COBRA: This trial is trying to understand how safe, well tolerated and effective a new targeted cancer drug is in patients with squamous cell carcinoma of the head and neck, non-small cell lung cancer or colorectal cancerA Phase 1/2, First-in-Human, Open Label, Dose Escalation Study of MVC-101, An EGFR x CD3 Conditional Bispecific Redirected Activation Protein in Patients With Unresectable Locally Advanced or Metastatic Cancer

Inclusion

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
• Ability to provide informed consent and documentation of informed consent before 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 whether conventional and modified RECIST criteria are applied. 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 before study enrollment or c) have been radiated at least 6 months before study enrollment.

  • Tumor Histology Types:

• Dose escalation will begin by initially enrolling participants with histologically proven, unresectable, locally advanced or metastatic solid tumors that based on prior literature reports are considered to express epidermal growth factor receptor (EGFR).

  * Tumors During Cohort Expansion:

• Participants with histologically proven, unresectable, locally advanced or metastatic solid tumors that based on literature reports are considered to express EGFR are eligible for enrollment:

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

  • HNSCC: HNSCC that has progressed during or following treatment with a checkpoint inhibitor (unless ineligible, e.g, PD-L1 negative) and platinum-based chemotherapy (unless ineligible for or intolerant to platinum-based chemotherapy) with or without cetuximab for metastatic or recurrent disease.

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

  • CRC: locally advanced or metastatic CRC that has progressed after systemic therapies, including irinotecan, oxaliplatin, an anti-EGFR inhibitor (if K-RAS or N-RAS is WT), a checkpoint inhibitor (if MSI-H), and a VEGF inhibitor.

    • Archival Tissue:

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

  • Tumor Biopsy:

Starting at dose escalation, participants are encouraged to provide fresh tumor biopsy samples first during screening (pretreatment) and then within 7 days before Cycle 2 Day 1 (on treatment), as specified in the Schedule of Assessments, when an accessible lesion is present for a low-risk biopsy procedure (those occurring outside the brain, lung/mediastinum, and intra-abdominal space, or those that are accessible by an endoscopic procedure beyond the stomach or bowel).

During the cohort-expansion phase, paired fresh tumor biopsy specimen, preferably from the same lesion, will be required from participants at specific study sites during screening and then within 7 days before Cycle 2 Day 1 (on treatment) as specified in the Schedule of Assessments.

Tumor lesions used for the biopsy procedure should not be lesions used as RECIST target lesions unless no other lesions are suitable for biopsy. If a RECIST lesion is used for biopsy, the lesion must be ≥2 cm in longest diameter. Tumor biopsies should only be obtained from lesions that are felt to be accessible with acceptable clinical risk in the judgment of the investigator. The sponsor should be contacted if the biopsy is considered to present a potentially unreasonable risk to the participant.

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

• 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 before the initiation of study drug administration. Female participants of childbearing potential must be willing to use 2 forms of contraception throughout the study, starting at screening through 90 days after the last dose of TAK-186. Examples of effective contraception are birth control pills, birth control patch (e.g., Ortho Evra), NuvaRing, IUD (intrauterine device), 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 before 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 during the entire study treatment period through 120 days after the last dose of study drug 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 before 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 criteria at the time of enrollment:

    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.