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.
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
- 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
12. For inclusion in optional genetic research, the patient must provide a written
informed consent for genetic research.
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
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
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
- 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
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
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
- Previous allogenic bone marrow transplant.
- Non-leukocyte leukocyte-depleted whole blood transfusion within 120 days of the
date of the genetic sample collection.