A Study Evaluating the Safety and Efficacy of the GMCN-508A Drug Product in Transfusion-dependent α-Thalassemia Participants

A Phase 1 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With Transfusion-dependent α-Thalassemia by Transplantation of Autologous CD34+ Cells Transduced Ex Vivo With a Lentiviral Vector (GMCN-508A Drug Product)

This is a non-randomized, open label, single-site, single-dose, phase 1 study in up to 5 participants (between 5 and 35 years of age, inclusive) with Transfusion-dependent α-thalassemia. The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) using GMCN-508A Drug Product [autologous CD34+ hematopoietic stem cells transduced with GMCN-508A lentiviral vector encoding the human α-globin gene].

Study Overview

• Status: Recruiting
• Conditions: Transfusion-dependent α-Thalassemia
• Intervention / Treatment: Genetic: GMCN-508A Drug Product

Detailed Description

Subject participation for this study will be 5 years.

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Guangxi
    • Nanning, Guangxi, China, 530021
      • Recruiting
      • The Affiliated Hospital OF Guangxi Medical University
      • Contact: yongrong lai, PhD; Phone Number: 86-771-5356746; Email: laiyongrong@hotmail.com
      • Principal Investigator: yongrong lai, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The subject himself/herself or one legal guardian/agent of the subject is required to fully understand the study and voluntarily sign a written informed consent.
2. Ages 5 to 35, no gender limitation.
3. The clinical diagnosis of Transfusion-dependent α-Thalassemia.Transfusion dependence was defined as ≥6 Units of transfusions of pRBCs for the prior 24 weeks without >56 days of non-transfusion.
4. Karnofsky Level of Performance (KPS) score or Lansky Level of Performance (LPS) score ≥70.
5. Subjects were determined to undergo autologous hematopoietic stem cell transplantation and conditioning procedure by the principle investigator.
6. Subjects were willing to comply with the protocol.
7. Fertile Subjects are willing to take effective contraceptive measures during the study.

Exclusion Criteria:

1. Diagnosed with mild α-thalassemia, Hb Bart's edema, ATRx α-thalassemia, hemoglobin S/β-thalassemia, myelodysplastic subtype anemia, or with HbE homozygous β gene mutation, or with any type of β-thalassemia Thalassemia.
2. Uncorreted Bleeding disorders with frequent bleeding (eg, menorrhagia, epistaxis, coagulation disorders).
3. Bacterial, fungal, parasitic or viral infection as determined by the investigator to be clinically significant.
4. Presence of severe iron overload.
5. Any prior or current malignancy, myeloproliferative disorders or immunodeficiency disorders.
6. Any major medical disease, laboratory test abnormality or mental illness that would render the participant ineligible for the study.
7. Immediate family member with a known Familial Cancer Syndrome.
8. Prior receipt of gene therapy, allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation.
9. Participation in another clinical study with an investigational drug 3 months prior to Screening.
10. Pregnancy, plan to be pregnant during study or breastfeeding in a postpartum female.
11. Known hypersensitivity to any ingredients or excipients of the test drug.
12. Eligible for allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation with a known and available donor.
13. Any other condition that would render the participant ineligible for the study, as determined by the investigator.

