Clinical trial NCT03313219: Pharmacokinetics and Tolerancebility Studies of Gentuximab Injection in the Treatment ofPatients With Late Recurrence of Metastatic Solid Tumors in China
Official title: Pharmacokinetics and Tolerabilitynce Studies of Gentuximab (Recombinant Anti-VEGFR2 Human-mouse Chimeric Monoclonal Antibody) Injection in the Treatment of Late Recurrence of Metastatic Solid Tumors in China: An Open-label，Non-randomised，Uncontrolled，Dose-escalation，Single Center，Pphase Ia Study in Patients With Late Recurrence of Metastatic Solid Tumors in China
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Solid Tumor
Lead sponsor: Changchun GeneScience Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Shanghai East Hospital
First posted: 2017-10-18
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective is to evaluate the safety and, tolerabilitytolerance, pharmacokinetices and immunogenicity of escalating single doses and subsequent multiple dose of Gentuximab Injection in patients with late recurrence of metastatic solid tumors and to determine the maximum tolerated dose（MTD） and dose limiting toxicities（DLT）.with single and subsequent multiple intravenous infusion in patients with late recurrence of metastatic solid tumors and to provide a basis for the protocol design of later clinical trials.

The secondary objective is to evaluate the pharmacokinetics, pharmacodynamics and immunogenicity, and tumor response of multiple dose of Gentuximab Injection in patients with late recurrence of metastatic solid tumors.

Detailed description: The safety profile of Gentuximab Injection will be explored together with the pharmacokinetics, pharmacodynamics and tumour response to treatment with Gentuximab Injection to recommend the dosing regimen for further clinical studies. The pharmacokinetic properties of Gentuximab Injection will be evaluated after single and multiple dose administrations at different dose levels.

Eligibility criteria: Inclusion Criteria:

* Male or female. aged between 18 and 75 years.
* Participants with histopathologically or cytologically diagnosed advanced or metastatic malignant solid tumor.
* Did not respond to standard therapy or no standard therapy is available.
* At least one Measurable lesion.
* At least 4 weeks after the last chemotherapy (at least 14 days from the last medication with oral fluorouracil drugs), at least 6 weeks after the last medication with mitomycin C and nitrosourea; wait for at least a elution periods for 5 half-life if anti-tumor biological products are dosed.
* The subject should restore to ≤1 level (NCI-CTCAE4.03) if they have toxicity response caused by previous treatment, except hair loss.
* Performance status (PS) score, ECOG0-1 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 ≥100×109/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, creatinine clearance ≥ 60ml / min.
* Adequate coagulation function, as defined by: International normalized ratio (INR) ≤1.5× ULN, activated partial thromboplastin time (aPTT) ≤1.5 x ULN.
* Qualified subjects (male and female) who have fertility must agree to use reliable contraceptive methods (hormones or barriers or abstinence) during the trial and at least 12 weeks after the last administration. Female in childbearing age must be negative for blood pregnancy test within 7 days prior to enrollment.
* Subjects should be informed of the study prior to trial and voluntarily signed a written informed consent.
* The subject is able to communicate well with the investigator and be able to complete the study in accordance with the study.

Exclusion Criteria:

* Subject who has HIV infection, active hepatitis B, hepatitis C or syphilis infection.
* Subject is histologically confirmed as lung squamous cell carcinoma or squamous cell carcinoma of the head and neck, or subjects with lung metastases and metastases with the void ，or bleeding tendency or risk which researchers conformed.
* Has known alcohol or drug dependency.
* Has participated in a clinical study of a non-approved experimental agent within 4 weeks prior to study entry.
* Have serious infection need antibiotic therapy by intravenous injection .
* Has documented and/or symptomatic brain or leptomeningeal metastases.
* Has urinary protein prior to study entry (urinary protein ≥1+，need to detection 24h urinary protein，if 24h urinary protein≥1g,then entry not allowed）.
* Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess \<6 months before study entry.
* Has a serious or nonhealing wound, ulcer, or bone fracture.
* Has undergone major surgery within 28 days before study entry (not including needle biopsy) or have had significant trauma.
* Has active bleeding within 3 months before enrollment.
* Venous thrombosis currently required treatment; myocardial infarction, stroke, or other severe arterial thromboembolic events occurred within 6 months before enrollment.
* Using anticoagulation and antiplatelet drugs.
* Left ventricular ejection fraction ≤ 50%, New York Heart Association (NYHA) Grade II and above heart failure, uncontroled hypertension (systolic blood pressure\> 140 mmHg and/ or diastolic blood pressure\> 90 mmHg after treatment with a drug) .
* 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.
* Is not considered to be suitable for this study, in the opinion of the investigator.

Primary outcomes:
measure: Dose-limiting toxicities (DLT)
timeFrame: Up to 7 weeks
measure: Pharmacokinetics: Maximum Concentration (Cmax) in single dose
timeFrame: Cycle 1(day1-day21)& Cycle 2(day 21-day 49): Predose, 15 minute, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours、day 3, day 4, day 7, day 14 after completion of infusion, Cohort 5 only)
measure: Pharmacokinetics: Cmax in multiple dose
timeFrame: Predose and 15 minutes after completion of Infusion at day 21, day 28, day 42，Predose and 15 minutes, 3 hours, 8 hours, 24 hours, 48 hours, 96 hours after completion of Infusion at day 35，Predose at day 49（the last follow-up）
measure: Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) in single dose
timeFrame: Cycle 1(day1-day 21)& Cycle 2(day 21-day49): up to day 21（blood collection time are as follows ：Predose, 15 minutes, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, day 3, day 4, day 7, day 14 after completion of infusion, Cohort 5 only)
measure: Pharmacokinetics: AUC in multiple dose
timeFrame: From day 21 up to day 49（blood collection time：Predose and 15 minutes after completion of Infusion at day 21, day 28, day 42，Predose and 15 minutes, 3hours, 8hours, 24hours, 48hours, 96hours after completion of Infusion at day 35，Predose at day 49
Secondary outcomes:
measure: Adverse Events
timeFrame: 4 weeks after disease progression or 4 weeks after the intolerant toxicity occurs or until the subject begins a new tumor treatment (whichever is shorter)
measure: Anti-drug antibody:Number of Participants With Anti-drug Antibodies
timeFrame: Cycle 1（day 1-day 21）: Cycle 2:day 21-day 49, cycle 3：day 50-up to study completion, an average of 2 years
measure: Objective response rate: Number of Participants With Objective Response (ORR)
timeFrame: Time Between Meeting Response Criteria and Progressive Disease or Death Due to Any Cause (Up to 1 year)
measure: Progression-free survival (PFS)
timeFrame: Time from randomization to the patient tumor progression or death.（up to 1 year）
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai East Hospital
Study officials:
affiliation: Ethics Committee of Drug Clinical Trials
name: Jin Li
role: PRINCIPAL_INVESTIGATOR
References: