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

Phase 1

Terminated

• Conditions: Advanced Solid Tumors
• Interventions: Drug: BEL-X-HG

• Registration Number: NCT03256331
• Lead Sponsor: Belx Bio-Pharmaceutical (Taiwan) Corporation

Brief Summary

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

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.

Study Timeline

• Study Start: 2017-06-21
• Study First Submitted: 2017-08-13
• Study First Submitted QC: 2017-08-17
• Study First Posted: 2017-08-22
• Primary Completion: 2020-03-30
• Study Completion: 2020-03-30
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-29
• Last Update Posted: 2020-06-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

1. Male or female patients of age ≥20 years

2. 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).

3. Evaluable disease, at least one measurable target lesion on imaging by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria.

4. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2

5. Life expectancy ≥ 3 months

6. 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

7. 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

8. 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

9. 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

10. 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

11. Must have recovered from toxicities of previous anti-cancer treatments to NCI-CTCAE version 4.03 grade 1 or lower, except for alopecia

12. 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

13. 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

14. Given signed and dated written informed consent and willing/able to comply with all protocol required visits/procedures

Exclusion Criteria

1. Primary major surgery < 4 weeks prior to the planned first study treatment day

2. Lactating or pregnant women or plans to be become pregnant

3. 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

4. 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.

5. Known allergy to BEL-X-HG or its formulation excipients

6. History of autoimmune disease that in the investigator's opinion may be significant to exclude participation in the study

7. Use of any investigational agents or non-registered product within 4 weeks of baseline

8. Known human immunodeficiency virus (HIV) positivity

9. 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)

10. With conditions, judged by the investigator, as unsuitable for the study

11. Mean QTc with Fridericia's correction (QTcF*) greater than 450 ms in screening ECG or history of familial long QT syndrome

    *: Fridericia's formula:

12. Any cancer-directed therapy (chemotherapy, radiotherapy, biological or immunotherapy, etc.) within 4 weeks or 5 half-lives, (whichever is shorter) of baseline

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
BEL-X-HG	BEL-X-HG	3+3 dose escalation

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (2)

National Cheng Kung University Hospital; 🇨🇳 Tainan, Taiwan

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan