A Phase 1/2 Study to Evaluate the Safety, Tolerability and PK of JIN-A02 in Patients With EGFR Mutant Advanced NSCLC

• Status: Not yet recruiting
• Trial end date: 2024-12-31
• Target enrollment: 0
• Participant gender: All

Summary

This study is a phase 1/2, open-labeled, multicenter clinical trial to evaluate the safety, tolerability, PKs, and preliminary efficacy of JIN-A02, the 4th generation of orally administered EGFR-TKI, in patients with EGFR mutation(+) advanced NSCLC after standard antitumor treatment including the currently approved EGFR-TKIs and platinum-based chemotherapy up to once. To evaluate DLT and to determine RP2D in patients with EGFR T790M or C797X mutation(+) advanced NSCLC who have progressed the disease after standard antitumor treatment including EGFR TKIs and platinum-based chemotherapy up to once by using BOIN (Bayesian optimal interval) design in phase 1 dose-escalation study To evaluate the safety and tolerability within 2 levels of preliminary effective dose, which have been determined by SRC, in patients with EGFR T790M or C797X mutation(+) advanced NSCLC who have progressed the disease after standard antitumor therapies including EGFR-TKIs and platinum-based chemotherapy up to once, and to evaluate safety and tolerability of JIN-A02 as a monotherapy in order to determine RP2D The subjects enrolled in the dose-escalation study will be included for evaluation at this time. In phase 2 dose-expansion study, to evaluate the antitumor activity of JIN-A02 as a monotherapy by dividing into 3 cohorts of EGFR mutation(+) patients who have progressed the disease after standard antitumor treatments including the approved EGFR-TKIs with activity against T790M, such as osimertinib, and platinum-based chemotherapy up to once. In the phase 1 study, the presence of EGFR mutation will be confirmed with the results from the plasma-based ctDNA test and/or tumor biopsy by using a method validated locally and approved by the sponsor. In the phase 2 study, the presence of C797X mutation will be confirmed with the ctDNA test from tumor tissue and/or plasma as mandatory. However, it may be submitted if the specimen has been stored after disease progression in the previous treatment.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: J Ints Bio

Criteria

Inclusion Criteria:

1. Age ≥ 18 (19 in Korea)

2. The patients who are diagnosed as active EGFR mutation(+) advanced NSCLC and/or metastasis NSCLC (confirmed pathologically)

3. The subjects who have progressed the disease after standard antitumor treatments including the approved EGFR TKIs and platinum-based chemotherapy up to once However, the phase 2 dose-expansion will include the subjects who have been treated with the approved EGFR-TKIs with activity against T790M, such as osimertinib.

4. The patients who are confirmed as the presence of EGFR mutation with plasma-based ctDNA tests and/or tumor biopsy by the method validated locally and approved by the sponsor Samples used for analysis are preferably collected during or after disease progression with treating EGFR targeting TKI just prior to this study. It may be submitted if the specimen has been stored after disease progression in the previous treatment.

1. The phase 1 dose-escalation and -expansion study: the patients with EGFR T790M or C797X mutation(+) advanced NSCLC

2. The phase 2 dose-expansion study: the patients with EGFR T790M and C797X mutation(+) advanced NSCLC for cohort 1, the patients with EGFR T790M mutation(-)and C797X mutation(+) advanced NSCLC for cohor 3

5. In the case of phase 2, the patients with at least 1 measurable lesion, who have not experienced radiation previously, defined by RECIST version 1.1

6. The patients with ECOG performance status 0 or 1

7. The case when the acute effects of previous therapy recover to baseline in severity or the grade of CTCAE ≤1 except for AEs which are not considered as risks in terms of safety by the discretion of investigators after discussion with the sponsor NOTE: except for the stable chronic conditions (the grade of CTCAE ≤2; e.g., neuropathy, myalgia, alopecia, etc.) that are not expected to recover, the subjects with these conditions may be enrolled.

