A Study of MVC-101 (Also Known as TAK-186) 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 prior to initiation of any study-related tests or procedures that are not part of standard of care for the participant's disease. Participants must also be willing and able to comply with study procedures, including the acquisition of specified research specimens.
• Life expectancy ≥ 12 weeks

• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria and documented by Computed tomography (CT) and/or magnetic resonance imaging (MRI). The definitions for measurable lesions are the same in conventional and modified RECIST criteria. Cutaneous or subcutaneous lesions must be measurable by calipers. Lesions to be used as measurable disease for the purpose of response assessment must either a) not reside in a field that has been subjected to prior radiotherapy, or b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment.

  • Tumor Histology Types:

• Dose escalation will begin by initially enrolling participants with histologically proven, unresectable, locally advanced or metastatic cancers that based on prior literature studies are considered to express epidermal growth factor receptor (EGFR). Participants will either have exhausted all available approved therapies with demonstrated clinical benefit (as listed below) or be ineligible for standard therapy.

  * Cohort Expansion Tumors:

• Participants with histologically proven, unresectable, locally advanced or metastatic malignant neoplasms for whom there is no approved therapy with demonstrated clinical benefit available or are ineligible or intolerant of standard therapy (except in cases where the therapy outlined is not available) as listed below:

  1. NSCLC that has progressed during or following treatment with platinum-based chemotherapy and an anti-PDx therapy for unresectable, locally advanced or metastatic disease. NSCLC harboring an activating EGFR mutation or ALK rearrangement must have progressed following available EGFR or ALK targeted therapy in addition to treatment with platinum-based chemotherapy (unless ineligible/intolerant of platinum-based therapy).

  2. HNSCC that has progressed during or following treatment with an anti-PDx (unless ineligible, e.g. participants failing chemotherapy and PD-L1 CPS < 1) and platinum-based chemotherapy (unless ineligible/intolerant of platinum-based chemotherapy) for metastatic or recurrent disease.

     1. Participants with upper esophageal or salivary gland tumors will not be considered as HNSCC.
     2. Participants who refuse radical resection for recurrent disease where the surgery would result in severe morbidity are eligible. The reason for the refusal will be captured in the case report form (CRFs).
     3. A minimum of 6 participants positive for human papillomavirus (HPV) will be enrolled. HPV status will be determined by retrospective evaluation using either polymerase chain reaction or p16 based assays.

  3. CRC

     1. K-Ras WT: Participants who have progressed during or after, or are ineligible for, both irinotecan and oxaliplatin based chemotherapy and who are relapsed or refractory to at least 1 prior systemic therapy that included an anti-EGFR antibody, such as cetuximab or panitumumab.

     2. K-Ras mutant: Participants who have progressed during or after, or are ineligible for, both irinotecan and oxaliplatin based chemotherapy (± bevacizumab). No more than 4 prior therapeutic regimens for metastatic disease are allowed.

        • Archival Tissue:

• Participants must allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) archival tumor sample, either a block or unstained slides.

  * Tumor Biopsy:

• The following participants populations must have at least one lesion considered capable of being biopsied and be willing to provide consent for biopsy samples. An attempt at a tumor biopsy of locally accessible lesions will be required for these participants:

  1. Dose Escalation beginning in the first cohort.
  2. Backfill participants in Dose Escalation: the additional participants enrolled in Dose Escalation at a dose level deemed below or at the maximum tolerated dose (MTD).

  3. All participants in the Cohort Expansion Phase.

     • 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 × upper limit of normal (ULN); for participants with hepatic metastases, ALT and AST ≤ 5 × ULN
  6. Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, who may enroll if the conjugated bilirubin is within normal limits.

  7. Creatinine < 1.8 mg/dL, or a calculated or measured creatinine clearance ≥ 30 mL/min.

     • Reproductive Features:
• Female participants of childbearing potential (not surgically sterilized and between menarche and 1-year post-menopause) must have a negative serum or urine pregnancy test performed within 72 hours prior to the initiation of study drug administration. Female participants of childbearing potential must be willing to use 2 forms of contraception throughout the study, starting with the Screening through 90 days after the last dose of MVC-101 (TAK-186). Examples of effective contraception are birth control pills, birth control patch (e.g., Ortho Evra), NuvaRing, IUD, female condom, diaphragm with spermicide, cervical cap, use of a condom by the sexual partner, documented sterile sexual partner or documented evidence of surgical sterilization at least 6 months prior to Screening (e.g., tubal ligation or hysterectomy). Abstinence is acceptable if this is the established and the preferred contraception method for the participant.

• Male participants with partners of childbearing potential must use barrier contraception from the time of consent through 90 days after discontinuation of MVC-101 (TAK-186) and must not donate sperm during this period. In addition, male participants should also have their partners use contraception (as documented for female participants) for the same period of time.

