Phase I Clinical Trial of RC1012 Injection in Patients With r/r AML

A Single-arm, Single/Multiple Dose-escalation and Dose-extension Phase I Clinical Trial of RC1012 Injection (Allogeneic DNT Cells) in Patients With Relapsed/Refractory Acute Myeloid Leukemia

To evaluate the safety and tolerability of RC1012 infusion in patients with relapsed or refractory Acute Myelocytic Leukemia (r/r AML).

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Biological: RC1012 injection (allo-DNT cells)

Detailed Description

This study aims to evaluate the safety and tolerability of RC1012 injection in patients with relapsed or refractory Acute Myelocytic Leukemia (r/r AML).

DNT cells are mature T lymphocytes that comprise 3-10% of T cells in human peripheral blood mononuclear cells (PBMC). Allo-DNT cells from healthy donors have been proved to be safe and demonstrated potent cytotoxicity against AML blasts from AML patients in preclinical and preliminary clinical studies. Allo-DNT cells will be collected from healthy donors (NO MHC match needed) and infused into patients. The drug for this study is an off-the-shelf product. Patients DO NOT need to wait for the cell manufacturing.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Zhen Cai, MD, PhD; Phone Number: +086-0571-56734707; Email: caizhen1@sina.com
• Study Contact Backup: Name: Jingsong He, MD, PhD; Phone Number: 086-13600547247; Email: hejingsong@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • First affiliated Hospital of Zhejiang University
      • Contact: Huili Zhou, MD, PhD; Phone Number: 086-0571-87236685; Email: 1482055406@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily sign an ICF and expect to complete the study procedures for follow-up examinations and treatment.
2. Aged 18 to 70 years (including cut-offs), regardless of gender.

3. Accordance with the diagnostic criteria of AML in the 2016 WHO staging and meeting the diagnostic criteria of relapsed and refractory in the Chinese Guidelines for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia (2017 edition).

   • Diagnostic criteria for Relapsed AML: reappearance of leukemic cells in peripheral blood or >5% primitive/naive cells in bone marrow after CR (except for other causes such as bone marrow regeneration after consolidation chemotherapy) or extra-marrow infiltration of leukemic cells.
   • Diagnostic criteria for refractory AML: primary refractory disease that has not achieved complete remission after two courses of induction chemotherapy with a standard regimen (containing cytarabine and an anthracycline or anthraquinone).
4. The patient has recovered from the toxicity of the prior treatment, i.e., less than a grade 2 CTCAE toxicity rating (unless the abnormality is tumor-related).
5. ECOG score 0 to 1.

6. Appropriate organ function, and accordance with the following criteria within 7 days prior to lymphodepleting chemotherapy.

   • Glutathione aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN)
   • Glutamic aminotransferase (ALT) ≤ 3 times ULN.
   • Total bilirubin ≤ 1.5 times ULN, unless the patient has documented Gilbert syndrome. Patients with Gilbert-Meulengracht syndrome with total bilirubin ≤ 3.0 times ULN and direct bilirubin ≤ 1.5 times ULN may be included.
   • Serum creatinine ≤ 1.5 times ULN or a creatinine clearance ≥ 60 ml/min.
   • Hemoglobin ≥ 60 g/L or hemoglobin maintained at that level following transfusion.
   • Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L.
   • A platelet count ≥ 30 x 10^9/L or a platelet count maintained at that level following a platelet transfusion
   • Left ventricular ejection fraction (LVEF) ≥ 45%.

7. Female patients with of childbearing potential should have a negative pregnancy test during the screening period. Any male and female patients of childbearing potential must agree to use an effective contraception method for at least six months from the time that they sign the informed consent form until the end of the cell infusion. Female patients without childbearing potential (meeting at least 1 of the following criteria) is described below.

   • Have undergone a hysterectomy or bilateral oophorectomy
   • Medically recognized as ovarian failure.
   • Medically recognized as post-menopausal (at least 12 consecutive months of menopause without pathological or physiological cause).

Exclusion Criteria:

1. A diagnosis of acute promyelocytic leukemia.
2. Patients with extramedullary infiltration of leukemia.
3. Evidence or history of central nervous system invasion or cranial neuropathy.
4. Patients with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and peripheral blood hepatitis B virus (HBV) DNA titration assay not within the normal reference range, positive hepatitis C virus (HCV) antibody and peripheral blood HCV RNA ,positive for human immunodeficiency virus (HIV), or positive for cytomegalovirus (CMV) DNA, or positive syphilis test.
5. Persons with hypersensitivity to excipients of RC1012 injection (e.g., human albumin) or other drugs recommended in the study protocol (e.g., lymphodepleting treatment, Tocilizumab).
6. Serious cardiac disease, including but not limited to severe arrhythmia, unstable angina, massive heart attack, New York Heart Association class III or IV cardiac insufficiency, refractory hypertension.
7. Persons who have previously received an organ transplant or are preparing to receive an organ transplant (except for hematopoietic stem cell transplantation)
8. Persons with acute and chronic graft-vs-host disease (GVHD)
9. Those who have received a hematopoietic stem cell transplant within 2 months prior to screening tests.
10. Active neurological autoimmune or inflammatory diseases (e.g. Guillain-Barre Syndrome (GBS), Amyotrophic lateral sclerosis (ALS)) and clinically significant active cerebrovascular disease (e.g. cerebral oedema, Posterior Reversible Encephalopathy Syndrome (PRES)).
11. Patients with a life expectancy of less than 3 months
12. Patients have been involved in other clinical studies within 3 months prior to screening.
13. Patients, in the judgement of the investigator and/or clinical criteria, are contraindicated to any study procedure or have other medical conditions that may place them at unacceptable risk.

