Brain metastases secondary to non-small cell lung cancer

Primary Objectives: • To evaluate the efficacy of PAX-1 monotherapy on BM, as assessed by intracranial objective response rate (ORR) and disease control rate (DCR at 3 months) evaluated by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria Secondary Objectives: • To evaluate the activity of PAX-1 monotherapy on BM, as assessed by time to response (TTR), duration of response (DOR), overall survival (OS) and progression-free survival (PFS at 6 months) based on RANO-BM criteria • To evaluate the activity of PAX-1 monotherapy on primary tumor, as assessed by TTR, DOR, OS and PFS at 6 months based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 • To investigate the safety and tolerability profile of PAX-1 monotherapy as well as PAX-1 in combination with radiotherapy (RT), as assessed by clinically significant events • To compare the response of PAX-1 monotherapy against PAX-1 in combination with RT, as assessed by TTR, DOR, OS and PFS at 6 months based on RANO-BM criteria for BM and RECIST v1.1 for primary tumor • To determine the pharmacokinetic (PK) profile of PAX-1

PAX-1

Sodium meta arsenite

tablet

2.5mg

Primary Endpoint (Arm A):
Evaluation based on RANO-BM criteria for BM:
• Intracranial ORR (defined as confirmed CR or PR)
• DCR (confirmed CR, PR or SD) at 3 months
Secondary Endpoints (Arm A):
• OS
Evaluation based on RANO-BM criteria for BM and RECIST v1.1 for primary tumor:
• PFS (Time from treatment allocation to PD) at 6 months
• TTR (Time from treatment allocation to first confirmed CR or PR)
• DOR (Time from the first tumor response to PD)
Secondary Endpoints (Arm A vs Arm B):
• OS
Evaluation based on RANO-BM criteria for BM and RECIST v1.1 for primary tumor:
• Intracranial ORR (defined as confirmed CR or PR)
• PFS (at 6 months),
• DCR (confirmed CR, PR or SD)
• TTR
• DOR

Secondary Endpoints (Arm A and Arm B)
Safety and tolerability: Safety assessments will be based on medical review of AEs, serious adverse
events (SAEs), adverse events of special interest (AESIs) (Grade 3 prolongation of QT interval, major
cardiac events and drug induced liver injuries) and lab abnormality reports. Toxicity will be
evaluated according to NCI-CTCAE version 5 or higher. The following evaluations will be performed
during the study to measure the safety and tolerability of PAX-1: vital sign measurements, clinical
laboratory tests, pregnancy tests, ECG, ECOG performance status evaluations, physical
examinations, and incidence and severity of treatment emergent adverse events (TEAEs), treatment
emergent serious adverse events (TESAEs) and treatment emergent adverse events of special
interest (TEAESIs).

All patients enrolling into the study must meet all the following inclusion criteria:
1. Willing to sign written informed consent
2. Histological or cytological confirmation advanced NSCLC (stage IV) with radiologically documented BM. Contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) confirmed BM with at least one measurable lesion (according to RANO-BM and Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
3. Patient with any of the following conditions:
a. Patients with BM secondary to NSCLC who are intolerant to standard treatment or resistant to standard therapy (per NCCN guidelines) or for whom curative therapy is no longer an option or
b. Newly diagnosed NSCLC patients with BM or
c. Patients confirmed as BM during the standard of treatment

4. Age ≥ 18 years at time of study entry (Taiwan subjects must be ≥ 20 years of age)
5. ECOG performance status < 2 i.e. 0 or 1
6. Body weight >30kg
7. Life expectancy of at least 3 months
8. Availability of archival tumor tissue and consent to provide archival tumor for retrospective biomarker analysis, or consent to undergo a fresh tumor biopsy during screening
9. Adequate hematology laboratory data within 6 weeks prior to start of treatment: Absolute neutrophils > 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 9 g/dL
10. Adequate biochemistry laboratory data within 6 weeks prior to start of treatment: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patient with confirmed Gilbert's syndrome or liver metastasis: total bilirubin ≤ 3 X ULN), transaminases ≤ 2.5 x ULN or ≤ 5.0 × ULN for patients with documented liver metastases, alkaline phosphatases ≤ 5 x ULN, creatinine clearance > 40 mL/min (Cockcroft), albumin > 24 g/L, serum magnesium > 0.9 mmol/L, serum potassium > 4.0 mmol/L
11. Women should be post-menopausal or willing to accept the use an effective contraceptive regimen during the treatment period and at least 3 months after the end of the study treatment. All non-menopausal women should have a negative pregnancy test within 72 hours prior to registration. Men should accept to use an effective contraception during treatment period and at least 3 months after the end of the study treatment
12. Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment and examinations including follow up as per scheduled visits

Exclusion Criteria:
Any of the following criteria will exclude patients from study participation:
1. Central nervous system(CNS) complications for which urgent neurosurgical intervention is indicated (e.g., resection, shunt placement)
2. Known leptomeningeal metastases
3. Patient unable to have MRI for any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity)
4. Known history of elevated risks for torsade de point (TdP), such as hyperkalemia, or family history of long QT syndrome.
5. Any of the following cardiac abnormalities:
• Unstable angina pectoris,
• Congestive heart failure ≥ New York Heart Association (NYHA) Class 3, or
• ECG evidence of a QT interval with Frederica’s correction (QTcF) >450 ms in males and >470 ms in females
6. Any unresolved toxicity National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
7. Participation in another therapeutic trial within the 30 days prior to entering this study (participation in a survival follow-up period of a clinical study is not an exclusion criterion)
8. Patients known or suspected to have hypersensitivities, allergies to sodium meta-arsenite related compounds or any of the excipients of the IP
9. Current or prior use of immunosuppressive medication within 14 days before the first fraction of RT (exception: systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) - Topical, inhaled, nasal and ophthalmic steroids are not prohibited).

10. Known primary immunodeficiency or active human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies)
11. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV RNA antibody)
12. History of active tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
13. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of IP
14. Patients with an inability to comply with study procedures or any condition which in the Investigator's opinion makes the patient unsuitable for study participation.
15. History or evidence of any other clinically significant condition that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with study procedures, evaluation or completion.
16. Inability to swallow oral medications or pre-existing gastrointestinal disorders that might interfere with proper absorption of oral drugs.

You will be asked to give permission for the use and disclosure of your health information. Without this permission, the study staff and/or your study doctor will not be able to collect the information needed to evaluate the study drug, PAX-1.