Evaluate the Safety of BEL-X-HG in Advanced Cancer Patients

Study Overview
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Brief Summary
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This is a Phase I, open-label, uncontrolled, multicenter dose escalation and extension study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), to evaluate safety / tolerability and preliminary effects of BEL-X-HG in patients with advanced refractory solid tumors. Dose escalation during the study will be made based on dose-limiting toxicity (DLT).

Detailed Description
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This study will be carried out in 2 parts: Part 1: A sequential Dose Escalation Part of four doses following a 3 + 3 design where dose escalation will be made based on dose-limiting toxicity (DLT), for a single cycle (28-days) of BEL-X-HG treatment Part 2: A Dose Extension Part of up to 5 cycles (28-days each) at the same dose level (starting dose) of BEL-X-HG treatment Approximately 24-48 eligible subjects with confirmed advanced refractory solid tumors will be enrolled sequentially, in 3 subject cohorts, from the lower to the higher dose cohort into the study. Escalating dose levels of BEL-X-HG in 4 study cohorts and one modified dose will be as follows: Cohort 1: Dose level 1 - 0.5 g/day (0.25 g, bid) Cohort 2: Dose level 2 - 1.0 g/day (0.5 g, bid) Cohort 3: Dose level 3 - 2.0 g/day (1.0 g, bid) Cohort 4: Dose level 4 - 4.0 g/day (2.0 g, bid) Modified dose level Cohort 5: Dose level 5 - 1.5 g/day (0.75g bid) This re-escalation is allowed only when dose de-escalates from Dose level 3 to Dose level 2, and 1 DLT in 6 evaluable subjects of Dose level 2. BEL-X-HG will be administered orally at the assigned dose level for a single cycle consisting of 28 days during the Dose Escalation Part to each subject. Thereafter, if eligible and willing, subjects can continue to Extension Part for 5 more cycles of treatment (each cycle lasting 28 days), at the same assigned dose level of BEL-X-HG treatment.

Official Title
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A Phase I, Open-Label, Dose Escalation and Extension Study to Evaluate the Safety, Tolerability and Preliminary Effects of Oral BEL-X-HG in Patients With Advanced Refractory Solid Malignancies

