BPI-361175 Tablets in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

This is a Phase I/II, open-label, non-randomized study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of BPI-361175 tablets in patients with advanced NSCLC with EGFR C797S mutation and other EGFR-related mutations. Adult patients (18 and above) will receive a single dose of BPI-361175 followed by a 7-day washout period with continuous oral dosing of BPI-361175 in 28 days cycle.

This is a three-stage study, consisting of Phase Ia dose-escalation, Phase Ib dose expansion, and pivotal Phase II study.

It is expected to provide a brand-new treatment for advanced NSCLC. The study design utilizes a Bayesian Optimal Interval (BOIN) method to guide the dose level assignment of BPI-361175 and estimate the MTD/RP2D based on cumulative information on DLTs in the Cycle 0 + Cycle 1 of treatment.

Inclusion criteria

• Male or female ≥ 18 years old;
• Life expectancy ≥ 12 weeks;
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
• Patients with histologically or cytologically confirmed diagnosis of inoperable locally advanced or recurrent/metastatic NSCLC with EGFR mutations. Patients must have progressed from or be intolerant to or be unfit for standard treatment.
• For dose escalation: patients with documented EGFR mutation that have progressed on or after third-generation EGFR-TKI. In addition, other lines of therapy may have been given.
• For dose expansion and Phase II: patients with EGFR C797S mutation confirmed prior to enrollment on tissue or blood samples with radiological documentation of disease progression from first-generation, second-generation or third-generation EGFR-TKIs. In addition, other lines of therapy may have been given;
• For dose expansion and Phase II, patients must have at least one measurable tumor lesion per RECIST v1.1 criteria as per Investigator's assessment;
• Adequate bone marrow, liver, and renal function:

• Blood: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500/mm3), platelets count ≥ 100 × 109/L, hemoglobin ≥ 9 g/dL (90 g/L) (must not have received transfusion or granulocyte colony-stimulating factor within 2 weeks of screening tests and procedures);
• Liver function: total bilirubin ≤ 1.5 × ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN; if liver metastases exist, AST and ALT ≤ 5.0 × ULN; for patients with documented Gilbert's syndrome, total bilirubin ≤ 3.0 × ULN;
• Renal function: Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min (calculated by CKD-EPI);
• All acute toxic effects of any prior antitumor therapy or surgery must have resolved to baseline or ≤ CTCAE Grade 1 (with the exception of alopecia);
• For women with childbearing potential, serum pregnancy test will be performed within 7 days before dosing, with a negative result, and they must be non-lactating; all patients should take medically recognized contraceptive measures throughout the treatment period and 3 months after the last dose (see section Error! Reference source not found.);
• Men with partners of childbearing potential willing to use adequate contraceptive measures during the study and for 90 days after the last dose of study medication.
• Patients must have fully understood and voluntarily signed informed consent form (ICF).

Exclusion criteria

• Presence of another active primary malignant tumors;
• Unstable, symptomatic primary CNS tumors/metastasis or leptomeningeal metastases which are not suitable for enrollment, as judged by investigators. A patient can be enrolled if his/her clinical condition is stable and imaging evidence does not show disease progression within 2 weeks prior to the first dose, and who is off corticosteroid, anticonvulsant or mannitol treatment for longer than 2 weeks prior to the first dose.
• Treatment with the most recent therapy (e.g., chemotherapy, immunotherapy, targeted therapy, radiation therapy, investigational therapy/agent) within 4 weeks or approximately 5 half-lives, whichever is the longer, before the first dose. (If sufficient wash-out time has not occurred due to schedule or PK properties, an alternative appropriate wash-out time based on known duration and time to reversibility of drug related adverse events could be agreed upon by the sponsor and investigators);
• Gastrointestinal disorders that would affect oral swallowing or the investigators judge the absorption of the study drug will be interfered;
• Use of strong or moderate CYP3A inhibitors or inducers within 7 days prior to the first dose;
• Autologous (within 3 months) or allogeneic (within 6 months) organ or stem cell transplantation prior to the first dose; any major surgery or severe trauma (except biopsy sampling) within 4 months prior to the first dose;
• Palliative radiation therapy within 2 weeks prior to the first dose;
• Patients who have active viral hepatitis B (HBV) infection (exception: HBV DNA ≤ 500 IU/mL and has been stable for longer than 4 weeks);
• Patients who have active infections that required systemic therapy within 1 week prior to the first dose;
• Any of the following cardiac conditions within the last 6 months:

Unexplained or cardiovascular cause of presyncope or syncope, tachycardia, ventricular fibrillation, or sudden cardiac arrest. Prolonged corrected QT interval [mean resting corrected QT interval QTcF > 450 msec for males or > 470 msec for females from 3 electrocardiogram (ECG)];

• Any > CTCAE Grade 1 prior to the first dose;
• Medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease, any uncontrolled systemic disease, and other serious illnesses;
• Patients with deep venous thrombosis, pulmonary embolism or any other serious thromboembolism within 3 months prior to the first dose (implantable venous access-port, catheter-related thrombosis or superficial venous thrombosis is not considered as "serious" thromboembolism);
• The presence of drug abuse and medical, psychological, or social conditions that do not permit compliance with the protocol or will not be available for protocol-required study visits or procedures.