Overview

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.

Eligibility

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 <=3.0ULN or
                  <=5.0ULN 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.