8. The proper bone-marrow and organ function, including the following:

1. Hemoglobin ≥ 9.0 g/dL

2. Platelet ≥ 75×109/L

3. Absolute neutrophil count (ANC) ≥ 1.0×109/L

4. Total bilirubin ≤ 1.5×ULN (≤ 3 x ULN when a subject has documented Gilbert's syndrome)

5. AST and ALT ≤ 3 × ULN; or ≤ 5.0 × ULN when the liver invasion by tumor occurs

6. When estimated creatinine clearance ≥ 40 mL/min/1.73m2 calculated by the standard method at the study sites

7. International Normalized Ratio (INR) ≤ 2.3 or prothrombin time (PT) ≤ 6 seconds; patient-specific INR or PT abnormality that the treating investigator considers clinically relevant and/or increases the risk for hemorrhage in that individual patient

9. If the subject is a woman, the patient will not breastfeed and use at least two appropriate and effective contraception (a condom including diaphragms and spermicides [foam/gel/cream/film/suppository]) from 2 weeks before the first administration of the IPs to 90 days after the last administration. The additional contraceptions, such as the intrauterine devices (IUD or IUS), a vasectomy of the male partner, and approved hormonal therapies of oral, injectable, and implanted administration

10. If the subject is a male, the patient will use at least one of the suggested contraception (such as abstinence, use of a condom with spermicides [foam/gel/cream/file/suppository]) for 90 days after the last dose of IPs.

Exclusion Criteria:

1. NSCLC with mixed-squamous cell histology and tumor with histological transformation (the presence of epithelial-mesenchymal transition from NSCLC to SCLC)

2. The patient who has uncontrolled spinal cord compression or central nervous system (CNS) metastasis, the patient who requires dose-increase in the steroids, the patient who needs to treat CNS diseases, or the patient with leptomeningeal diseases However, the subjects may be included if he/she is asymptomatic and stable after 2 weeks of Gamma Knife therapy and 4 weeks of whole-brain irradiation.

3. The subjects who have received the following treatments:

1. Treatment of EGFR TKI within 7 days after the first administration of IPs

2. Treatment of whole-body chemotherapy during the period less than 5-fold of half-life or within 14 days after the first administration of IPs

3. Limited-area radiotherapy within 7 days, or extended-area chest radiotherapy within 14 days after the first administration of IPs

4. Immunotherapy or other antibody treatment within 14 days after the first administration of IPs

5. A subject who has experienced the major surgery* (by the discretion of investigators) except for the vascular access placement or who has not recovered from the AEs due to these treatments within 28 days after the first administration of IPs * The major surgery is an operation on the abdominal, pelvic, intracranial, or intrathoracic tissues. Also, it is defined as a surgical procedure that has a risk to the function or resuscitation of organs and tissues in consideration of lesion or patient's conditions, difficulties, and operation time. The major surgery usually requires general anesthesia, hospitalization (for varying durations, often a week), and any performance of a surgeon.

4. The subjects who meet the followings:

1. Significant baseline prolongation of QT/QTc interval (e.g., repeated measurements of QTc interval >270 ms (CTCAE grade 1) using Fridericia's formula)

2. Long QT syndrome

3. Medical history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, and family history of Long QT syndrome)

5. The subjects with cardiac dysfunction or clinically significant heart disease as the followings:

1. Left ventricular ejection fraction (LVEF) < 50%

2. Clinically significant/uncontrolled heart diseases, such as congestive heart failure (which requires medical treatment; the grade of NYHA ≥3), uncontrolled hypertension, clinically significant arrhythmias, etc

3. Medical history of acute myocardial infarction or unstable angina within 6 months of study initiation

6. The subjects who have been diagnosed with other active malignancies within 2 years prior to enrollment, except for appropriately treated basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ Enrollment will be possible only if all chemotherapy has been completed at least 2 years before enrollment and it is considered as being free from the other active malignancies.

7. The subjects with evidence/history of interstitial lung disease (ILD) or radiation pneumonia requiring steroid treatment

8. The subjects who are unable to swallow orally administered drugs and have clinically significant gastrointestinal abnormalities that may cause the major restricted function of the stomach/intestines or malabsorption

9. The subjects who have been diagnosed with active infections including HIV, HBV, or HCV

*Notes for COVID-19/SARS-CoV2 The subjects with the aforementioned active infections will be excluded based on this protocol. Although the SARS-CoV2 test is not mandatory for enrollment, the test may be conducted according to the standards of the local clinical practices. The subjects with a positive SARS-CoV2 test result, asymptomatic infection, or suspension of SARS-CoV2 will be excluded from this study. However, if the subject is negative to SARS-CoV2 in the follow-up, the subject may be re-screened when meeting the protocol requirements.

10. The subjects who have known hypersensitivity to the IPs or related substances

11. The subjects with drug abuse and unstable medical, mental, or social conditions that may interfere with participating in this study or evaluation of results

12. The subjects who are unable to follow the protocol according to the discretion of investigators