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

Study Overview
=================
Brief Summary
-----------------
The main aim of this study is to check for side effects and tolerability of TAK-186 (also known as MVC-101) in adults with unremovable advanced or metastatic cancer. Another aim is to characterize and evaluate the activity of TAK-186 (MVC-101). Participants may receive treatment throughout the study for a maximum of 13 months and will be followed up at 30 days and then every 12 weeks for up to 48 weeks after the last treatment.

Detailed Description
-----------------
This Phase 1/2, open-label study will characterize safety and dose-limiting toxicities (DLTs) of TAK-186. Dose escalation will occur in participants with advanced solid tumors. A Cohort Expansion Phase will be enrolled to further characterize safety and initial anti-tumor activity in participants with HNSCC, CRC or NSCLC.

Official Title
-----------------
A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of TAK-186 (Also Known as MVC-101), An EGFR x CD3 COnditional Bispecific Redirected Activation (COBRA) Protein in Patients With Unresectable Locally Advanced or Metastatic Cancer

Conditions
-----------------
Squamous Cell Cancer of Head and Neck (SCCHN), Non-small Cell Lung Cancer (NSCLC), Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: TAK-186


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: 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. Participants with salivary gland tumors will not be considered as having HNSCC. 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: Albumin ≥ 3.0 g/dL Platelet count ≥ 75 × 103/μL Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count ≥ 1.0 × 103/μL Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN); for participants with hepatic metastases, ALT/AST ≤ 5 × ULN Total bilirubin ≤ 1.5 × ULN, except participants with Gilbert's syndrome, who may enroll if the conjugated bilirubin is within normal limits. 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: No concurrent treatment for CNS disease (e.g., surgery, radiation, corticosteroids ≥ 10 mg prednisone per day or equivalent). No concurrent leptomeningeal disease or spinal cord compression. Key Exclusion Criteria: Participants with a history of known autoimmune disease with the exceptions of: Vitiligo. Psoriasis not requiring systemic treatment for > 1 year before receiving TAK-186. History of Graves' disease in participants now euthyroid for > 4 weeks. Hypothyroidism managed by thyroid replacement. Alopecia. 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 other immune-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 as follows: Cytotoxic chemotherapy, small molecule inhibitors, radiation, interventional radiology procedure, or similar investigational therapies: ≤ 2 weeks or 5 half-lives, whichever is shorter. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar investigational therapies: ≤ 4 weeks. 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) or osteoporosis. Clinically significant cardiovascular or vascular disease including: Myocardial infarction or unstable angina < 6 months before the initiation of study drug. Clinically significant cardiac arrhythmia (e.g., with potential for hemodynamic instability). Uncontrolled hypertension: systolic blood pressure > 180 mmHg; diastolic blood pressure > 100 mmHg. Pulmonary embolism, stroke, or transient ischemic attack < 6 months before initiation of TAK-186. QTcF (QT interval by Fridericia correction) prolongation > 480 msec. Congestive heart failure (New York Heart Association Class III or IV). Pericarditis or clinically significant pericardial effusion. Myocarditis. Vasculitis not resolved < 6 months before TAK-186 initiation. Clinically significant gastrointestinal disorders including: 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. 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. Pancreatitis < 6 months before 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 before the initiation of TAK-186. Diverticulitis flare < 2 months before study drug administration. Participants must have a CT scan negative for evidence of remaining disease before the initiation of TAK-186. 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 before the initiation of study drug. Systemic antiviral, antifungal, or antibacterial therapy must be completed > 1 week before 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 before the initiation of study drug administration or vaccination with other vaccines 2 weeks before 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. Participants with 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. 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 having required therapy, excluding 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 TAK-186 (or any excipient [trehalose, histidine, arginine, or polysorbate-80] contained in the drug or diluent formulation) known hypersensitivity to tocilizumab. Investigative site personnel or sponsor personnel directly affiliated with this study or known hypersensitivity to tocilizumab. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Phase<br>TAK-186 initial 60 minutes infusion and 30 minutes subsequent infusions on Day 1 of every week in Dose Escalation Phase. Participants may receive additional treatment with TAK-186. Dose escalation will be carried out in sequential cohorts of escalating doses. | Drug: TAK-186<br>* TAK-186 IV infusion.<br>* Other names: MVC-101;|
