A Study of TAK-186 (Also Known as MVC-101) in Adults With Advanced or Metastatic Cancer

Key Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1

• Ability to provide informed consent and documentation of informed consent beforeinitiation of any study-related tests or procedures that are not part of standard ofcare for the participant's disease. Participants must also be willing and able tocomply with study procedures, including the acquisition of specified researchspecimens.

• Life expectancy ≥ 12 weeks

• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1criteria and documented by Computed tomography (CT) and/or magnetic resonanceimaging (MRI). The definitions for measurable lesions are the same whetherconventional and modified RECIST criteria are applied. Cutaneous or subcutaneouslesions must be measurable by calipers. Lesions to be used as measurable disease forthe purpose of response assessment must either a) not reside in a field that hasbeen subjected to prior radiotherapy, or b) have demonstrated clear evidence ofradiographic progression since the completion of prior radiotherapy and before studyenrollment or c) have been radiated at least 6 months before study enrollment.

• Tumor Histology Types:

• Participants with pathologically proven, unresectable, locally advanced ormetastatic solid tumors that based on literature reports are considered to expressEGFR. During cohort expansion, participants with locally advanced or metastaticsolid tumors expressing EGFR including advanced or metastatic NSCLC, CRC, and HNSCCare eligible for enrollment.

• Tumors During Cohort Expansion:

• Participants with pathologically proven, unresectable, locally advanced ormetastatic solid tumors that based on literature reports are considered to expressEGFR are eligible for enrollment:

• NSCLC: locally advanced or metastatic NSCLC that has progressed during orfollowing treatment with platinum-based chemotherapy, a checkpoint inhibitor (unless known to be PD-L1 negative), or targeted therapy (for participants witha known actionable mutation).

• CRC: locally advanced or metastatic CRC that has progressed after systemictherapies, including irinotecan, oxaliplatin, an anti-EGFR inhibitor (if K-RASor N-RAS is WT), a checkpoint inhibitor (if MSI-H), and a VEGF inhibitor (iflocally approved and accessible as a standard-of-care).

• HNSCC: HNSCC that has progressed during or following treatment with acheckpoint inhibitor (unless ineligible, e.g, PD-L1 negative) andplatinum-based chemotherapy (unless ineligible for or intolerant toplatinum-based chemotherapy) with or without cetuximab for metastatic orrecurrent disease.

1. Participants with salivary gland tumors will not be considered as havingHNSCC.
2. Participants who refuse surgery for potentially curable disease where thesurgery or radiotherapy could result in severe morbidity are eligible. Thereason for the refusal will be captured in the electronic case report form (eCRFs).

• Archival Tissue:

• Participants must allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) archival tumor sample, either a block or unstained slides. Participants whoprovide fresh pretreatment biopsy samples will not be required to submit archivaltumor samples.

• Tumor Biopsy: • Participants must be willing to consent to mandatory pretreatment (duringscreening) and on-treatment fresh tumor biopsies for cohort expansion phase andbackfill in dose escalation. Once the target number of biopsies have beencollected, additional paired pretreatment and on-treatment biopsies will not berequired; sample collection will be optional after this time point. For freshtumor biopsies, the lesion must be accessible (those occurring outside thebrain or those that are accessible by an interventional or endoscopicprocedure) for a low-risk biopsy procedure that does not place the participantat an unjustifiable risk in the opinion of the investigator. Participants whohave an archived biopsy specimen available that was obtained up to 90 daysprior to treatment initiation and have received no other treatment from thetime of biopsy until the start of treatment with TAK-186, may submit thatarchived specimen in lieu of a pretreatment biopsy upon agreement from thesponsor.

• Laboratory Features:

• Acceptable laboratory parameters as follows:

1. Albumin ≥ 3.0 g/dL

2. Platelet count ≥ 75 × 103/μL

3. Hemoglobin ≥ 9.0 g/dL

4. Absolute neutrophil count ≥ 1.0 × 103/μL

5. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × upperlimit of normal (ULN); for participants with hepatic metastases, ALT/AST ≤ 5 ×ULN

6. Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, whomay enroll if the conjugated bilirubin is within normal limits.

7. Creatinine clearance of ≥ 30 mL/minute using Cockcroft-Gault equation.

• Reproductive Features:

• WOCBP must have a negative serum pregnancy test performed within 72 hours before theinitiation of study drug administration. WOCBP must use 1 form of highly effectivemethod and 1 additional effective (barrier) method of contraception at the same timethroughout the study, starting at screening through 90 days after the last dose ofTAK-186. Contraception methods may be considered highly effective if they canachieve a failure rate of less than 1% per year when used consistently andcorrectly.

• Male participants with partners of childbearing potential must use barriercontraception during the entire study treatment period through 120 days after thelast dose of study drug and must not donate sperm during this period. In addition,male participants should also have their partners use contraception (as documentedfor female participants) for the same period of time.

• Previous Checkpoint Inhibitor Therapy:

• Participants who have previously received an immune checkpoint before enrollmentmust have checkpoint inhibitor immune-related toxicity resolved to either Grade ≤ 1or baseline

• Symptomatic central nervous system (CNS) metastases must have been treated, beasymptomatic for ≥ 14 days, and meet the following criteria at the time ofenrollment:

1. No concurrent treatment for CNS disease (e.g., surgery, radiation,corticosteroids ≥ 10 mg prednisone per day or equivalent).