  * Previous Checkpoint Inhibitor Therapy:

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

• Symptomatic central nervous system (CNS) metastases must have been treated, be asymptomatic for ≥ 14 days, and meet the following at the time of enrollment:

  1. No concurrent treatment for CNS disease (e.g., surgery, radiation, corticosteroids ≥ 10 mg prednisone / day or equivalent).
  2. No concurrent leptomeningeal disease or cord compression.

Key Exclusion Criteria:

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

  1. Vitiligo.
  2. Psoriasis not requiring systemic treatment for > 1 year prior to receiving MVC-101 (TAK-186).
  3. History of Graves' disease in participants now euthyroid for > 4 weeks.
  4. Hypothyroidism managed by thyroid replacement.
  5. Alopecia.
• Major surgery or traumatic injury within 8 weeks before first dose of MVC-101 (TAK-186).
• Unhealed wounds from surgery or injury.
• Radiation therapy < 2 weeks prior to initiation of MVC-101 (TAK-186).
• Treatment with > 10 mg per day of prednisone (or equivalent) or other immune-suppressive drugs within the 7 days prior to 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 MVC-101 (TAK-186) as follows:

  1. Cytotoxic chemotherapy, small molecule inhibitors, radiation, interventional radiology procedure, or similar investigational therapies: ≤ 2 weeks or 5 half-lives, whichever is shorter.
  2. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar investigational therapies: ≤ 4 weeks.
  3. Concurrent use of hormones either to maintain castrate levels of testosterone in participants with castration-sensitive prostate cancer or for non-cancer-related conditions (e.g., insulin for diabetes, hormone replacement therapy) is acceptable. Bisphosphonates are permitted for supportive care of bone metastases (e.g., breast or prostate cancer).

• Clinically significant cardiovascular / vascular disease including:

  1. Myocardial infarction or unstable angina < 6 months prior to the initiation of study drug.
  2. Clinically significant cardiac arrhythmia (e.g., with potential for hemodynamic instability).
  3. Uncontrolled hypertension: systolic blood pressure > 180 mmHg, diastolic blood pressure > 100 mmHg.
  4. Pulmonary embolism, stroke, or transient ischemic attack < 6 months prior to initiation of MVC-101 (TAK-186).
  5. QTcF (Fridericia correction) prolongation > 480 msec.
  6. Congestive heart failure (New York Heart Association Class III-IV).
  7. Pericarditis/clinically significant pericardial effusion.
  8. Myocarditis.
  9. Vasculitis not resolved < 6 months prior to MVC-101 (TAK-186) initiation.

• Clinically significant gastrointestinal disorders including:

  1. Gastrointestinal perforation < 6 months prior to 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 prior to study drug administration. Participants must have documented evidence (e.g., upper endoscopy, colonoscopy) of completely healed area of prior bleeding.
  3. Pancreatitis < 6 months prior to the initiation of study drug. Participants must have a CT scan negative for evidence of remaining disease or normal pancreatic enzyme levels for > 4 weeks prior to the initiation of MVC-101 (TAK-186).
  4. Diverticulitis flare < 2 months prior to study drug administration. Participants must have a CT scan negative for evidence of remaining disease prior to the initiation of MVC-101 (TAK-186).
  5. History of Crohn's disease or ulcerative colitis.
• Inflammatory process that has not resolved for ≥ 4 weeks from the date of first study dose. Participants with chronic low-grade inflammatory processes such as radiation-induced pneumonitis are excluded regardless of duration.
• Clinically significant pulmonary compromise (e.g., requirement for supplemental oxygen on a continuous basis).
• Active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 days prior to the initiation of study drug. Systemic antiviral, antifungal, or antibacterial therapy must be completed > 1 week prior to the initiation of study drug. Antimicrobial prophylaxis (e.g., for pneumocystis carinii infection) may continue the antimicrobial for that purpose.
• Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug administration or vaccination with other vaccines 2 weeks prior to the initiation of study drug administration. Inactivated annual influenza vaccination is allowed.
• Participants who are known to be human immunodeficiency virus positive or who are known to be hepatitis B or C positive. Participants treated for hepatitis C must have viral titers of 0 for ≥ 2 years to be eligible. Participants with hepatitis B having undetectable or ≤ 500 IU hepatitis B viral titers are eligible. HCC participants with known history of hepatitis B are excluded, regardless of hepatitis B viral titers.
• Second primary invasive malignancy not in remission for ≥ 1 year. Exceptions include non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer (Gleason score ≤ 7), resected melanoma in situ, or any malignancy considered to be indolent and never required therapy, with the exception of indolent lymphomas.
• Any serious underlying medical or psychiatric condition that would preclude understanding and rendering of informed consent or impair the ability of the participant to receive or tolerate the planned treatment.
• Known hypersensitivity to MVC-101 (TAK-186) or any excipient (trehalose, histidine, arginine, or polysorbate-80) contained in the drug or diluent formulation.
• Investigative site personnel or Sponsor personnel directly affiliated with this study.
• Prisoners or other individuals who are involuntarily detained.
• Any medical or non-medical issue that would contraindicate the participant's participation in the study or confound the results of the study.
• Female participants who are breastfeeding.