Non-small Cell Lung Cancer

Primary Objective: • To assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). Secondary Objectives: • To assess secondary measures of clinical efficacy including disease control rate (DCR), duration of overall response (DR), progression-free survival (PFS), overall survival (OS), time to progression (TTP) and tumor shrinkage. • To determine the pharmacokinetic (PK) profile of HM61713 in this patient population using population based PK (PopPK) methods and to explore potential exposure-response (E-R) relationships. • To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment related symptoms of lung cancer, and general health status. • To evaluate the effect of HM61713 on the QT interval. • To assess the safety and tolerability of HM61713.

HM61713

HM61713

film coated tablet
film coated tablet

200
400

Efficacy:
The primary and secondary efficacy analyses will be based on independent centralized assessment of medical images.
The primary endpoint of the study is objective response rate (ORR), defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to the RECIST version 1.1.
The secondary efficacy endpoints of the study include the following:
• Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and stable disease (SD) during the treatment cycles according to the RECIST version 1.1.
• Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death.
• Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first.
• Overall survival (OS), defined as the time from first administration of study drug until death from any cause.
• Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1.
• Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response.
Patient Reported Outcomes:
• European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 (QLQ-C30).
• EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13).
• EuroQOL 5 dimension, 5 level (EQ-5D-5L) health state utility index.
Pharmacokinetics:
• Peak concentration (Cmax).
• Trough plasma concentration (Ctrough).
• Area under the plasma concentration time curve over the 24-hour dosing interval (AUC).
ECG/QTc:
• ECG/QTc intervals (absolute values and change from baseline).
Safety:
• Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4).
• QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: Frederica's method (QTcF), Bazett's method (QTcB), and a study-specific correction (QTcS).
Exploratory:
• Evaluation of pharmacogenetic data (DMET array).
• Evaluation of biomarkers associated with response/resistance to HM61713.

Patients eligible for enrolment in the study must meet all of the following criteria:
1. Provide written informed consent before any study-specific procedures (including special Screening tests) are performed.
2. At least 20 years of age at the time of signing informed consent.
3. Cytologically or histologically confirmed, locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy.
4. Radiologically confirmed disease progression following:
a. 1st line EGFR-TKI treatment without further anticancer treatment in the intervening period before the first administration of start drug OR
b. Prior therapy with a platinum-based doublet chemotherapy and with an EGFR TKI in any sequence. Patients may have received additional lines of anticancer treatment.
5. Documented EGFR mutations which are known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q).
6. World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months.
7. Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen.
8. At least one lesion (excluding the brain), not previously irradiated and not chosen for biopsy during the study Screening period, that can be accurately measured per RECIST version 1.1.
9. Adequate hematological and biological function as follows:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 109/L without the use of hematopoietic growth factors.
b. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), or ≤ 3 x ULN for patients who are known to have Gilbert’s syndrome.
c. Creatinine ≤ 1.5 x ULN.
d. Albumin ≥ 2.5 g/dL.
e. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if no demonstrable liver metastases, or otherwise ≤ 5 x ULN.
f. Amylase ≤ 1.5 x ULN.
g. Potassium and magnesium ≤ 1.0 x ULN (supplementation is permissible).
10. Females of child-bearing potential (not surgically sterilized and between menarche and one-year post menopause) must agree to use adequate contraception (one of the following listed below) during the study (both men and women as appropriate) and for 3 months after the last dose of study drug. Patients who are not surgically sterilized must have a negative urine or serum pregnancy test completed during the Screening period. The following measures need to be followed for females of child-bearing potential:
a. Total abstinence from sexual intercourse as the preferred lifestyle of the patient.
b. Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream).
c. Intra-uterine device (IUD).
11. Male patients should be documented to be sterile or agree to use barrier contraception i.e. condoms.
12. Recovery to ≤ Grade 1 or baseline of any toxicity due to prior treatments, except for alopecia.

Patients meeting any of the following criteria must not be enrolled in the study:
1. Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713.
2. Treatment with any of the following:
a. Anticancer therapies including chemotherapy, hormonal treatment, or immunotherapy within 14 days of the first administration of study drug.
b. Treatment with an EGFR-TKI (including erlotinib, gefitinib, and afatinib) within 10 days or 5 fold half-life, whichever is the longer, of the first administration of study drug.
c. Previous treatment with HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type EGFR (e.g. AZD9291, CO-1686).
d. Treatment with any investigational agent(s) within 28 days prior to the first administration of study drug.
e. Radiotherapy with wide-field or more than 30% of the bone marrow within the past 2 weeks prior to the first administration of study drug; localized palliative radiation (e.g. localized skeletal metastasis) is permitted.
f. Current treatment with medications with known potential to prolong the QT interval which cannot be discontinued or switched to alternate medication prior to the first administration of study drug.
g. Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug, except those related to this study.
h. Current use of any drugs known as strong inducers or inhibitor of CYP2D6 or CYP3A4, unless the use is terminated before ≥ 1 week of the first administration of study drug.
3. Spinal cord compression, leptomeningeal carcinomatosis or other untreated or symptomatic brain metastases; patients with treated brain metastases are eligible if stable for at least 4 weeks without the requirement for steroids or anti-epileptic therapy.
4. History of any other malignancy (other than curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors Ta [non invasive tumor] and TIS [carcinoma in
situ]) unless it has been definitively treated with no ongoing therapy or evidence of relapse or recurrence within the past 3 years.
5. Clinically significant uncontrolled condition(s), including but not limited to:
a. Refractory nausea and vomiting, inability to swallow the formulated product, or any gastrointestinal disorder, which may interfere with the administration or metabolism of the study drug.
b. Active infection that requires parenteral antibiotics.
c. Known human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C.
d. Psychiatric illness/social situations that would limit compliance with study requirements.
e. Known or suspected substance abuse or alcohol abuse.
f. Any medical condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities.
6. Pancreatitis within the past 6 months prior to the date of the first administration of study drug. Pancreatic assessment must be within normal limits at Screening Visit.
7. Any of the following cardiac abnormalities or history:
a. Abnormal 12-lead ECG considered to be clinically significant by the investigator.
b. QT interval corrected using Fridericia’s (QTcF) or Bazett’s (QTcB) method > 450 msec.
c. Personal or family history of long QT syndrome, second or third degree heart block.
d. Implanted pacemaker or cardioverter defibrillator.
e. Resting bradycardia < 55 beats/min.
f. Uncontrolled hypertension.
8. Presence or history of interstitial lung disease (ILD), drug-induced ILD, or radiation pneumonitis which requires steroid treatment.
9. Pregnant or breast feeding.
10. The following are considered criteria for exclusion from the exploratory genetic research:
a. Prior allogenic bone marrow transplant.
b. Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.
11. In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713.