Clinical Study of HEC68498 in Patients With Advanced Refractory Solid Tumors

An open label multicentric Phase 1 study of HEC68498 in patients with advanced refractory solid tumors.The study will follow a 3+3 design until significant toxicity as described in the protocol and considering pharmacokinetics of the study drug determined from cohorts.

Inclusion criteria

（1）Target subjects

• 18 years of age ≤ age ≤ 70 years of age, regardless of gender;
• Patients with various types of advanced solid tumors confirmed by cytological or histological examination.

Dose escalation test phase: including breast cancer, colorectal cancer, neuroendocrine tumors, etc .; Extended trial phase: limited to patients with HR + / HER2-, triple-negative, breast, colorectal, and neuroendocrine tumors, and patients with HR + / HER2- and colorectal cancer need genetic testing (blood and / or tumor tissue) PIK3CA mutations have been confirmed. Patients with triple negative breast cancer need genetic testing (blood and / or tumor tissue) to confirm PIK3CA / PTEN- mutations.

• Requires at least standard treatment failure or no standard treatment. Definition of treatment failure: a. Disease progression during or after treatment must have clear imaging or clinical evidence; b. Withdrawal from treatment due to intolerable response.
• According to the solid tumor evaluation criteria (RECIST 1.1), there is at least one measurable lesion.
• Relieve from previous chemotherapy, hormone therapy, targeted therapy, radiotherapy or surgical treatment of toxic reactions (according to CTCAE v5.0 grading ≤ 1 except hair loss)
• ECOG score is 0 or 1 (see Annex 2 for ECOG score criteria);
• Expected survival time ≥ 12 weeks;

(2) The subject must have proper organ function

• Blood routine: absolute neutrophil (ANC) ≥ 1.5 × 109 / L; platelet (PLT) ≥ 75 × 109 / L; hemoglobin (Hb) ≥ 90 g / L; Have received hematopoietic cell colony-stimulating growth factors (eg G-CSF, GM-CSF) or have not received blood transfusions. Erythropoietin or erythropoietin therapy can be maintained if it is used immediately before enrollment.
• Liver function: ALT and AST ≤ 2.5 × ULN (for patients with liver metastases, ALT and AST can be relaxed to ≤ 5.0 × ULN); serum bilirubin ≤ 1.5 × ULN;
• Renal function: serum creatinine ≤ 1.5 × ULN; or creatinine clearance (CrCl) ≥ 60 mL / min calculated according to the Cockcroft-Gault formula:

Urine routine urinary protein ≤ 1+; if urinary routine urinary protein ≥ 2+, a 24-hour urine protein quantification is less than 1 g.

• Electrolyte: LLN ≤ blood potassium ≤ ULN;
• Coagulation function: international standardized ratio (INR) ≤ 1.5 × ULN; activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; prothrombin time (PT) ≤ 1.5 × ULN;

Exclusion criteria

(1) previous treatment history

• Have previously been treated with PI3K inhibitors, mTOR inhibitors (such as everolimus) or AKT inhibitors.
• Patients who have received targeted therapy within 4 weeks before the first dose or ≤ 5 × drug half-life (if the half-life of the drug is specified, it is calculated as 5 times the half-life, otherwise 4 weeks);
• Patients who have received chemotherapy, hormonal antitumor therapy, immunotherapy or major surgery within 4 weeks before the first dose.

Note: If the previous treatment was nitrosourea or mitomycin, the treatment must be discontinued at least 6 weeks before the first study drug is administered.

• Patients who have received radiation therapy within 4 weeks before the first dose.
• Have received clinical trial drug treatment within 4 weeks before the first medication, or are receiving other clinical trial drug treatment;

(2) History of disease and surgery

• CNS metastases requiring current treatment or uncontrolled CNS metastases; or CNS metastases confirmed but not stable for more than 4 weeks after treatment;
• Patients with spinal cord compression, cancerous meningitis, or meningitis;
• Currently diagnosed with type I or type II diabetes or fasting blood glucose levels> 6.7 mmol / L, or HbA1c> 7%;
• Patients with hypertension controlled by two or more drugs, or uncontrolled hypertension (systolic blood pressure> 140 mmHg or diastolic blood pressure> 90 mmHg);
• Left ventricular ejection fraction (LVEF) <50%; QTcF> 450 ms for men, QTcF> 470 ms for women (QTcF is calculated using Fridericia's correction formula QTcF = QT / RR 0.33); any room with obvious clinical significance History of arrhythmia (such as ventricular tachycardia, ventricular fibrillation, torsional ventricular tachycardia or frequent ventricular premature beats, congenital prolonged QT interval syndrome).
• Multiple factors affecting oral medication (eg, inability to swallow, chronic diarrhea, and intestinal obstruction, etc.);
• Patients with a clear tendency to gastrointestinal bleeding, including the following: local active ulcer lesions and positive fecal occult blood; those with a history of melena and vomiting within 2 months before the first medication; researchers believe that digestion may occur Major bleeding