A Study to Evaluate Safety, PK and Efficacy of HS-10296 in Patients With NSCLC

This is a Phase 1/2, open-label, multicenter study of HS-10296 with dose escalation, dose expansion and extension cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent. The study is designed to evaluate safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of once-daily and orally (PO) administered HS-10296. The overall study design is shown in the flow chart below, which consists of 3 phases: dose escalation, dose expansion and extension cohort.


Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed and dated written informed consent prior to any study-specific procedures, sampling, and analyses. If a patient declines to participate in any voluntary exploratory research and/or genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study.
2. Age at least 18 years.
3. Histological or cytological confirmation diagnosis of NSCLC.
4. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, e.g., gefitinib or erlotinib. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered, prior to enrolling in the study.
5. Patients must fulfill one of the following:

   * Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (followed by systemic objective progression (RECIST or World Health Organization \[WHO\]) while on continuous treatment with an EGFR TKI.
6. For the dose expansion and extension cohorts, patients also must have confirmation of tumor T790M+ mutation status from a biopsy sample taken after disease progression on the most recent treatment regimen with an EGFR TKI.

   Prior to entry, a result from the central analysis of the patient's T790M mutation status must be obtained.
7. World Health Organization (WHO) performance status equal to 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
8. At least 1 lesion that has not previously been irradiated, that has not been chosen for biopsy during the study Screening period,and that can be accurately measured at Baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), which is suitable for accurately repeated measurements.
9. Females of child-bearing potential should be using adequate contraceptive measures throughout the study, should not be breast feeding at the time of screening, during the study and until 3 months after completion of study, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling 1 of the following criteria at screening:

   * Post-menopausal defined as age more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
   * Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more, following cessation of exogenous hormonal treatments, and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the laboratory.
   * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not by tubal ligation.
10. Male patients should be willing to use barrier contraception (i.e., condoms).
11. For the dose expansion paired biopsy cohort:

    * Presence of at least 1 non-target lesion suitable for multiple biopsies while on treatment.
12. For inclusion in optional genetic research, the patient must provide a written informed consent for genetic research.

Exclusion Criteria:

1. Treatment with any of the following:

   * An EGFR TKI (e.g., erlotinib, gefitinib, or osimertinib) within 8 days or approximately 5 times the half-life of the specific drug, whichever is longer, of the first dose of study treatment. (If sufficient wash-out time has not occurred due to scheduling or PK properties, an alternative appropriate wash-out time based on known duration and time to reversibility of drug-related adverse events must be agreed upon by Hansoh and the Investigator).
   * Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for advanced NSCLC used for a previous treatment regimen or clinical study within 14 days of the first dose of study treatment.
   * Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
   * Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed within 4 weeks of the first dose of study treatment.
2. Previously untreated NSCLC patients. To be eligible for this study, patients must have received and progressed on EGFR TKI therapy.
3. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE), Grade 1, at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
4. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study treatment.
5. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension or active bleeding diatheses, which, in the Investigator's opinion, makes it undesirable for the patient to participate in the trial OR which would jeopardize compliance with the protocol such as active infection (e.g., hepatitis B, hepatitis C or human immunodeficiency virus \[HIV\]). Screening for chronic conditions is not required.
6. Any of the following cardiac criteria:

   * Mean resting corrected QT interval (QTc) \> 470 msec obtained from 3 electrocardiograms (ECGs), using the Screening clinic ECG machine and Fridericia's formula for QT interval correction.
   * Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval \>250msec).
   * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
7. Past 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.
8. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   * Absolute neutrophil count \< 1.5 x 109/L.
   * Platelet count \< 100 x 109/L.
   * Hemoglobin \< 90 g/L (\< 9 g/dL).
   * Alanine aminotransferase \> 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or \> 5 times the ULN in the presence of liver metastases.
   * Aspartate aminotransferase \> 2.5 times the ULN if no demonstrable liver metastases or \> 5 times the ULN in the presence of liver metastases.
   * Total bilirubin \> 1.5 times the ULN if no liver metastases or \> 3 times the ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
   * Creatinine \> 1.5 times the ULN concurrent with creatinine clearance \< 50 mL/min (measured or calculated by the Cockcroft - Gault equation); confirmation of creatinine clearance is only required when creatinine is \> 1.5 times the ULN.
9. Refractory nausea, vomiting, or chronic gastrointestinal diseases, inability to swallow the study medication, or previous significant bowel resection that would preclude adequate absorption of HS-10296.
10. History of hypersensitivity to any active or inactive ingredient of HS-10296 or to a drug with a similar chemical structure or class to HS-10296.
11. Women who are breast feeding.
12. Involvement in study planning and conduct (i.e., Hansoh staff or staff at the study site).
13. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
14. Any disease or condition that, in the opinion of the Investigator, would compromise the safety of the patient or interfere with study assessments.
15. The following are considered criteria for exclusion from the exploratory genetic research:

    * Previous allogenic bone marrow transplant.
    * Non-leukocyte leukocyte-depleted whole blood transfusion within 120 days of the date of the genetic sample collection.