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: BEL-X-HG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients of age ≥20 years Pathologically or cytologically confirmed advanced refractory solid tumors for which standard therapy proven to provide clinical benefit does not exist or is no longer effective. It is acceptable for HCC subjects with Child Pugh stage A to confirm diagnosis of the advanced refractory solid tumors by imaging (CT scan). Evaluable disease, at least one measurable target lesion on imaging by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2 Life expectancy ≥ 3 months Patients able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major restriction of the stomach or bowels Laboratory values at screening and baseline (Day 1) of: Absolute neutrophil count (ANC) ≥ 1,500 /mm3 Platelets ≥ 75,000 /mm3 Hemoglobin (Hb) ≥ 8.5 g/dL Serum creatinine (Cr.) ≤1.5 mg/dL or estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m2. MDRD Study equation: eGFR = 186 x (SCr)^-1.154 x (age)^0.203 x (0.742 if female) x (1.210 if African American) SCr: serum creatinine in mg/dL; age: in year Patients with primary liver cancer or hepatic metastasis are eligible to enroll, provided that, at screening and baseline (Day 1), the following criteria are met: Total bilirubin (T-Bil) ≤2.0 mg/dL AST and ALT ≤ 5 times the institutional upper limit of normal Child-Pugh Class A; (Score ≤6) Serum albumin ≥2.8 g/dL Patients with a history of esophageal bleeding have varices that have been sclerosed or banded and no bleeding episodes have occurred during the prior 6 months If history of brain metastases treated with radiation therapy, radiation therapy is required to be completed at least 3 months prior to enrolment and metastasis achieve stable disease (SD) since radiation completion Must have recovered from toxicities of previous anti-cancer treatments to NCI-CTCAE version 4.03 grade 1 or lower, except for alopecia Females patient must be either of non-childbearing potential, i.e. surgically sterilized (e.g. tubal ligation, hysterectomy, or ovariectomy) or one year post- menopausal; or, if of childbearing potential, confirmed not pregnant at screening and use of two adequate contraceptive precautions (as per investigator) i.e. condoms plus oral contraceptives or condoms plus endometrial contraceptive devices, during the entire treatment period of this study and for 6 months after exiting from the study Male patients with female partners of childbearing potential must be willing to use a reliable form of contraception (condoms), from screening until 6 months after existing from the study Given signed and dated written informed consent and willing/able to comply with all protocol required visits/procedures Exclusion Criteria: Primary major surgery < 4 weeks prior to the planned first study treatment day Lactating or pregnant women or plans to be become pregnant Except for alopecia, any drug-related AE from any previous treatments not recovered to NCI-CTCAE version 4.03 grade 1 or lower prior to the planned first study treatment day With active systemic infections, active and clinically significant cardiac diseases, active gastrointestinal diseases, active pulmonary diseases, or medical conditions that may significantly affect adequate absorption of investigational product. Known allergy to BEL-X-HG or its formulation excipients History of autoimmune disease that in the investigator's opinion may be significant to exclude participation in the study Use of any investigational agents or non-registered product within 4 weeks of baseline Known human immunodeficiency virus (HIV) positivity Known hepatitis B virus (HBV) or hepatitis C virus (HCV) carrier who has: serum HBV DNA > 2,000 IU/mL and abnormal ALT (> 5 ULN) (for HBV carrier) abnormal ALT (> 5 ULN) (for HCV carrier) With conditions, judged by the investigator, as unsuitable for the study Mean QTc with Fridericia's correction (QTcF*) greater than 450 ms in screening ECG or history of familial long QT syndrome *: Fridericia's formula: Any cancer-directed therapy (chemotherapy, radiotherapy, biological or immunotherapy, etc.) within 4 weeks or 5 half-lives, (whichever is shorter) of baseline

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Sequential Assignment
Interventional Model Description: A sequential Dose Escalation Part of four doses following a 3 + 3 design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEL-X-HG<br>3+3 dose escalation | Drug: BEL-X-HG<br>* This study will be carried out in 2 parts: A sequential Dose Escalation Part of four doses following a 3 + 3 design where dose escalation will be made based on DLT, for a single cycle (28 days) of BEL-X-HG treatment A Dose Extension Part of up to 5 cycles (28 days each) at the same dose level (starting dose) of BEL-X-HG treatment Escalating dose levels of BEL-X-HG in 5 study cohorts and one modified dose will be as follows: Cohort 1: Dose level 1 - 0.5 g/day (0.25 g, bid) Cohort 2: Dose level 2 - 1.0 g/day (0.5 g, bid) Cohort 3: Dose level 3 - 2.0 g/day (1.0 g, bid) Cohort 4: Dose level 4 - 4.0 g/day (2.0 g, bid) Modified dose level Cohort 5: Dose level 5 - 1.5 g/day (0.75g bid) This re-escalation is allowed only when dose de-escalates from Dose level 3 to Dose level 2, and 1 DLT in 6 evaluable subjects of Dose level 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The prior dose level below the dose level at which ≥2/3 or ≥2/6 subjects suffer dose-limiting toxicity (DLT). | 28 days (first treatment cycle of every subjects) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| Tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) | Tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| Oxidative stress | Oxidative stress | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| nutritional status | serum prealbumin, triglyceride, and total cholesterol | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| immunological status | TNF-alpha, IL-1, IL-2, IL-4, and IL-6 | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| cachexia status | fast blood glucose, C-reactive protein, and testosteron | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| Quality of life (QoL) of patients with advanced refractory solid tumors | SF-36 Quality of Life (QoL) Questionnaire | up to 168 days (up to 6 cycles of each enrolled subjects) | 
| liver function | serum AST, ALT, AKP, albumin, gamma-GT, ferritin, PT/INR and APRI | up to 168 days (up to 6 cycles of each enrolled subjects) |