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: RC1012 injection (allo-DNT Cells); Experimental: RC1012 injection (allo-DNT Cells) The trial is divided into two parts: Part A1 is a single- dose escalation trial with three dose groups (5×10^7 cells/kg, 1.5×10^8 cells/kg, 4.5×10^8 cells/kg), with 9-18 patients planned to be enrolled. Part A2 is a multiple-dose escalation trial consisting of 2 dose groups (1.5×10^8 cells/kg and 4.5×10^8 cells/ kg at day 0, day 7 and day 14), with 9-12 patients planned to be enrolled. Part B is a multiple-dose extension trial in which the Safety Review Committee evaluates whether to extend an additional 3-6 patients to receive the multiple cell infusions based on available PK and safety data.

Biological: RC1012 injection (allo-DNT cells); RC1012 injection (allo-DNT cells) from healthy donors and have been proved to be safe and demonstrated potent cytotoxicity against AML blasts from AML patients in preclinical and preliminary clinical studies. Allo- DNT cells will be collected from healthy donors (NO MHC match needed) and injected into patients. The drug for this study is an off-the-shelf product. Patients DO NOT need to wait for the cell manufacturing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Limiting Toxicity (DLT)	To evaluate the safety, tolerability, and determine the recommended dosage of allo-DNT Cell Therapy for Relapsed/Refractory Acute Myelocytic Leukemia	Up to 28 days
Maximum Tolerated Dose (MTD)	MTD was the highest dose for DLT in ≤1/6 subjects	Up to 28 days
Incidence of abnormalities	Incidence of abnormalities in AE/SAE/laboratory tests/electrocardiograms/vital signs.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	The time from the start of the first assessment of CR or PR to the first assessment as disease recurrence or progression or death	Up to 2 years
Pharmacokinetics (PK) indicator (Cmax)	The peak concentration of allo-DNT cells amplified in the peripheral blood (Cmax, detected by Flow Cytometry).	Up to 90 days
Pharmacokinetics (PK) indicator (AUC)	Allo-DNT cells blood concentrations will be measured at different time points to evaluate the area under the curve (AUC). (AUC, detected by Flow Cytometry).	Up to 2 years
Pharmacokinetics (PK) indicator (Tmax)	Allo-DNT cells blood concentrations will be measured at different time points to evaluate the peak time (Tmax) in peripheral blood. Tmax is defined as the time to reach the highest concentration (Tmax, detected by Flow Cytometry).	Up to 2 years
Pharmacokinetics (PK) indicator (T1/2)	Allo-DNT cells blood concentrations will be measured at different time points to evaluate the elimination half-life in hours (T1/2). T1/2 is defined as the time point when the concentration of allo-DNT reaches half of maximum in a patient's peripheral blood (T1/2, detected by Flow Cytometry).	Up to 2 years
Overall Response Rate	ORR includes complete response (CR), CRi and PR. CR was defined as < 5% bone marrow blasts in an aspirate with spicules, no blasts with Auer rods or persistence of extramedullary disease, and independent of transfusions; CRi: was defined as<5% bone marrow blasts, either ANC<1×10^9/L or platelets<100×10^9/L, transfusion independence but with persistence of cytopenia; PR was defined as decrease of at least 50% in the percentage of blasts to 5-25% in the bone marrow aspirate and the normalization of blood counts.	Up to 2 years
Event-Free Survival	From the date of enrollment in the clinical trial until the failure of treatment, relapse or death.	Up to 2 years
Relapse-Free Survival	Relapse-free survival is the time from study enrollment until documented disease relapse, or death from any cause.	Up to 2 years
Overall Survival	From the date of entry into the clinical study until death from any cause.	Up to 5 years

Collaborators and Investigators

• Sponsor: Guangdong Ruishun Biotech Co., Ltd
• Collaborators: First Affiliated Hospital of Zhejiang University
• Investigators: Principal Investigator: Zhen Cai, MD, PhD, First affiliated Hospital of Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: July 20, 2022
• First Submitted That Met QC Criteria: July 20, 2022
• First Posted (Actual): July 22, 2022

Study Record Updates

• Last Update Posted (Actual): May 19, 2023
• Last Update Submitted That Met QC Criteria: May 17, 2023
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Cell Therapy; r/r AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: RC1012-AML001

Drug and device information, study documents

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