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or Metastatic Solid Tumors.

This study is about TAK-500, given either alone or with pembrolizumab, in adults with
select locally advanced or metastatic solid tumors.

The aims of the study are:

- to assess the safety profile of TAK-500 when given alone and when given with
pembrolizumab.

- to assess the anti-tumor effects of TAK-500, when given alone and when given with
pembrolizumab, in adults with locally advanced or metastatic solid tumors.

Participants may receive TAK-500 for up to 1 year. Participants may continue with their
treatment if they have continuing benefit and if this is approved by their study doctor.
Participants who are receiving TAK-500 either alone or with pembrolizumab will continue
with their treatment until their disease progresses or until they or their study doctor
decide they should stop this treatment.

Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. 2.
Individuals with the following pathologically confirmed (cytological diagnosis is
adequate) select locally advanced or metastatic solid tumors, whose disease has
progressed on or are intolerant to standard therapy:

1. Gastroesophageal (esophageal, gastroesophageal junction, and gastric)
adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma (HCC),
nonsquamous non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head
and neck (SCCHN), mesothelioma, triple-negative breast cancer (TNBC), renal clear
cell carcinoma (RCC) and nasopharyngeal carcinoma (NPC). Participants who are
intolerant to all standard therapies are those who have developed clinical or
laboratory abnormalities that prevent continued drug administration as evaluated by
the principal investigator at the time of screening.

2. For dose expansion in 2L nonsquamous NSCLC (TAK-500 plus pembrolizumab):

- Participants with pathologically confirmed (cytological diagnosis is adequate)
locally advanced or metastatic nonsquamous NSCLC.

- Participants may not have a known targetable driver mutation, rearrangement or
amplification (eg, EGFR, ALK, MET, ROS1, BRAF, KRASG12C, etc.).

- Must have had disease progression while on or following 1 prior line of
therapy:

1. Disease progression while on or following at least 6 weeks of 1 prior
anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic
setting.

OR Disease progression/recurrence within 6 months of the completion of anti-PD-(L)1
therapy if administered in the adjuvant/neoadjuvant setting.

Prior anti-PD-(L)1 therapy may have been given with or without an anti-CTLA4
antibody and/or chemotherapy (eg, carboplatin and pemetrexed).

• Participants are eligible regardless of PD-L1 status.

3. For dose expansion in 3L nonsquamous NSCLC (TAK-500 SA):

- Participants with pathologically confirmed (cytological diagnosis is adequate)
locally advanced or metastatic nonsquamous NSCLC.

- Participants may not have a known targetable driver mutation, rearrangement or
amplification (eg, EGFR, ALK, MET, ROS1, BRAF, KRASG12C, etc.).

- Must have had disease progression while on or following 2 prior lines of
therapy:

1. Disease progression while on or following at least 6 weeks of 1 prior
anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic
setting OR Disease progression/recurrence within 6 months of the
completion of 1 prior anti-PD-(L)1 therapy if administered in the
adjuvant/neoadjuvant setting.

Prior anti-PD-(L)1 therapy may have been given with or without an
anti-CTLA4 antibody and/or chemotherapy (eg, carboplatin and pemetrexed).

2. Participants must have had disease progression while on or after 1 or 2
lines of chemotherapy in the recurrent locally advanced or metastatic
setting. If the anti-PD-(L)1 therapy is given in combination with
chemotherapy, participant must have progressed on an additional line of
chemotherapy.

- Participants are eligible regardless of PD-L1 status.

4. For dose expansion in 2L pancreatic adenocarcinoma (TAK-500 SA and TAK-500 plus
pembrolizumab):

• Participants with pathologically confirmed (cytological diagnosis is adequate)
locally advanced or metastatic pancreatic adenocarcinoma.

• Must have had disease progression while on or following 1 prior line of therapy:

1. One prior line of fluorouracil- or gemcitabine-based chemotherapy (eg,
FOLFIRINOX, FOLFOX, FOLFIRI, gemcitabine/nab-paclitaxel) in the
metastatic/recurrent locally advanced setting.

Prior chemotherapy in the neoadjuvant/adjuvant setting does not qualify unless the
participant had progression of disease within 6 months of completion of
neoadjuvant/adjuvant chemotherapy.

• Must not have had prior exposure to anti-PD-(L)1 therapy.

• Participants with MSI-H/dMMR disease are not eligible.

• Participants are eligible regardless of PD-L1 status.

5. For dose expansion in 3L RCC (TAK-500 plus pembrolizumab):

- Participants with pathologically confirmed (cytological diagnosis is adequate)
locally advanced or metastatic RCC.

- Must have had disease progression while on or following 2 prior lines of
therapy:

1. Disease progression while on or following at least 6 weeks of 1 prior
anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic
setting.

OR Disease progression/recurrence within 6 months of the completion of
anti-PD-(L)1 therapy if administered in the adjuvant/neoadjuvant setting.

Prior anti-PD-(L)1 therapy may have been given with or without an
anti-CTLA4 antibody and/or an anti-VEGFR TKI.

2. Participants must have had prior therapy with 1 or 2 lines of VEGFR TKIs
in the metastatic/recurrent locally advanced setting. If anti-PD-(L)1
therapy was given in combination with a VEGFR TKI, the participant must
have had progressive disease on an additional line of therapy (eg, VEGFR
TKI or VEGFR TKI-containing combination).

