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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 95
- 试验地点
- 54
- 主要终点
- Number of Participants With Non-Cytokine Release Syndrome (CRS) Adverse Events (AEs)
研究概览
简要总结
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 90 days and then every 12 weeks for up to 48 weeks after the last treatment.
详细描述
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 solid tumors expressing epidermal growth factor receptor (EGFR), including head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC) or non-small cell lung cancer (NSCLC).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 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:
- •Participants with pathologically proven, unresectable, locally advanced or metastatic solid tumors that based on literature reports are considered to express EGFR. During cohort expansion, participants with locally advanced or metastatic solid tumors expressing EGFR including advanced or metastatic NSCLC, CRC, and HNSCC 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. Participants who provide fresh pretreatment biopsy samples will not be required to submit archival tumor samples.
- •Tumor Biopsy:
- •Participants must be willing to consent to mandatory pretreatment (during screening) and on-treatment fresh tumor biopsies for cohort expansion phase and backfill in dose escalation. Once the target number of biopsies have been collected, additional paired pretreatment and on-treatment biopsies will not be required; sample collection will be optional after this time point. For fresh tumor biopsies, the lesion must be accessible (those occurring outside the brain or those that are accessible by an interventional or endoscopic procedure) for a low-risk biopsy procedure that does not place the participant at an unjustifiable risk in the opinion of the investigator. Participants who have an archived biopsy specimen available that was obtained up to 90 days prior to treatment initiation and have received no other treatment from the time of biopsy until the start of treatment with TAK-186, may submit that archived specimen in lieu of a pretreatment biopsy upon agreement from the sponsor.
- •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:
- •WOCBP must have a negative serum pregnancy test performed within 72 hours before the initiation of study drug administration. WOCBP must use 1 form of highly effective method and 1 additional effective (barrier) method of contraception at the same time throughout the study, starting at screening through 90 days after the last dose of TAK-
- •Contraception methods may be considered highly effective if they can achieve a failure rate of less than 1% per year when used consistently and correctly.
- •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
- •Central nervous system (CNS) metastases must have been treated and meet the following criteria at the time of enrollment:
- •Definitive therapy was completed at least 2 weeks prior to the first dose of TAK-
- •No evidence of radiographic CNS progression following definitive therapy and by the time of study screening.
- •Any CNS disease is asymptomatic for at least 7 days (unless symptoms are deemed irreversible by the investigator), the patient is off steroids for at least 7 days, and the patient is either off or on stable doses of anti-epileptic drugs for malignant CNS disease for at least 7 days.
- •No concurrent leptomeningeal disease or spinal cord compression.
排除标准
- •Participants with a history of known autoimmune disease with the exceptions of:
- •Psoriasis not requiring systemic treatment for > 1 year before receiving TAK-
- •History of Graves' disease in participants now euthyroid for > 4 weeks.
- •Hypothyroidism managed by thyroid replacement.
- •Well-controlled diabetes type
- •Major surgery or traumatic injury within 8 weeks before first dose of TAK-
- •Unhealed wounds from surgery or injury.
- •Radiation therapy < 2 weeks before initiation of TAK-
- •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, requiring treatment occurring < 3 months before initiation of TAK-
- •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. I) Hypotension Grade ≥
- •j) 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-
- •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-
- •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 any history of Grade 2 or higher noninfectious pneumonitis will be excluded. (Participants with a radiation induced pneumonitis or Grade 1 noninfectious pneumonitis that has resolved may be eligible for enrollment).
- •Clinically significant pulmonary compromise (oxygen saturation ≤92% on room air and requirement for any supplemental oxygen at the time of enrollment).
- •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 lymphoid malignancies.
- •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.
研究组 & 干预措施
Dose Escalation Phase
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.
干预措施: TAK-186 (Drug)
Cohort Expansion Phase: NSCLC
Participants with 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. Based on the results for this cohort additional cohorts for HNSCC and CRC, may be enrolled.
干预措施: TAK-186 (Drug)
结局指标
主要结局
Number of Participants With Non-Cytokine Release Syndrome (CRS) Adverse Events (AEs)
时间窗: From start of study drug up to 90 days after last dose of the study drug (up to 22 months)
An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From start of study drug up to 90 days after last dose of the study drug (up to 22 months)
An AE was any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. TEAE was defined as an AE whose date of onset occurred on or after the first dose of study drug, or an already-present AE that worsened in intensity or frequency following the treatment start, occurring from the first dose of study drug to the day of last dose of study drug. SAE was any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect, or was a medically important event.
