Safety, Tolerability and Pharmacokinetics of Injectable PEG-Irinotecan (JK-1201I) in Patients with Malignant Solid Tumor

This study is a multicenter, open labeled, positive controlled, single, -combined, with multiple dose escalation trial.

The trial consists of 6 drug dose groups, which are 50mg/m2, 75mg/m2, 100mg/m2, 125mg/m2, 150mg/m2 and 180mg/m2 respectively. At each testing dose group, one patient will be treated with HCl-Irinotecan (CPT-11), at dose level of 175mg/m2.

The initial dose of 50mg /m2 will be administered once. Starting from the 75mg/m2 dose group, each patient will be given testing drug at least twice. During first and second drug administration, blood samples will be collected for PK characteristics analysis. Patients will be evaluated after every two rounds of drug delivery and preliminary efficacy of testing compound will be determined as PD, SD, CR etc.

Inclusion criteria

• 18 to 70 years of age (inclusive)；
• Body mass index (BMI) within the range of 19-30 (inclusive)
• Patient with a malignant solid tumor that has been confirmed by histopathology and/or cytology to be ineffective in conventional treatment or lack effective treatment。 Primary tumors include colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer and advanced breast cancer patients with brain metastases
• More than 4 weeks after the completion of previous anti-tumor therapy (including chemotherapy/radiotherapy, surgical treatment, targeted therapy, immunotherapy, Chinese herbal medicine therapy, endocrine therapy or other anti-tumor therapy), And it has recovered from the adverse reactions of previous treatments (treatment-related toxicity grade ≤1);
• At least one measurable or evaluable lesion was identified using RECIST 1.1;
• Physical state score (ECOG PS score) 0~1
• Estimated survival time ≥ 3 months
• Both standard blood tests and Blood Biochemistry tests are within normal range.
• All subjects and their partners have no plan to have children from screening to 6 month after the trial, and those who agree to use effective non-drug contraceptive methods during the trial period (e.g., condoms， etc.), those already have permanent contraceptive measures, such as bilateral tubal ligation, vasectomy, etc.
• Voluntarily participate in clinical research and sign informed consent

Exclusion criteria

• Patients with previous allergy history and known severe allergy to injectable PEG-Irinotecan or any excipient of the product;
• Have received HCl-Irinotecan (CPY-11) treatment in the past
• With active brain metastasis;
• Have other malignant tumors within 5 years before enrollment, except for previously treated with the purpose of radical cure such as carcinoma in situ of the cervix, squamous cell carcinoma or basal cell carcinoma
• Large amount of thorax and ascites that need treatment
• Serious cardiovascular disease, including grade II and above cardiac dysfunction (NYHA standard)
• Active hepatitis b (HBsAg and/or HBCAb positive, peripheral blood HBV DNA titer test ≥1×103 IU/mL, or hepatitis c patients; or testing positive for syphilis or human immunodeficiency virus (HIV);
• Subject is participating in other clinical studies or the presumed first time of drug administration is less than 4 weeks from the end of the previous clinical study (last administration or 5 half-lives of the previous study drug);
• Subjects who have been treated with anti-tumor vaccines or other anti-tumor drugs (interferon, interleukin, etc.) with immune-stimulatory effects within 28 days before the assumed first medication
• Subjects who had a severe infection within 4 weeks before the first medication， including but not limited to complications of infection, bacteremia, severe pneumonia and others requiring hospital stays;
• Patient has electrolyte disorder with clinically significance
• Subject has clinically severe gastrointestinal disorders, (positive fecal occult blood with severe gastrointestinal bleeding, gastrointestinal infection, obstruction or diarrhea of grade 1 or above on endoscopic examination (the number of stool increases ≥4 times per day))
• Patients with bleeding tendency or receiving thrombolytic or anticoagulant therapy
• Within 14 days before receiving the study drug treatment subject have used a strong CYP3A4 inducer (Phenytoin or Carbamazepine, Barbiturates, Rifampicin or Rifabutin, Hypericum perforatum, etc.);
• Within 7 days prior drug treatment, patients have used strong CYP3A4 inhibitors (Clarithromycin, Ketoconazole or Itraconazole, Indinavir, Lopinavir, Nafazodone, Nelfinavir, Ritonavir, Saquinavir, Trapavir, Voriconazole, etc.)
• Within 7 days before receiving study drug treatment, subject has used strong UGT1A1 inhibitors (Atazanavir, Gemfibrozil, etc.)
• Clear history of neuropathy or mental disorders (including epilepsy or dementia)
• Persons with a history of alcohol or drug abuse
• Pregnant or lactating women
• Investigator considered the subject who are not suitable to participate in this study