2. No concurrent leptomeningeal disease or spinal cord compression.

Key Exclusion Criteria:

• Participants with a history of known autoimmune disease with the exceptions of:

1. Vitiligo.

2. Psoriasis not requiring systemic treatment for > 1 year before receivingTAK-186.

3. History of Graves' disease in participants now euthyroid for > 4 weeks.

4. Hypothyroidism managed by thyroid replacement.

5. Alopecia.

6. Well-controlled diabetes type 1.

• Major surgery or traumatic injury within 8 weeks before first dose of TAK-186.

• Unhealed wounds from surgery or injury.

• Radiation therapy < 2 weeks before initiation of TAK-186.

• Treatment with > 10 mg per day of prednisone (or equivalent) or otherimmune-suppressive drugs within the 7 days before the initiation of study drug.Steroids for topical, ophthalmic, inhaled, or nasal administration are allowed.

• Prior therapy within the following timeframe before the planned start of TAK-186 asfollows:

1. Cytotoxic chemotherapy, small molecule inhibitors, radiation, interventionalradiology procedure, or similar investigational therapies: ≤ 2 weeks or 5half-lives, whichever is shorter.

2. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, orsimilar investigational therapies: ≤ 4 weeks.

3. Concurrent use of hormones either to maintain castrate levels of testosteronein participants with castration-sensitive prostate cancer or fornon-cancer-related conditions (e.g., insulin for diabetes, hormone replacementtherapy) is acceptable. Bisphosphonates are permitted for supportive care ofbone metastases (e.g., breast or prostate cancer) or osteoporosis.

• Clinically significant cardiovascular or vascular disease including:

1. Myocardial infarction or unstable angina < 6 months before the initiation ofstudy drug.

2. Clinically significant cardiac arrhythmia (e.g., with potential for hemodynamicinstability).

3. Uncontrolled hypertension: systolic blood pressure > 180 mmHg; diastolic bloodpressure > 100 mmHg.

4. Pulmonary embolism, stroke, or transient ischemic attack < 6 months beforeinitiation of TAK-186.

5. QTcF (QT interval by Fridericia correction) prolongation > 480 msec.

6. Congestive heart failure (New York Heart Association Class III or IV).

7. Pericarditis or clinically significant pericardial effusion.

8. Myocarditis.

9. Vasculitis not resolved < 6 months before TAK-186 initiation.

• Clinically significant gastrointestinal disorders including:

1. Gastrointestinal perforation < 6 months before study drug administration.Participants must have documented evidence (e.g., upper endoscopy, colonoscopy)of completely healed area of prior perforation.

2. Gastrointestinal bleeding < 2 months before study drug administration.Participants must have documented evidence (e.g., upper endoscopy, colonoscopy)of completely healed area of prior bleeding.

3. Pancreatitis < 6 months before the initiation of study drug. Participants musthave a CT scan negative for evidence of remaining disease or normal pancreaticenzyme levels for > 4 weeks before the initiation of TAK-186.

4. Diverticulitis flare < 2 months before study drug administration. Participantsmust have a CT scan negative for evidence of remaining disease before theinitiation of TAK-186.

5. History of Crohn's disease or ulcerative colitis.

• Inflammatory process that has not resolved for ≥ 4 weeks from the date of firststudy dose. Participants with chronic low-grade inflammatory processes such asradiation-induced pneumonitis are excluded regardless of duration.

• Clinically significant pulmonary compromise (e.g., requirement for supplementaloxygen on a continuous basis).

• Active viral, bacterial, or systemic fungal infection requiring parenteral treatmentwithin 7 days before the initiation of study drug. Systemic antiviral, antifungal,or antibacterial therapy must be completed > 1 week before the initiation of studydrug. Antimicrobial prophylaxis (e.g., for Pneumocystis carinii infection) maycontinue the antimicrobial for that purpose.

• Vaccination with any live virus vaccine within 4 weeks before the initiation ofstudy drug administration or vaccination with other vaccines 2 weeks before theinitiation of study drug administration. Inactivated annual influenza vaccination isallowed.

• Participants who are known to be human immunodeficiency virus positive or who areknown to be hepatitis B or C positive. Participants treated for hepatitis C musthave viral titers of 0 for ≥ 2 years to be eligible. Participants with hepatitis Bhaving undetectable or ≤ 500 IU hepatitis B viral titers are eligible. Participantswith hepatocellular carcinoma (HCC) known history of hepatitis B are excluded,regardless of hepatitis B viral titers.

• Second primary invasive malignancy not in remission for ≥ 3 years. Exceptionsinclude non-melanoma skin cancer, cervical carcinoma in situ, localized prostatecancer (Gleason score ≤ 7), resected melanoma in situ, or any malignancy consideredto be indolent and never having required therapy, excluding indolent lymphoidmalignancies.

• Any serious underlying medical or psychiatric condition that would precludeunderstanding and rendering of informed consent or impair the ability of theparticipant to receive or tolerate the planned treatment.

• Known hypersensitivity to TAK-186 (or any excipient [trehalose, histidine, arginine,or polysorbate-80] contained in the drug or diluent formulation) knownhypersensitivity to tocilizumab.

• Investigative site personnel or sponsor personnel directly affiliated with thisstudy or known hypersensitivity to tocilizumab.

• Prisoners or other individuals who are involuntarily detained.

• Any medical or non-medical issue that would contraindicate the participant'sparticipation in the study or confound the results of the study.

• Female participants who are breastfeeding.