Number of Participants With Cytokine Release Syndrome (CRS) According to American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading
时间窗: From start of study drug up to 90 days after last dose of the study drug (up to 22 months)
CRS was defined as a systemic inflammatory response caused by the rapid and excessive release of pro-inflammatory cytokines from activated immune cells. Grade 1=temperature greater than or equal to (\>=) 38°C; Grade 2= temperature \>= 38°C, hypotension not requiring vasopressors, and/or hypoxia requiring low-flow nasal cannula or blow-by oxygen; Grade 3=temperature \>= 38°C, hypotension requiring one vasopressor with or without vasopressin, and/or hypoxia requiring high-flow nasal cannula facemask, nonrebreather mask, or venturi mask; Grade 4=temperature \>= 38°C, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia requiring positive pressure (eg, continuous positive airway pressure \[CPAP\], bilevel positive airway pressure \[BiPAP\], intubation, and mechanical ventilation). Grade 5= Death due to CRS (if directly attributable). Number of participants with CRS according to ASTCT CRS consensus grading were reported.
Dose Escalation Phase: Number of Participants With a DLTs
时间窗: From start of study drug up to Cycle 1 Day 28
DLTs were evaluated according to national cancer institute common terminology criteria for adverse events (NCI CTCAE) version 5.0. DLT criteria were defined as any of the following events: Hematologic DLTs - Grade 4 neutropenia lasting greater than (\>) 5 days; Grade \>=3 febrile neutropenia lasting \>48 hours or Grade \>=3 febrile neutropenia associated with hemodynamic instability or infection; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia and clinically significant bleeding; Grade \>=3 hemolysis. Hepatic DLTs - Grade 3 ALT or AST increase; Grade 3 bilirubin increase. Nonhematologic DLTs are Grade \>=3 nonhematologic AEs.
Number of Participants with Treatment Emergent Adverse Events (TEAEs)
时间窗: From the signing of ICF through 30 days after the last dose of study drug for non immune-related AEs, and through 90 days after the last dose of study drug for immune-related AEs (Up to approximately 13 months)
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 non immune-related 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. All immune-related AEs with start date from first dose of study drug until 90 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.
Number of Participants with Cytokine Release Syndrome/Infusion Reactions
时间窗: From the signing of ICF through 30 days after the last dose of study drug (Up to approximately 13 months)
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).
Number of Participants with a Dose-Limiting Toxicity (DLT)
时间窗: DLT Evaluation Period (up to Day 28) in Dose Escalation Phase
次要结局
- t1/2: Terminal Half-Life of TAK-186(Cycle 1: Post-dose on Days 1, 8 and 15; Cycle 2: Post-dose Day 1 (Each cycle is 56 days))
- Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of TAK-186(Up to 19 months)
- Cmax: Maximum Observed Plasma Concentration of TAK-186(Cycle 1: Post-dose on Days 1, 8 and 15; Cycle 2: Post-dose Day 1 (Each cycle is 56 days))
- Overall Survival (OS)(From start of study drug up to end of study (up to 22 months))
- Tmax: Time of First Occurrence of Maximum Observed Plasma Concentration (Cmax) of TAK-186(Cycle 1: Post-dose on Days 1, 8 and 15; Cycle 2: Post-dose Day 1 (Each cycle is 56 days))
- AUCtau: Area Under the Plasma Concentration-time Curve for a Dosing Interval of TAK-186(Cycle 2: Post-dose Day 1 up to pre-dose Day 8 (Each cycle is 56 days))
- AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration for TAK-186(Cycle 1: Post-dose on Days 1, 8 and 15; Cycle 2: Post-dose Day 1 (Each cycle is 56 days))
- CL: Total Clearance of TAK-186(Cycle 1: Post-dose on Days 1, 8 and 15; Cycle 2: Post-dose Day 1 (Each cycle is 56 days))
- Vss: Volume of Distribution at Steady State for TAK-186(Cycle 1: Post-dose on Days 1, 8 and 15; Cycle 2: Post-dose Day 1 (Each cycle is 56 days))
- Number of Participants With Anti-drug Antibodies (ADA) in Plasma for TAK-186(From start of study drug up to 30 days after last dose of the study drug (up to 20 months))
- Percentage of Participants With Objective Response (OR)(From start of study drug up to end of study (up to 22 months))
- Duration of Response (DOR)(From start of study drug up to end of study (up to 22 months))
- Progression-free Survival (PFS)(From start of study drug up to end of study (up to 22 months))
- Recommended Phase 2 Dose (RP2D)(Up to approximately 13 months)
- Duration of Response(Up to approximately 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 up to end of treatment (Up to 13 months))
- Cmax: Maximum Observed Plasma Concentration of TAK-186(Pre-dose and at multiple time points post-dose on Days 1, 2, 8, 9, 10, 15, 22, 29, 36, 43, 50 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 up to end of treatment (Up to 13 months))
- Progression-free Survival (PFS)(Up to approximately 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 up to end of treatment (Up to 13 months))
- Objective Response Rate (ORR)(Up to approximately 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 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, 8, 9, 10, 15, 22, 29, 36, 43, 50 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)
- Overall Survival (OS)(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)