A Study of Gentuximab + Paclitaxel in Patients With Advanced Gastric or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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The objective of the study is to evaluate Tolerability, Safety, and primary Efficacy of Gentuximab Injection at different dosage in combination with Paclitaxel in Advanced Gastric or Gastroesophageal Junction Cancer patients, to ensure adequate treatment dosage for further study. Meanwhile, the study also evaluate Pharmacokinetics of Gentuximab Injection at different dosage in combination with Paclitaxel.

Detailed Description
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The study includes dose-limiting toxicity （DLT）observing period and randomization period with two cohorts as low-dose group（Gentuximab Injection 8mg/kg+ paclitaxel） and high-dose group（Gentuximab Injection 12mg/kg+ paclitaxel）. During the study，the anti-cancer efficacy, safety and anti-drug antibody were evaluated in all patients. DLT observation is only to subjects enrolled in DLT observation period and it lasts one treatment period. PK were doing in part of subjects.

Official Title
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An Multi-center, Open-label Phase Ib/II Study of Gentuximab Injection + Paclitaxel in Patients With Advanced Gastric or Gastroesophageal Junction Cancer to Evaluate Tolerability, Safety, Efficacy and Pharmacokinetics.

Conditions
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Advanced Gastric or Gastroesophageal Junction Cancer

Intervention / Treatment
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* Drug: Gentuximab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject can understand the process and methods of the study, complete the study in accordance with the protocol and is willing to sign a written informed consent. Male or female. aged between 18 and 75 years Histopathologically confirmed advanced advanced gastric or gastroesophageal junction cancer, and Documented progression during first-line fluoropyrimidine- and platinum- containing chemotherapy, or during the 3 months following the last cycle of such chemotherapy (or during the 6 months following the last dose of adjuvant therapy or new adjuvant therapy containing fluoropyrimidine and platinium). At least one Measurable lesion. ECOG Performance status (PS) score, 0-1 level. A life expectancy of >3 months. Adequate hematologic function, as defined by: Absolute neutrophil count (ANC) ≥1.5×109/L; hemoglobin concentration ≥90g/L (allowing blood transfusion); and platelet count ≥80×109/L. Adequate hepatic function, as defined by: ALT ≤ 2.5 × ULN, AST ≤ 2.5 × ULN, TBIL ≤ 1.5 × ULN (liver metastases patients ALT ≤ 5 × ULN, AST ≤ 5 × ULN, TBIL ≤ 3 × ULN). Adequate renal function, as defined by: serum creatinine level≤ 1.5 × ULN, or creatinine clearance ≥ 50ml / min when serum creatinine level> 1.5 × ULN. Adequate coagulation function, as defined by: International normalized ratio (INR) ≤1.5× ULN, activated partial thromboplastin time (aPTT) ≤1.5 x ULN. 24-hour urine protein quantitation is <1g（24-hour urine protein quantitative test should be performed when urine protein ≥1+ is found during screening visit）. Subjects (male and female) who have fertility must agree to use reliable contraceptive methods during the trial and in 3 months after the last administration. Female subjects in childbearing age must be negative for blood pregnancy test prior to enrollment. Exclusion Criteria: Previously administrated with anti-angiogenic drugs or paclitaxel. Systematic anti-tumor therapy (non-anti-angiogenic drugs or paclitaxel) such as chemotherapy, radiotherapy, macromolecular targeted therapy, immunotherapy, endocrine therapy, etc. within 4 weeks before the first dose of investigational drug, except for the following: nitrourea or mitomycin C is within 6 weeks before the first dose, oral fluorouracil and small molecule targeted drugs are within 2 weeks or 5 half-life of the drug(whichever is longer) before the first dose，Chinese medicine with anti-cancer indications is within 2 weeks before the first dose. Has participated in a clinical study of a non-approved experimental agent within 4 weeks prior to screening visit. Has undergone major surgery within 4 weeks before screening visit (not including needle biopsy)， or would undergo planned surgery during the study. Subject with positive HCV-Ab, Anti-HIV or TP-Ab, or positive HBS-Ag with copies of HBV DNA > ULN. Patients with previously confirmed malignant tumors. History of arterial thrombosis or deep vein thrombosis within 6 months prior to screening, or a bleeding event no less than Grade level 3 within 2 months prior to screening， or the investigator determines that there is a risk of bleeding. History of severe cardiovascular and cerebrovascular diseases. Subjects with confirmed brain tumor metastases，but subjects in steady situation can be enrolled. Active bleeding confirmed by gastroscopy when fecal occult blood positive (only subjects with primary lesions not removed need to do fecal occult blood test. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 12 months before screening visit. Thoracic，abdominal or pericardial effusion that cannot be controlled by repeated drainage or with obvious symptoms. Has a nonhealing wound, serious ulcer, or unrecovered bone fracture. Active infections requiring systemic treatment, including but not limited to active tuberculosis. Using anticoagulation and antiplatelet drugs. Female subjects who is pregnant (confirmed by urine or serum pregnancy test) or lactating. Has a known serious allergy reaction to recombination monoclonal antibody (MAb) drug, ,or infusion reaction. Has known alcohol or drug dependency.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 Gentuximab+ Paclitaxel<br>8 mg/kg Gentuximab administered intravenously (IV) on D1 and D15（28 days every cycle）+ 80 mg/m² paclitaxel administered IV on D1, D8 and D15 | Drug: Gentuximab<br>* Administered intravenously (IV)<br>Drug: Paclitaxel<br>* Administered intravenously (IV)<br>|
| Experimental: 2 Gentuximab+ Paclitaxel<br>12 mg/kg Gentuximab administered intravenously (IV) on D1 and D15（28 days every cycle）+ 80 mg/m² paclitaxel administered IV on D1, D8 and D15 | Drug: Gentuximab<br>* Administered intravenously (IV)<br>Drug: Paclitaxel<br>* Administered intravenously (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (DLT) | Number of Participants With One or More Drug-Related Adverse Events (AEs) defined as DLT in the protocol | Up to 4 Weeks | 
| AEs or SAEs | Drug-Related Adverse Events (AEs) or Any Serious Adverse Events (SAEs) | Baseline through Study Completion, about 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate（ORR） | Proportion of Participants With CR and PR | Up to 6 cycles (28 days for every cycle) | 
| Progression-free survival (PFS) | The time from randomization to the patient tumor progression or death. | Up to 6 cycles (28 days for every cycle) | 
| Disease control rate (DCR) | Proportion of Participants With CR, PR and SD | Up to 6 cycles (28 days for every cycle) | 
| Time-to-progress (TTP) | The time from randomization to the patient tumor progression. | Up to 6 cycles (28 days for every cycle) | 
| Time-to-failure (TTF) | The time from randomization to the patient withdraw from the study. | Up to 6 cycles (28 days for every cycle) | 
| Anti-drug antibody | Number of Participants With Anti-drug Antibodies | Up to 6 cycles (28 days for every cycle) | 
| Pharmacokinetics Cmax | Maximum Concentration (Cmax) | Cycle 1(day1-day 15)& Cycle 2(day 15-day26) & Cycle 3(day 1) (28 days for every cycle) | 
| Area Under the Concentration-Time Curve (AUC) |  | Cycle 1(day1-day 15)& Cycle 2(day 15-day26) & Cycle 3(day 1) Cycle 1(day1-day 15)& Cycle 2(day 15-day26) & Cycle 3(day 1) （28 days for every cycle） |