The Study of BGB-283 in Chinese Subjects With Local Advanced or Metastatic Malignant Solid Tumor

"This study is conducted on the basis of the completed multi-dose, dose escalation, Phase IA trial in Australia, is a dose-finding, dose expansion and food effects study of BGB-283 capsules in Chinese patients with locally advanced or metastatic solid tumor to determine the tolerability, safety, pharmacokinetic profiles, preliminary efficacy, food effects under high-fat meal on the absorption and metabolism of BGB-283, and preliminary anti-tumor efficacy.

The study was conducted in three phases: Stage I for dose escalation, Stage II for dose expansion and Stage III for food effects on pharmacokinetics under high fat meal.

Stage I Dose escalation: In a open-label, dose-escalation design, dose escalation will be performed with the '3 + 3' scheme and the dosage levels of BGB-283 capsules will be gradually increased.

Stage II Dose expansion: 20 mg/qd and 30 mg/qd are considered as effective and safe doses, based on preliminary results from Phase IA clinical studies in Australia. To further understand the preliminary pharmacodynamic results of BGB-283 in Chinese patients with malignant melanoma, 20mg/qd dose expansion study in B-RAF mutated malignant melanoma will be further explored if it has been proved to be a safe dose in Chinese population according to the '3 + 3' scheme.

Stage III uses multi-center, open, two-group crossover self-control design to compare the high-fat meal effect on pharmacokinetics."

Inclusion criteria

• Provided written informed consent prior to enrollment.
• Male or female and between 18 and 75 years old.
• A life expectancy of more than 12 weeks.
• Stage I and III: Histologically or cytologically confirmed advanced or metastatic solid tumor for which no effective standard therapy is available. We simultaneously require patients with one of B-RAF, N-RAS, or K-RAS mutation positive solid tumor.
• In Stage II: we require advanced or metastatic melanoma with the B-RAF mutation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
• Able to swallow and retain oral medication.
• Adequate bone marrow, liver, and renal function:

• Hemoglobin > 90 g/L
• Absolute neutrophil count ≥ 1.5x10^9/L
• Platelets ≥ 100 x10^9/L
• Total bilirubin ≤1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN for subjects with known liver metastasis)
• Creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft Gault formula).

Exclusion criteria

• Female subjects who are pregnant or lactating.
• Prior chemotherapy, radiotherapy, immunotherapy or any investigational therapies used to control cancer must have been completed at least 4 weeks or at least 5 half-lives (whichever is shorter before study drug administration, but at least 21 days)
• Any major surgery within 28 days prior to enrollment.
• Any radiotherapy for metastatic foci within 14 days prior to enrollment,
• Unresolved toxicity > Grade 1 (according to NCI-CTCAE, Version 4.03) from previous anti cancer therapy.
• History or presence of gastrointestinal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
• Any clinical significant active infection that need systematic treatment, including HIV positive subjects, or known Hepatitis B or C.