- Participants are eligible regardless of PD-L1 status. 3. Must have at least 1
RECIST version 1.1 measurable lesion. Lesions in previously irradiated areas
(or other local therapy) should not be selected as measurable/target lesions
unless there has been demonstrated radiographic progression in that lesion.
RECIST v1.1 target lesions must include at least 1 lesion that was not
previously irradiated.

4. Adequate bone marrow, renal, and hepatic functions, as determined by the
following laboratory parameters:

- Absolute neutrophil count (ANC) greater than or equal to (>=) 1000/microliter
(mcL), platelet count >=75,000/mcL, and hemoglobin >= 8.0 grams per deciliter
(g/dL) without growth factor support for ANC or transfusion support for
platelets within 14 days before the first study treatment dose.

- Total bilirubin <=1.5 times the institutional upper limit of normal (ULN). For
participants with Gilbert's disease or HCC, <=3 milligrams per deciliter
(mg/dL).

- Serum alanine aminotransferase and aspartate aminotransferase <=3.0*ULN or
<=5.0*ULN with liver metastases or HCC.

- Albumin >=3.0 g/dL.

- Calculated creatinine clearance using the Cockcroft-Gault formula >=30
mL/minute.

5 . Left ventricular ejection fraction (LVEF) >50%, as measured by
echocardiogram or multiple gated acquisition scan (MUGA) within 4 weeks before
receiving the first dose of study drug.

6. For participants with HCC only: Child-Pugh score less than or equal to 7
(Child-Pugh A or B7).

7. Clinically significant toxic effects of previous therapy have recovered to
Grade 1 (per National Cancer Institute Common Terminology Criteria for
Adverse Events [NCI CTCAE] Version 5.0) or baseline, except for alopecia,
Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with
stable endocrine replacement therapy.

8. Participants previously treated with fully human/humanized antineoplastic
monoclonal antibodies must not have received treatment with such
antibodies for at least 4 weeks or the time period equal to the dosing
interval, whichever is shorter. No washout period is required for prior
treatment with pembrolizumab or other anti-programmed cell death protein 1
(PD-1) antibodies, although the first study dose of these drugs must not
occur at an interval less than standard of care (that is, 3 weeks for 200
mg of IV pembrolizumab).

Exclusion Criteria:

1. History of any of the following <=6 months before first dose of study drug(s):
congestive heart failure New York Heart Association Grade III or IV, unstable
angina, myocardial infarction, persistent hypertension >=160/100 millimeters of
mercury (mmHg) despite optimal medical therapy, ongoing cardiac arrhythmias of Grade
>2 (including atrial flutter/fibrillation or intermittent ventricular tachycardia),
other ongoing serious cardiac conditions (example, Grade 3 pericardial effusion or
Grade 3 restrictive cardiomyopathy), or symptomatic cerebrovascular events. Chronic,
stable atrial fibrillation on stable anticoagulation therapy, including low
molecular-weight heparin, is allowed.

2. QT interval with Fridericia correction method >450 milliseconds (men) or >475
milliseconds (women) on a 12- lead ECG during the screening period.

3. Grade >=2 hypotension (that is, hypotension for which nonurgent intervention is
required) at screening or during C1D1 predose assessment.

4. Oxygen saturation <92% on room air at screening or during C1D1 predose assessment.

5. Treatment with other STING agonists/antagonists, Toll-like receptor agonists or CCR2
agonist/antagonist within the past 6 months.

6. Active diagnosis of pneumonitis, interstitial lung disease, severe chronic
obstructive pulmonary disease, idiopathic pulmonary fibrosis, other restrictive lung
diseases, acute pulmonary embolism, or Grade >=2 pleural effusion not controlled by
tap or requiring indwelling catheters.

7. Grade >=2 fever of malignant origin.

8. Chronic, active hepatitis (example, participants with known hepatitis B surface
antigen seropositive and/or detectable hepatitis C virus [HCV] RNA).

9. History of hepatic encephalopathy.

10. Prior or current clinically significant ascites, as measured by physical
examination, that requires active paracentesis for control.

11. Treatment with any investigational products or other anticancer therapy (including
chemotherapy, targeted agents, and immunotherapy), within 14 days or 5 half-lives,
whichever is shorter, before C1D1 of study drug(s).

12. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or
systemic treatment with radionuclides within 42 days before C1D1 of study drug(s).
Participants with clinically relevant ongoing pulmonary complications from prior
radiation therapy are not eligible.

13. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or
within 14 days of C1D1 of study drug(s), with the following exceptions:

- Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic
corticosteroids.

- Physiological doses of replacement steroid therapy (example, for adrenal
insufficiency), not to exceed the equivalent of 10 mg prednisone daily.

14. Recipients of allogeneic or autologous stem cell transplantation or organ
transplantation.

Additional criteria specific for participants in TAK-500 and pembrolizumab combination
arm only:

1. Contraindication to the administration of a pembrolizumab or prior intolerance to
pembrolizumab or other anti-PD-1 or anti-programmed cell death protein ligand 1
antibody.

2. History of intolerance to any component of the study treatment agents or known
serious or severe hypersensitivity reaction to any of the study drugs or their
excipients. (Pembrolizumab is formulated with L-histidine, polysorbate 80, and
sucrose.