“A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of TAK-186 (also knownas MVC-101), An EGFR x CD3 COnditional Bispecific Redirected Activation (COBRA)Protein in Patients with Unresectable Locally Advanced or Metastatic Cancer”
“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”
NCT #
NCT04844073
Condition(s)
Adrenocortical, Cervical, Cholangio, Colorectal, Endometrial, Gastric/GEJ (Gastroesophageal Junction)/Esophageal, head and neck squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), Hepatocellular carcinoma, Non-Small Cell Lung Exp: non-small cell lung cancer (NSCLC), or Colorectal, Ovarian, Pancreatic, Renal Cell Carcinoma, Skin, Thyroid, triple negative Breast, urothelial
Molecular Target(s)
CD3, EGFR
Drug Classification(s)
Bispecific Monoclonal Antibody
Agents(s)
Phase(s)
I/II
Mechanism of Action
MVC-101 is a EGFR targeting T-cell engaging bispecific antibody
Purpose
- How much of the study agent can be given with an acceptable level of side effects
- The effects of the study agent (good and bad)
- How much of the study agent is absorbed into the blood and how fast it is removed
- If research tests can be used in the future to predict who will benefit from TAK-186
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
- 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.
- 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:
- 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.
- Acceptable laboratory parameters as follows:
- 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.
- 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.
- Urothelial: progressed
following treatment w/ a checkpoint inhibitor (PD-1 or PD-L1 therapy). - RCC: progressing following at least 2 approved regimens.
- TNBC: unresectable and refractory to standard first-line therapy.
- HNSCC: progressed following treatment w/ an anti-PDx and platinum based chemo.
- GEJ & Esophageal: progressing after cytotoxic chemo.
- Pancreatic: at least 1 prior chemo regimen.
- Cholangio: ≥1 line of systemic chemo.
- HCC: progressing following at least 2 or more approved regimens.
- CRC: K-Ras WT (wild type): progression after systemic therapies that included irinotecan,oxaliplatin, an anti-EGFR antibody (if K-RAS or N-RAS is WT), a
checkpoint inhibitor (if MSI-H), and a VEGF inhibitor. - Ovarian: progressing following at least 1 prior cytotoxic
chemo regimen, and subsequent PARP inhibitor therapy in BRCA mutation-positive patients. - Cervical: progressing following first-line cytotoxic chemo and
second-line cytotoxic chemo or anti-PDx therapy in PD-L1 positive (CPS ≥1) or
MSI-H/dMMR positive tumors. - Endometrial: progressing following either cytotoxic chemo
(±trastuzumab) or hormone therapy, and an anti-PDx therapy in MSI-H/dMMR-positive
tumors. - Thyroid: iodine refractory and has progressed
following at least 1 prior systemic antineoplastic regimen. - NSCLC: progressed following treatment w/ a platinum-based chemo, a checkpoint inhibitor (unless known to be PD-L1
negative) or targeted therapy (for patients with a known actionable mutation).
Location
MCD
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