JMT101 Combined With Afatinib in Patients With Advanced Esophageal Squamous Cell Carcinoma After Standard Therapy

Study Overview
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Brief Summary
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This study is a multi-center, open-label, phase Ib study to evaluate the safety, tolerability and efficacy of JMT101 combined with afatinib in patients with advanced esophageal squamous cell carcinoma who have failed standard treatment.

Detailed Description
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This is a multicenter, open-label, dose-escalated phase Ib study aimed to evaluate the safety, tolerability, and efficacy of JMT101 combined with afatinib in patients with advanced esophageal squamous cell carcinoma who have failed standard treatment. This study consists of two stages: dose-escalation stage and dose expansion stage. The dose-escalation stage will be conducted to determine the maximum tolerated dose (MTD) of JMT101 combined with afatinib in patients with advanced esophageal squamous cell carcinoma based on a 3+3 design. JMT101 will be given by intravenous infusion at 6 mg/kg (q2w) of each 28-week cycle. Afatinib will be sequentially administered at 30 mg and 40 mg (qd) of each 28-week cycle. One dose cohort which is verified to be well-tolerated and safe in dose-escalation stage will be selected for dose-expansion to further explore the safety, pharmacokinetic and efficacy of the study drug.

Official Title
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A Multicenter, Open-label, Phase Ib Study to Evaluate the Safety and Efficacy of JMT101 Combined With Afatinib in Patients With Advanced Esophageal Squamous Cell Carcinoma Who Have Failed Standard Therapy

Conditions
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Esophageal Squamous Carcinoma

