Efficacy and Safety Study of Recombinant Human Arginase 1 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

A Phase II Open-label Study of the Efficacy and Safety of Recombinant Human Arginase 1 (PEG-BCT-100) in Patients With Relapsed or Refractory Acute Myeloid Leukemia

To evaluate the efficacy of PEG-BCT-100 in patients with relapsed or refractory acute myeloid leukemia (AML) in terms of remission rate.

Study Overview

• Status: Unknown
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Biological: PEG-BCT-100

Detailed Description

This is a phase 2, non-randomised, open-label study that aims at evaluating the efficacy of single agent PEG-BCT-100 in adult patients with relapsed/refractory AML. Eligible patients will receive intravenous (IV) infusion of PEG-BCT-100 weekly until disease progression, unacceptable drug-related toxicity(ies), allogeneic haematopoietic stem cell transplantation or withdrawal of subject consent.

Pharmacokinetic (PK) of PEG-BCT-100 and pharmacodynamics (PD) activity of PEG-BCT-100 on arginine depletion will be evaluated throughout the study. Plasma arginine level, intracellular blast arginine level (IBAL) in peripheral blood (PB) and bone marrow (BM) will be measured at specific time points. PEG-BCT-100 will be given once weekly at 1600 Units/kg (2.7mg/kg) per dose for three weeks (Cycle 1). If the post-treatment IBAL-BM examined within 5 days prior to each cycle fails to drop at least 70% from baseline value and disease response fails to achieve complete remission (CR) or complete remission with incomplete blood count recovery (CRi), PEG-BCT-100 may be increased to 2500 U/kg (the maximum tolerated dose as reported previously) at investigator's discretion. Disease response will be assessed within 5 days prior to each cycle according to the International Working Group (IWG) AML Response Criteria.

Safety and toxicity will be assessed through physical examinations, vital signs, blood tests and urinalysis throughout the study. Adverse event (AE) and serious adverse events (SAE) will be reported according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.03 (CTCAE v4.03) until 28 days after the last dose of PEG-BCT-100.

Immunogenicity response including anti-drug antibody (ADA) level and neutralizing antibody level will be assessed weekly for the first 2 cycles of PEG-BCT-100, pre-dose of each cycle thereafter and End of Study (EoS). Specific response predictive biomarkers in circulating and BM blasts, and emerging genetic markers will also be explored in the study.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • The University of Hong Kong, Queen Mary Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patients ≥18 year-old at the time of informed consent
2. Documented relapsed or refractory AML after at least two standard chemotherapy regimen or in whom the treating physicians considered unfit for further chemotherapy treatment
3. The Eastern Cooperative Oncology Group (ECOG) performance status equal or less than 2
4. Patients from whom valid consent is obtained

Exclusion Criteria:

1. Patients who have received any induction chemotherapy, investigational treatment and arginine depleting agent within 2 weeks prior to the start of the PEG-BCT-100 (not including hydroxyurea or thioguanine)
2. Any toxic effects (except hair loss) of the prior therapy have not been resolved to Grade 1 or less according to National Cancer Institute Common Terminology Criteria for Adverse Events
3. Total bilirubin > 1.5 x Upper Limit of Normal (ULN) not related to haemolysis or Gilbert's disease, and ratio of concentrations of aspartate transaminase and alanine transaminase (AST/ALT) > 5 x ULN
4. Creatinine > 2 x ULN or estimated glomerular filtration rate using Modification of Diet in Renal Disease formula < 60 ml/min/1.73 m2
5. Second active malignancy within the past year except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
6. Uncontrolled concomitant illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia
7. History of HIV-1 seropositivity
8. Active infection not adequately responding to appropriate therapy
9. Patient is pregnant or lactating
10. Female with childbearing potential who is not willing to use contraceptive methods which, in the opinion of the investigator, are effective and adequate while on study treatment and for 6 months after the last dose of study treatment
11. Male with a female partner with childbearing potential who is not willing to use contraceptive methods which, in the opinion of the investigator, are effective and adequate while on study treatment and for 6 months after the last dose of study treatment
12. Any condition that is unstable or can jeopardize the safety of the patients and their compliance to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PEG-BCT-100; PEG-BCT-100 (PEGylated recombinant human arginase)	Biological: PEG-BCT-100; PEGylated recombinant human arginase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete remission (CR) rate	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)		3 years
Overall survival (OS)		3 years
Overall response rate (ORR)	proportion of patients achieving CR or CRi or partial remission (PR)	3 years
Duration of remission		3 years
Time to progression (TTP)		3 years
AE and SAE	Incidence of AE and SAE by severity grading as assessed according to CTCAE v4.03	3 years
PK - Area under the plasma concentration versus time curve (AUC)		2 years
PK - Peak plasma concentration of PEG-BCT-100 after administration (Cmax)		2 years
PK - Lowest concentration that PEG-BCT-100 reaches before the next dose is administered (Cmin)		2 years
PK - clearance		2 years
PK - volume of distribution		2 years
PK - elimination half-life		2 years
PD	arginine depletion	2 years
PK/PD relationship	dose response	2 years
Anti-drug antibody (ADA)	amount of ADA in patient sample (ng/mL)	2 years
neutralizing anti-drug antibody (nADA)	amount of nADA in patient sample (ng/mL)	2 years

Collaborators and Investigators

• Sponsor: Bio-Cancer Treatment International Limited
• Investigators: Principal Investigator: Anskar Leung, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Anticipated): September 1, 2019
• Study Completion (Anticipated): March 1, 2020

Study Registration Dates

• First Submitted: September 6, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (Estimate): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: July 27, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: AML; Acute myeloid leukemia; PEG-BCT-100; pegylated recombinant human arginase
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; BCT-100
• Other Study ID Numbers: BCT-100-007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED