Phase Ⅰ Clinical Trail Of Intravenous Pegylated Recombinant Human Granulocyte Colony-stimulating Factor(PEG-rhG-CSF) Phase Ⅰ Clinical Trail Of Intravenous Combretastatin A4 Phosphate (CA4P)

OBJECTIVE To evaluate the safety of Pegylated Recombinant Human Granulocyte Colony-stimulating Factor (PEG-rhG-CSF), which developed by Beijiing SL Pharmaceutical Co., Ltd, and to explore its efficacy of enhancing absolute neutrophil count(ANC) and CD34+ cell count in peripheral blood after chemotherapy, as well as pharmacokinetic data, as the basis for phase II clinical study.METHODSInclusion criteria:(1) the histopathological or cytological diagnosis of cancer patients, chemotherapy based on carboplatin and paclitaxel; (2) The KPS score> 60,18-75 years of age, male or female, is expected to survive more than three months; (3) untreated, no prior radiotherapy or chemotherapy; (4) bone marrow function normal (bone marrow aspiration cytology showed bone marrow hyperplasia, and no malignant cell infiltration); (5) peripheral blood cells is normal, without bleeding tendency; (6) No significant cardiac dysfunction or metabolic diseases, liver function parameters, such as AST, ALT, total bilirubin less than 2.5 times the upper limit of normal, creatinine, blood urea nitrogen were less than 1.5 times the upper limit of normal, conformed; (7) voluntary participation in the trial and signed informed consent; (8) be able to comply with the trial medication and blood sample collection procedures. Packet and method of administration: tolerance test were enrolled 30 healthy subjects, with reference to the modified Fibonacci dose escalation, increments administered to 200μg/kg starting dose of 30μg/kg increments. A total of five dose groups, each group based on body weight, respectively, subcutaneous injection PEG-rhG-CSF. Each subject was only accepted an appropriate dose, start with small dose, after the end of each dose, the result was observed before the next dose started. Observation after administration of human polyethylene glycol recombinant human granulocyte colony stimulating factor injected included response and tolerability.30 cases should come into pharmacokinetics test, including pre-trial study with 30μg/kg dose group, the official test include three dose group as 60μg/kg,100μg/kg,150μg/kg with 8 cases in each group. As an open, single-center Phase I trial, untreated patients received sequential two cycles of chemotherapy with paclitaxel and carboplatin. The first cycle of chemotherapy was the control cycle, different groups of patients received a single injection of PEG-rhG-CSF (30μg/kg,60μg/kg, 100μug/kg,150μg/kg or 200μg/kg) 48h after administration of the second cycle of chemotherapy.RESULTS 30 of 34 cases were evaluable for safety and efficacy of PEG-rhG-CSF. Main adverse events related to PEG-rhG-CSF was mild musculoskeletal pain or arthralgia(8/30). With less severe neutropenia founded after chemotherapy, PEG-rhG-CSF enhanced ANC in a dose-dependent manner to some extent with peripheral nadir ANC to move forward, and significantly improved.Pharmacokinetic test:During the tolerance test of PEG-rhG-CSF, pharmacokinetic trials show that with the increase of the dose, the increased elimination half-life, clearance rate per unit time decreases indicated that there is a certain accumulation of drugs in the body. The results show that with the dose range, the PEG-rhG-CSF which produced by Beijing SL Pharmaceutical Co., Ltd. presents nonlinear pharmacokinetic characteristics in the clinical trial.CONCLUSIONS PEG-rhG-CSF is well tolerated, neither the dose limiting toxicity(DLT) dose, nor the maximum tolerance dose(MTD) was reached in the trial. The recommended dose of PEG-rhG-CSF for phase Ⅱ trial is 60μg/kg and 100μg/kg, with its adequate efficacy.OBJECTIVE To evaluate the safety of Combretastatin A4 phosphate (PEG-rhG-CSF), we determined the maximum tolerated dose (MTD) and human pharmacokinetics dynamics parameters, to analysis the dose-effect relationship and the dose-toxicity relationship of CA4P.METHODSInclusion criteria:(1) The histopathological or cytological diagnosis of relapsed cancer patients, including thyroid cancer or ovarian cancer patients; (2) The ECOG score≤2, expected survival of more than 3 months,18-65 years of age, male or female; (3) The patient’s condition allows DCE-MRI examination. Measurable tumor lesions, routine testing of maximum tumor diameter≥20mm, the maximum diameter of the spiral CT detects tumors≥10mm; (4) The level of blood pressure<140/90mmHg with normal ECG, cardiac QTc interval<440ms; UCG shows that left ventricular ejection fraction(LVEF)≥ 50%; (5) No major organ (liver, kidney) and hematologic obstacle; (6) hemoglobin≥ 10.0 g/L, white blood cells≥4.0× 109/L, neutrophils≥1.5 ×109/L, platelets≥100.0 109/L; potassium> 4.0mmol/L; TT, PT and APTT within normal range; liver function: ALT/AST≤2.0 times the upper limit of normal; bilirubin normal; albumin≥30g/L; renal function:serum creatinine≤1.5μmol/L; (7) six weeks after the withdrawal of nitrosourea and mitomycin chemotherapy patients to enter the trial; (8) informed consent obtained.Packet and method of administration:CA4P was added to 100 ml N.S, after dissolved in 5ml saline dilution of 1 Omg/ml liquid, then infused intravenous within 60-minute.RESULTS 12 of 20 patients were completed multiple dose of different groups, with 8 patients were excluded. Main adverse events related to CA4P included headache/dizziness (19.80%), tumor pain (14.21%), vagotonia (10.66%) and nausea (9.39%), the number of occurrences of adverse events increased with the dose increased significantly. Pulse and blood pressure before and after treatment were changed obviously and regularly, especially in the high dose group, as the QT interval and HR variations. As 2 patiens appeared drug induced DLT in the 85mg/m2 group, therefore MTD was 65mg/m2 in this test.CONCLUSIONS In patients with relapsed advanced carcinoma, the single injection of CA4P 20mg/m2 and 85mg/m2, repeatedly given CA4P in 33mg/m2,50mg/m2,65mg/m2 dose groups, the security of the test results reported are similar with in the literature; SAE occurs frequency lower than that reported in the literature-no deaths occurred. Only one case of SAE may be not related to the study drug, which indicating that CA4P test dose range, subjects was well tolerated and safe. Pharmacokinetic results showed a linear elimination of CA4P in the body, no accumulation in the body. We recommended dose of 33mg/m2～65mg/m2 group interval as the right dose combined with other chemotherapy drugs in the safety and efficacy studies with larger samples.