Intervention / Treatment
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* Drug: JMT101
* Drug: Afatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 years or above, without gender limitation; Histological or cytologically confirmed esophageal squamous cell carcinoma; Patients with metastatic disease or locally advanced disease (UICC or AJCC 8th Edition) unsuitable for radical surgery or radiotherapy; with direct invasion of adjacent organs (such as aorta or trachea) (T4b) should be closely assessed for the risk of bleeding before enrollment; Patients who have failed first-line or above treatments. The treatment failure is defined as disease progression or intolerable toxicity during or after the last dose of systemic standard chemotherapy, and recurrence or metastasis during treatment or within 6 months of discontinuation of radical therapy including radical concurrent chemoradiotherapy and neoadjuvant/adjuvant therapy (chemotherapy or chemoradiotherapy); At least 1 measurable lesion according to RECIST 1.1 at baseline; if there is only one measurable lesion at baseline, the area must have not had prior radiotherapy or there must be evidence of apparent progression after radiotherapy; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; Life expectancy exceeds 3 months; The function of major organs and bone marrow meet the following criteria within 7 days before treatment (No blood transfusion, erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), or other support therapy within 7 days prior to administration of the study drug): Blood routine: absolute neutrophil count (ANC) ≥1.5×10^9/L, platelet count ≥80×10^9/L, hemoglobin ≥80 g/L; Kidney function test: Serum creatinine ≤1.5×upper limit of normal (ULN); Liver function tests: total bilirubin ≤1.5×ULN (≤3×ULN for patients with liver metastasis), aspartate aminotransferase ( AST) and alanine aminotransferase (ALT ) ≤3×ULN ( ≤5×ULN for patients with liver metastasis); Blood coagulation: International normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN, activated partial thromboplastin time (APTT) ≤ 1.5×ULN. The fertile women should have a negative blood pregnancy test within 7 days before enrollment; fertile men or women must agree to use effective contraceptive methods during the whole trial period and six months after the last administration; Patients fully understand and voluntarily participate in this study and sign informed consent. Exclusion Criteria: Previously treated with EGFR antibody; Patients whose tumor has invaded important blood vessels or is much more likely to invade important blood vessels and cause fatal hemorrhage during the study according to the investigator's judgement; patients who have hemorrhage in the lung or other parts, have a bleeding tendency, or are receiving thrombolytic or anticoagulant therapy; Anti-tumor therapy such as chemotherapy, biological therapy, targeted therapy, immunotherapy, etc. within 4 weeks before the first administration of the study drug; oral small molecule targeting drugs within 2 weeks of the first dose or within the 5 half-life of known drugs (whichever is longer); radiotherapy within 2 weeks before the first administration of the study drug; Received other investigational product within 4 weeks before the first administration of the study drug; Received major organ surgery (excluding needle biopsy) or suffered significant trauma within 4 weeks before the first administration of the study drug; Received strong inducers and strong inhibitors of P-gp within 2 weeks before the first administration of the study drug; Uncontrolled cancer pain; not at a stable dose of anesthetic analgesics at the time of enrollment. Adverse reactions of previous anti-tumor treatments have not yet recovered to ≤ grade 1 according to CTCAE 5.0 (except for the toxicity without safety risk judged by investigator, such as alopecia); Central nervous system metastasis or meningeal metastasis; History of autoimmune disease or immunodeficiency disease including human immunodeficiency virus antibody (HIV-Ab) positive, or suffering from other acquired or congenital immunodeficiency diseases, or history of organ transplantation; Active hepatitis B, active hepatitis C, or positive for treponema pallidum antibodies; History of severe cardiovascular disease; History of other malignancies within 5 years before the first administration of the study drug, except: malignant lesions that have been treated with therapeutic measures and no known active lesions within 5 or more years before enrolment, and are judged by the treating physician to be at low risk of recurrence; adequately treated non-melanoma skin cancer and cervical cancer in situ without evidence of progression; or prostatic intraepithelial neoplasia without evidence of recurrence of prostate cancer. Patients with any severe or uncontrollable disease are unsuitable to participate in this clinical trial according to the investigator's judgement; Known hypersensitivity or intolerance to any component of the study drug or its excipients; Past or present interstitial pneumonia/pulmonary disease; Pregnant or lactating women; Other situations that may increase the risks related to the study drug or affect compliance of the trial compliance are not suitable for the trial as determined by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>JMT101 combined with two dose levels of afatinib will be tested according to the 3 + 3 dose-escalation design. The dose-limiting toxicity (DLT) will be assessed from the first administration to the end of the first cycle (28 days). | Drug: JMT101<br>* JMT101 will be administered intravenously at 6 mg/kg every 2 weeks (q2w) in each 28-week cycle.<br>Drug: Afatinib<br>* Afatinib will be administered orally at 30 mg or 40 mg per day (qd) in each 28-week cycle.<br>|
| Experimental: Dose Expansion Cohort<br>Once the safe and effective dose has been determined, an expansion cohort will be recruited to further evaluate the efficacy and safety of the selected dose. | Drug: JMT101<br>* JMT101 will be administered intravenously at 6 mg/kg every 2 weeks (q2w) in each 28-week cycle.<br>Drug: Afatinib<br>* Afatinib will be administered orally at 30 mg or 40 mg per day (qd) in each 28-week cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-related Adverse Events，afety and Tolerability | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Throughout the study period, with an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Percentage of patients who achieve partial response (PR) or complete response (CR) based on Response Evaluation Criteria In Solid Tumors (RECIST). | Up to approximately 2 years | 
| Duration of response (DOR) | Measure of time from first response to disease progression or death | Up to approximately 2 years | 
| Disease control rate (DCR) | Percentage of patients who achieve partial response (PR) or complete response (CR) or stable disease (SD) based on Response Evaluation Criteria In Solid Tumors (RECIST) | Up to approximately 2 years | 
| Progression free survival (PFS) | Measure of time from study treatment to disease progression or death | Up to approximately 2 years | 
| Overall survival (OS) | Measure of time from study treatment to patient's death or lost to follow-up | Up to approximately 2 years | 
| Pharmacokinetic profile of JMT101 (AUC0-t) | area under the plasma concentration versus time curve | Pre-dose and multiple timepoints up to 30 days after the lase dose | 
| Pharmacokinetic profile of JMT101 (Cmax) | Peak plasma concentration | Pre-dose and multiple timepoints up to 30 days after the lase dose | 
| Pharmacokinetic profile of JMT101 (Tmax) | Time for peak concentration | Pre-dose and multiple timepoints up to 30 days after the lase dose | 
| Pharmacokinetic profile of JMT101 ( t½) | half life of JMT101 | Pre-dose and multiple timepoints up to 30 days after the lase dose | 
| The incidence of anti-drug antibody (ADA) | anti-drug antibody which can result in treatment failure by blocking the pharmacological function of the drug. | Pre-dose and multiple timepoints up to 30 days after the lase dose | 
| The incidence of neutralizing antibody (Nab) | neutralizing anti-drug antibody which can result in treatment failure by blocking the pharmacological function of the drug. | Pre-dose and multiple timepoints up to 30 days after the lase dose |