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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10296 in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Conditions
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Nonsmall Cell Lung Cancer

Intervention / Treatment
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* Drug: HS-10296


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Age at least 18 years. Histological or cytological confirmation diagnosis of NSCLC. 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. 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. 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. 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. 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. 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. Male patients should be willing to use barrier contraception (i.e., condoms). For the dose expansion paired biopsy cohort: Presence of at least 1 non-target lesion suitable for multiple biopsies while on treatment. For inclusion in optional genetic research, the patient must provide a written informed consent for genetic research. Exclusion Criteria: 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. Previously untreated NSCLC patients. To be eligible for this study, patients must have received and progressed on EGFR TKI therapy. 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. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study treatment. 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. 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. 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. 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. 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. 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. Women who are breast feeding. Involvement in study planning and conduct (i.e., Hansoh staff or staff at the study site). 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. Any disease or condition that, in the opinion of the Investigator, would compromise the safety of the patient or interfere with study assessments. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation Cohort 1<br>Oral Once-Daily Administration of HS-10296 55mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Escalation Cohort 2<br>Oral Once-Daily Administration of HS-10296 110mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Escalation Cohort 3<br>Oral Once-Daily Administration of HS-10296 220mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Escalation Cohort 4<br>Oral Once-Daily Administration of HS-10296 260mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Expansion Cohort 1<br>Oral Once-Daily Administration of HS-10296 55mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Expansion Cohort 2<br>Oral Once-Daily Administration of HS-10296 110mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Expansion Cohort 3<br>Oral Once-Daily Administration of HS-10296 220mg | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|
| Experimental: Phase 2 Extension<br>Oral Once-Daily Administration of HS-10296 110mg (RP2D) | Drug: HS-10296<br>* HS-10296: 5-, 10-, 40-, and 55-mg tablet, immediate-release formulation. Patients should avoid consumption of food for at least 1 hour prior to and 2 hours post dosing. RP2D is determined at 110 mg QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicity (DLT) Phase I Part | DLT is defined as one of the following HS-10296 related adverse event (AE) ：(1) Hematological toxicity ≥ Grade 4 neutropenia lasting more than 5 days, febrile neutropenia of any duration (absolute neutrophil count [ANC]) < 1.0 × 109/L and fever ≥ 38.5°C), Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding, any requirement for platelet transfusion, Grade 4 anemia (unexplained by underlying disease); (2)Non-hematological toxicity ≥ CTCAE Grade 3 including Infection (including febrile neutropenia), confirmed prolongation of QT interval corrected with Fridericia's (QTcF) (> 500 ms absolute or > 60 ms above Baseline) and cardiac toxicity greater than Grade 3；(3)Any other toxicity that is greater than that at Baseline (clinically significant and/or unacceptable, and judged to be a DLT by the SRC), meets a protocol-defined stopping criteria (i.e., confirmed corneal ulceration), or results in a disruption of dosing schedule of more than 7 days. | 21 days | 
| Overall Response Rate (ORR) Phase II Part | ORR is defined as the percentage of patients with a complete response (CR) or partial response (PR) that was confirmed at a subsequent scan at least 6 weeks later, as assessed according to RECIST (Response Evaluation Criteria In Solid Tumors Criteria) version 1.1 for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | From the date of first dose until the date of disease progression or withdrawal from study, approximately 15 months | 
| Incidence and Severity of Adverse Events (AEs) Phase I Part | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory findings, ECG). Any deterioration of the disease under study and associated symptoms or findings should not be regarded as an AE as far as the deterioration can be anticipated. The AE was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. | From the screening period to 28 days after treatment completion, approximately 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve (AUC) of HS-10296 and HAS-719 From Zero to the 24-Hour Sampling Time (AUC0-24) After Single Dose of HS-10296 | Area under the plasma concentration versus time curve from time zero to the 24-hour sampling time at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-24 was to be calculated according to the mixed log-linear trapezoidal rule. | From pre-dose to 24 hours after single dose on Day 1 of Cycle 0 | 
| Elimination Half-life(T1/2) of HS-10296 and HAS-719 | Elimination half-life is the time measured for the concentration to decrease by one half. Half-life calculated by natural log 2 divided by λz. | From pre-dose to 120 hours after single dose on Day 1 of Cycle 0 | 
| Css Max of HS-10296 and HAS-719 After Multiple Dose | Observed maximum plasma concentration (Css max) after multiple dose of HS-10296 and HAS-719 | From pre-dose to 21 days after multiple dose on Day 1 of Cycle 2 | 
| AUCss of HS-10296 and HAS-719 After Multiple Dose of HS-10296 | Area Under the Plasma Concentration Versus Time Curve at steady state (AUCss) of HS-10296 and HAS-719 after multiple dose of HS-10296 | From pre-dose to 21 days after multiple dose on Day 1 of Cycle 2 | 
| Overall Response Rate (Phase I Part) | ORR is defined as the percentage of patients with a complete response (CR) or partial response (PR) that was confirmed at a subsequent scan at least 6 weeks later, as assessed according to RECIST (Response Evaluation Criteria In Solid Tumors Criteria) version 1.1 for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | From the date of first dose until the date of disease progression or withdrawal from study, approximately 15 months | 
| Progression-free Survival (PFS) | The PFS is defined as the time from date of first dosing until the date of objective disease progression as defined by Response Evaluation Criteria in Solid Tumors （RECIST） v1.1 or death (by any cause in the absence of progression) regardless of whether the patients withdraws from HS-10296 therapy or receives another anti-cancer therapy prior to progression. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | From the date of enrollment until the date of disease progression or death from any cause, approximately 15 months | 
| Disease Control Rate (DCR) | Objective response is assessed by RECIST 1.1 thereby to evaluate disease control rate. The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD (stable disease). | From the date of first dose until the date of disease progression or withdrawal from study, approximately 15 months | 
| Overall Survival (OS) Phase II Part | Overall survival will be assessed based on the date of first dose and survival status at the time of analysis. Overall survival is defined as the time from date of first dose until the documentation of death from any cause. | From the date of enrollment until the date of death from any cause, approximately 48 months | 
| Depth of Response (DepOR) | Depth of Response (DepOR) Only in part II dose-extention phase. DepOR is defined as the percentage change in tumor size, based on longest diameter or reconstructed volume, observed at the lowest point compared with baseline. | From the date of enrollment until the date of disease progression or death, approximately 15 months | 
| Duration of Response (DoR) | Duration of response (DoR) is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. The end of response should coincide with the date of progression or death from any cause used for the PFS endpoint. The time of the initial response will be defined as the latest of the dates contributing towards the first visit response of PR or CR. If a patient does not progress following a response, then DoR will be used as the PFS censoring time. | From the date of enrollment until the date of disease progression or death, approximately 18 months | 
| Incidence and Severity of AEs Phase II Part | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory findings, ECG). Any deterioration of the disease under study and associated symptoms or findings should not be regarded as an AE as far as the deterioration can be anticipated. The AE was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. | From the screening period to 28 days after treatment completion, approximately 16 months |