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: GMCN-508A; GMCN-508A infusion	Genetic: GMCN-508A Drug Product; Transplant of autologous hematopoietic stem and progenitor cells transduced with GMCN-508A lentiviral vector.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Transfusion Independence (TI)	TI was defined as a weighted average hemoglobin (Hb) >= 9 g/dL without any packed red blood cells (pRBC) transfusions for a continuous period of >=12 months at any time during the study after GMCN-508A Drug Product infusion. Percentage of participants who achieved TI from time of drug product infusion up to 24 months was reported.	From time of drug product infusion up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Serum Ferritin		Baseline, Month 12 and 24
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Score	PedsQL GCS is designed to measure health-related quality of life in pediatric participants and adolescents (2 to 18 years of age). It encompasses 4 dimensions of functioning (physical [8 items], emotional [5 items], social [5 items], school [3 items]). Age groups: Toddler (2-4 years), Young pediatric (5-7 years), Pediatric (8-12 years), and Teens (13-18 years). Depending on the participant's age, the questionnaire may be completed by parent/caregiver as appropriate. For the Toddler group, the PedsQL GCS consist of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consist of 23 items, with a 3-point Likert scale (0, 2, 4) for the young pediatric, and a 5-point Likert scale for the pediatric and teens groups. Scores are transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicate improved quality of life.	Baseline, Month 12 and 24
Change From Baseline in liver Iron Content by Magnetic Resonance Imaging (MRI)		Baseline, Month 12 and 24
Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 24	TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after GMCN-508A Drug Product infusion.	Month 24
Duration of Transfusion Independence (TI)	TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after GMCN-508A Drug Product infusion. Time period of TI will start when participants achieve a Hb >= 9 g/dL with no transfusions in the preceding 60 days. Duration of TI was calculated as the time from the start of TI (i.e. first Hb >= 9 g/dL with no transfusions in the preceding 60 days) up to the last available Hb at which the TI criteria are still met.	From time of drug product infusion up to 24 months
Time From GMCN-508A Drug Product Infusion to Achieving Transfusion Independence (TI)	TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after GMCN-508A Drug Product infusion. Time from drug product infusion to initial achievement of TI was calculated as the time from drug product infusion to the first Hb at which a participant can be declared as TI.	From time of drug product infusion up to 24 months
Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI)	The weighted average Hb is an average area under the curve during the period of TI, from the start of TI when the Hb is first >= 9 g/dL with no transfusions in the preceding 60 days to the last available Hb at which the TI criteria are still met.	From time of drug product infusion up to 24 months
Annualized Number of pRBC Transfusions	Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized number of transfusions during the 24 months prior to enrollment.	From 12 to 24 months post drug product infusion
Annualized Volume of pRBC Transfusions	Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized volume of transfusions during the 24 months prior to enrollment.	From 12 to 24 months post drug product infusion
Proportion of Participants Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion.		From 6 to 24 months
Change From Baseline in Cardiac T2* on MRI		Baseline, Month 12 and 24
Time to Neutrophil Engraftment	Time to neutrophil engraftment was defined as the time to the first of 3 consecutive absolute neutrophil count (ANC) >= 0.5 × 10^9/L obtained on different days after a post-transplant value of < 0.5 × 10^9/L. The Day of neutrophil engraftment is the first day of the 3 consecutive measurements, where Day 0 is the day of drug product infusion.	From time of drug product infusion up to 24 months
Proportion of Participants With Successful Platelet Engraftment	Platelet engraftment was defined as achieving 3 consecutive platelet values >= 20 × 10^9/L on different days after a post-transplant value of < 20 × 10^9/L, while no platelet transfusions administered for 7 days immediately preceding and during the evaluation period.	From time of drug product infusion up to 24 months
Time to Platelet Engraftment	Platelet engraftment was defined as achieving 3 consecutive platelet values >= 20 × 10^9/L on different days after a post-transplant value of < 20 × 10^9/L, while no platelet transfusions administered for 7 days immediately preceding and during the evaluation period.	From time of drug product infusion up to 24 months
Change From Baseline in Short Form-36 Health Survey (SF-36)	SF-36 is a generic quality-of-life instrument that had been widely used to assess HRQL of participants. Generic instruments were used in general populations to assess a wide range of domains applicable to a variety of health states, conditions, and diseases. The SF-36 consisted of 36 items that were aggregated into 8 multi-item scales (physical functioning [1=yes, limited a lot to 3=no, not limited at all], role-physical [1=all of the time to 5=none of the time], bodily pain [1=very severe to 6=none], general health [1=poor to 5=excellent], vitality [1=none of the time to 5=all of the time], social functioning [1=all of the time: to 5=none of the time], role emotional [1=all of the time to 5=none of the time] and mental health [1=all of the time to 5=none of the time]), with scores ranged from 0 to 100. Higher scores indicating better HRQL.	Baseline, Month 12 and 24
Proportion of Participants With Successful Neutrophil Engraftment	Neutrophil engraftment was defined as achieving 3 consecutive absolute neutrophil count (ANC) >= 0.5 × 10^9/L on different days after a post-transplant value of < 0.5 × 10^9/L within 42 days after drug product infusion.	From time of drug product infusion up to 24 months
Transplant-related Mortality	Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant.)	Through 100 and 365 days post GMCN-508A Drug Product infusion
Proportions of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was defined as any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE, occurring at any dose and regardless of causality that: results in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect.	From signing of informed consent to 24 months after the drug product infusion
Overall Survival	Overall survival was defined as time from date of GMCN-508A Drug Product infusion (Day 0) to date of death. Overall survival was censored at the date of last visit if the participant was still alive. Percentage of participants who survived throughout the study were reported.	From time of drug product infusion up to 24 months
Incidence of acute and/or chronic graft-versus-host disease (GVHD)	acute and/or chronic graft-versus-host disease (GVHD) was determined by the investigator.	From time of drug product infusion up to 24 months
Percentage of Participants Detected With Replication-competent Lentivirus (RCL)		From time of drug product infusion up to 24 months
Percentage of Participants with occurrence of malignant disease		From time of drug product infusion up to 24 months

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Guangxi Medical University
• Collaborators: Genmedicn Biopharma Ltd.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 8, 2023
• Primary Completion (Anticipated): August 1, 2028
• Study Completion (Anticipated): December 31, 2030

Study Registration Dates

• First Submitted: February 24, 2023
• First Submitted That Met QC Criteria: February 24, 2023
• First Posted (Actual): March 7, 2023

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 16, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: gene therapy; GMCN-508A; Transfusion-dependent α-Thalassemia; Human Hematopoietic Stem Cell
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; alpha-Thalassemia
• Other Study ID Numbers: GMCN-508A-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No