A Phase I Study of FCN-411 in Advanced Non-small Cell Lung Cancer Chinese Patients With EGFR Positive Mutation

A Phase I, Multi-center, Open-label, Single-arm, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Anti-tumor Activities of FCN-411 Monotherapy in Advanced Non-small Cell Lung Cancer

This phase I trial with dose-escalation stage and dose-expansion stage is the first-in-human study of FCN-411, a drug being developed for treatment of advanced cancers. The initial purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of FCN-411 monotherapy in EGFR-positive mutation non-small cell lung cancer chinese patients. The study will also provide early information on how the body handles the drug (pharmacokinetics) and on the anti-tumor activities of FCN-411.

This is a multicenter, open, single arm phase I clinical trial to explore the dose of FCN-411 in advanced lung cancer patients with disease progression after standard treatment or unsuitable for standard treatment and to expand the dose in advanced NSCLC patients who failed EGFR-TKI treatment. During the screening period, patients need to provide tumor tissue/ blood samples collected after their disease progression for tumor biomarker detection. In this study, the safety, tolerance and pharmacokinetic characteristics of FCN-411 were observed by dose escalation study and dose expansion study, and the antitumor activity of FCN-411 was preliminarily evaluated to determine maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). The phase I dose escalation study includes two stages: single dose stage and continuous dose stage; phase I dose expansion study is continuous dose administration.

The research cycle is made up of screening period (day-28-day-1), single administration period (7 days), continuous administration period (every 21 days, evaluated every 6 weeks, until disease progression, intolerable toxicity, death, decision of the investigator or voluntary withdrawal of the patient), end of treatment, EOT) visit, safety follow-up (30 days after the last administration), survival follow-up (survival follow-up every 3 months from the safety follow-up until the end of the study). The end of study is one year after the first administration of the last enrolled patient or the end of treatment (whichever is earlier).

Inclusion Criteria:

1. Age 18 years and older.

2. Histological or cytological confirmed diagnosed advanced or metastatic NSCLC.

3. Documentation of disease progression while on previous continuous treatment with first-line EGFR TKI; patients must have confirmation of tumor EGFR activating mutations (exon 19 del, or exon 21 ins) and T790M status by biopsy sample or optical microscopy.

4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG).

5. Have a life expectancy of at least 12 weeks.

6. Have measurable disease based on RECIST v1.1. Note: previously irradiated not chosen, unless disease progression after irradiation.

7. Adequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   1. Neutrophils (absolute value) ≥ 1.5×10^9/L;
   2. Hemoglobin ≥ 90 g/L;
   3. Platelet ≥ 90×10^9/L;
   4. Serum total bilirubin ≤ 1.5× ULN（for Patients with Gilbert Syndrome, total bilirubin ≤ 3×ULN and bilirubin ≤ 1.5×ULN should be permitted）
   5. Aspartate aminotransferase、alanine aminotransferase ≤ 2.5×ULN; for patients with hepatic metastases, AST、ALT ≤ 5×ULN;
   6. Creatinine < 1.5×ULN creatinine clearance rate≥ 45 mL/min (Cockcroft Gault for calculating)

8. Female subjects have a negative urine or serum pregnancy.

Exclusion Criteria:

1. Treatment with any of the following:

   1. Treatment with an EGFR TKI within 14 days or about 5 half-lives, whichever is the longer, of the first dose of study drug;
   2. Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 14 days of the first dose of study treatment;
   3. Major surgery within 4 weeks of the first dose of study treatment;
   4. Systemic irradiation including whole brain irradiation;
   5. Previously treated by EGFR-TKI for T790M (for example Osimertinib).

2. P-glycoprotein inducers (for example Rifampicin) or inhibitors (for example ritonavir) are required during the study.

3. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

4. Meningeal metastases or CNS metastasis received intervention or malignancy related epilepsy; brain metastases without symptom are eligible.

5. Any serious or uncontrolled systemic disease, including but not limited to:

   1. Uncontrolled hypertension;
   2. Active hemorrhage;
   3. Active infections including hepatitis B, or hepatitis C;
   4. Human immunodeficiency virus positive;
   5. Child Pugh C;
   6. Bullous or exfoliative skin diseases;
   7. Severe malnutrition;
   8. History of keratitis or ulcerative keratitis or dry eye;
   9. Uncontrolled large amount of third interstitial fluid retention;
   10. Other serious diseases or mental disorders or laboratory abnormalities.

6. Cardiac function and disease are consistent with the following:

   1. QTc> 470 milliseconds from 3 electrocardiograms (ECGs);
   2. Any clinically important abnormalities in rhythm;
   3. Any factors that increase the risk of QTc prolongation;
   4. Congestive heart failure ≥ grade 3 by New York Heart Association (NYHA);

7. Previous history with interstitial lung disease、drug-induced interstitial lung disease or radiation pneumonitis require hormone therapy, or other active interstitial lung diseases required treatments.

8. Lung function met one of the following criteria:

   1. Oxygen saturation ≤ 88%;
   2. The first second forced expiratory volume< 50% of the predicted value;
   3. Diffusion capacity for CO < 50% of the predicted value.

9. Dysphagia, or active digestive system diseases or medical conditions potentially affect FCN-411 absorption.

10. Hypersensitivity to FCN-411 or similar compounds or excipients.

11. Pregnant or lactating women.