A Study of TAK-676 as Single Agent and TAK-676 in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors

Open to people ages 18 years and up

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

2. TAK-676 SA (dose escalation Part 1A):

   o With histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies.

3. TAK-676 in combination with pembrolizumab (dose escalation Part 1B):
   • With histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to them, including:
   • Tumors that have relapsed or are refractory to anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) therapy.
   • Tumors that are naive to anti-PD-1/ anti-PD-L1 therapy.

4. For expansion phase only:

   • SCCHN (Part 2):

   • Participants with histologically confirmed (cytological diagnosis is acceptable) metastatic or recurrent, unresectable SCCHN that is considered incurable by local therapies. Participants should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months before signing consent if given as part of multimodal treatment of locally advanced disease is allowed.
   • Anatomic subsites to be included are oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, and paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal). The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.
   • Participants with oropharyngeal cancer or tumors arising in the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal) must agree to provide archival tissue for human papilloma virus (HPV) testing or if known, HPV testing results using CINtec® p16 Histology assay and a 70% cutoff point must be provided. If HPV status was previously tested using this method, no additional testing is required.
   • For Part 2A, tumors must have a combined positive score (CPS) ≥1. For Part 2B, any CPS is eligible.
   • For Part 2B, participants must be eligible to receive treatment with either cisplatin or carboplatin in combination with 5-fluorouracil (5-FU) per the treating physician.
5. CRC (Part 3):
   • Third-line or later MSI-H/dMMR CRC (Part 3A): Participants with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSI-H/dMMR CRC whose disease has progressed on or following therapy with 1) an anti-PD-1 or PD-L1 antibody (ie, pembrolizumab) and 2) at least one line of combination chemotherapy including a fluoropyrimidine and irinotecan OR oxaliplatin with or without an anti- epidermal growth factor receptor (EGFR) or anti-vascular endothelial growth factor (VEGFR) monoclonal antibody (ie, cetuximab or bevacizumab). MSI-H/dMMR CRC participants must have received at least 6 weeks of prior treatment with an anti-PD-1 or anti-PD-L1 antibody.
   • Third-line MSS/pMMR CRC (Part 3B): Participants with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSS/pMMR CRC whose disease has progressed on or following therapy with 2 different lines of combination chemotherapy, including therapy with a fluoropyrimidine and irinotecan AND therapy with a fluoropyrimidine and oxaliplatin. Both lines of therapy may be given with or without an anti-EGFR or anti-VEGFR monoclonal antibody (ie, cetuximab or bevacizumab). Participants with MSS/pMMR CRC must have progressed on or after combination chemotherapy regimens containing BOTH irinotecan AND oxaliplatin.
   • Participants with MSI-H/dMMR or MSS/pMMR CRC must have MSI/MMR status confirmed by a clinically-approved immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) assay.
   • Participants with MSI-H/dMMR or MSS/pMMR CRC must have been treated with 2 prior lines of therapy in the recurrent locally advanced or metastatic setting.
6. Adequate bone marrow, renal, hepatic and cardiac functions.
7. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug.
8. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE Version 5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
9. In dose escalation Part 1, once peripheral evidence of TAK-676 pharmacodynamic stimulation of the innate and/or adaptive immune system is observed in the blood and/or clinical response/partial response (CR/PR) is observed in at least 1 participant, subsequent participants must:
   • Have at least 1 lesion amenable for biopsy.
   • Agree to have 2 tumor biopsies: 1 during the screening period and 1 while on TAK-676 treatment.
     1. Must have at least 1 RECIST v.1.1-evaluable (measurable) lesion. For the dose escalation phase (Part 1) only, nonmeasurable only disease is acceptable.
        1. Pharmacokinetic (PK)/pharmacodynamic blood must be drawn on a peripherally-inserted catheter. TAK-676 is preferentially administered through a central line, but peripheral infusion is acceptable. If a peripheral line is used for TAK-676 and/or pembrolizumab infusion, it must be separate than the one used for PK/pharmacodynamic collection.

1. Corrected QT interval by Fredericia (QTcF) greater than (>) 450 milliseconds (men) or >475 milliseconds (women) on a 12-lead electrocardiogram (ECG) during the screening period.
2. Grade greater than or equal to (>=) 2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during Cycle 1 Day 1 (C1D1) predose assessment.
3. Oxygen saturation less than (<) 92 percent (%) on room air at screening or during C1D1 predose assessment.
4. Treated with other STING agonists/antagonist and toll-like receptors agonists within the past 6 months.
5. Active vaping within 90 days of C1D1 of study drug(s).
6. Active smoking.
7. Current history 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 or ascites not controlled by tap or requiring indwelling catheters.
8. History of brain metastasis unless:
   • Clinically stable (that is, >=6 weeks) after prior surgery, whole-brain radiation, or stereotactic radiosurgery, AND
   • Off corticosteroids.

9. Ongoing Grade >= 2 infection or participants with Grade >=2 fever of malignant origin.

   10. Chronic, active hepatitis (example: participants with known hepatitis B surface

   antigen seropositive and/or detectable hepatitis C virus [HCV]-RNA).

   11. For participants in the dose escalation SA Part 1A only: refusal of standard

   therapeutic options.

   12. For participants receiving pembrolizumab only: contraindication and/or intolerance to

   the administration of pembrolizumab.

   13. For participants receiving chemotherapy in Part 2B: contraindication and/or

   intolerance to the administration of both platinum agents (cisplatin and carboplatin) and/or 5-FU.

   14. Concurrent chemotherapy (except for Part 2B), immunotherapy (except for pembrolizumab

   in Part 1B, Part 2, and Part 3), biologic, or hormonal therapy (except for adjuvant endocrine therapy for a history of breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones), unless allowed per exclusion criterion 16.

   15. 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.

   16. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or

   within 7 days of C1D1 of study drug(s), with the following exceptions:

   • Topical, intranasal, inhaled, ocular, intra-articular, and/or other non-systemic corticosteroids.
   • Physiological doses of replacement steroid therapy (example: for adrenal insufficiency).
   • For participants enrolled in Part 2B, chemotherapy premedication with steroids can be administered according to local standards of care practice.
     1. Use of medications that are known clinical organic anion-transporting polypeptide B1 (OATP1B1) and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s).
        1. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s).
        2. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.