| Experimental: Cohort Expansion Phase: HNSCC<br>Participants with head and neck squamous cell carcinoma (HNSCC) will be randomized to receive low dose or high dose of Recommended Dose for Expansion (RDE) of TAK-186 infusion on Day 1 of every week during Dose Expansion Phase of the study. Participants may receive additional treatment with TAK-186. | Drug: TAK-186<br>* TAK-186 IV infusion.<br>* Other names: MVC-101;|
| Experimental: Cohort Expansion Phase: NSCLC<br>Participants with non-small cell lung cancer (NSCLC) will be randomized to receive low dose or high dose of RDE of TAK-186 infusion on Day 1 of every week during Dose Expansion Phase of the study. Participants may receive additional treatment with TAK-186. | Drug: TAK-186<br>* TAK-186 IV infusion.<br>* Other names: MVC-101;|
| Experimental: Cohort Expansion Phase: CRC<br>Participants with colorectal cancer (CRC) will be randomized to receive low dose or high dose of RDE of TAK-186 infusion on Day 1 of every week during Dose Expansion Phase of the study. Participants may receive additional treatment with TAK-186. | Drug: TAK-186<br>* TAK-186 IV infusion.<br>* Other names: MVC-101;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. All AEs with start date from first dose of study drug until 30 days after the last dose of study drug will be considered as TEAEs. AEs will be reported based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. | Up to approximately 13 months | 
| Number of Participants with Cytokine Release Syndrome/Infusion Reactions | Number of participants with infusion reactions as per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria will be reported. Grade 1 - Mild (Symptomatic Management): Fever ≥38^o C, No hypotension, No hypoxia, Grade 2 - Moderate (Moderate Intervention): Fever ≥38^ o C, Hypotension not requiring vasopressors, Hypoxia requiring low-flow nasal cannula or blow-by oxygen, Grade 3 - Severe (Aggressive Intervention): Fever ≥ 38^ o C , Hypotension requiring a vasopressor with or without vasopressin, Hypoxia requiring high-flow nasal cannula, facemask, nonrebreather mask, or Venturi mask, Grade 4 - Life-threatening (Life-sustaining intervention): Fever ≥38^oC, Hypotension requiring multiple vasopressors (excluding vasopressin), Hypoxia requiring positive pressure (e.g. Continuous positive airway pressure, BiPAP, intubation and mechanical ventilation). | Up to approximately 13 months | 
| Number of Participants with a Dose-Limiting Toxicity (DLT) |  | DLT Evaluation Period (up to Day 28) in Dose Escalation Phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) |  | Up to approximately 24 months | 
| Cmax: Maximum Observed Plasma Concentration of TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| Tmax: Time of First Occurrence of Maximum Observed Plasma Concentration (Cmax) of TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| AUCtau: Area Under the Plasma Concentration-time Curve for a Dosing Interval for TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration for TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| Ctrough: Trough Plasma Concentration of TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| CL: Clearance of TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| Vss: Volume of Distribution at Steady State for TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| t1/2: Terminal Half-Life of TAK-186 |  | Pre-dose and at multiple time points post-dose on Days 1, 2, 3, 8, 15, 22, 36 up to end of treatment (Up to 13 months) | 
| Number of Participants with Anti-drug Antibodies (ADA) in Plasma for TAK-186 |  | Up to approximately 13 months | 
| Preliminary Anti-tumor Activity of TAK-186 in Participants with Advanced Cancer Based on Tumor Protein Marker Changes in Serum |  | Up to approximately 13 months | 
| Objective Response Rate (ORR) | ORR will be calculated based on the percentage of participants achieving Complete Response [CR] or Partial Response [PR] as per RECIST v1.1 (both confirmed and unconfirmed) and modified RECIST v1.1. | Up to approximately 13 months | 
| Duration of Response | Duration of response will be calculated for responders as the time from initial confirmed objective response (CR or PR) to the time of documented Progressive Disease (PD) or death from any cause, whichever occurs first. | Up to approximately 13 months | 
| Progression-free Survival (PFS) | PFS will be calculated as the time from the date of the first dose of study drug to the date of any documented confirmed PD using both RECIST v1.1 and modified RECIST v1.1 or the date of death from any cause. | Up to approximately 13 months | 
| Overall Survival (OS) | OS will be calculated as the time from the first dose of study drug until the date of death due to any cause. | Up to approximately 13 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Unresectable locally advanced cancer, Metastatic cancer, EGFR expressing cancers, EGFR, CD3, CD3-Bispecific, Bispecific, CRC, NSCLC, HNSCC, SCCHN, Squamous head and neck cancer, Lung cancer, Colon cancer