A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of RJK-RT2831 Injection in Patients With Hematologic Malignancies.
Overview
- Phase
- Phase 1
- Intervention
- RJK-RT2831 dose-escalation phase Ia
- Conditions
- Hematologic Malignancies
- Sponsor
- Nanjing RegeneCore Biotech Co., Ltd.
- Enrollment
- 71
- Locations
- 32
- Primary Endpoint
- phase Ia and phase Ib: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
This study is a first-in-human (FIH) study which is required to understand the safety, tolerability, pharmacokinetics and preliminary efficacy of RJK-RT2831 injection in patients with hematologic malignancies
Detailed Description
This is the first-in-human, Phase 1, open-label, multicenter, dose-escalation and dose expansion phase study to investigate the safety, Tolerability, pharmacokinetics and preliminary efficacy of RJK-RT2831 injection in patients with hematologic malignancies. About 70 subjects with malignant blood tumors will be recruited. The specific tumor type will be determined based on the results of the Phase Ia trial and may be expanded to other malignant blood tumor types.The primary goal of the study is to assess the safety, tolerability, maximum tolerated dose (MTD),determine the recommended doses for expansion (RDEs) and recommended phase 2 dose (RP2D) in patients with hematologic malignancies.
Investigators
Eligibility Criteria
Inclusion Criteria
- •1\. A male or female aged ≥ 18 and \<75 years old.
- •2\. The following three points are evaluated by the investigator and are deemed suitable to participate in the study: a) The subject fully understands the requirements of this study and voluntarily signs a written informed consent form; b) Be able to comply with the medication requirements of this study as well as all study related procedures and assessments; c) Not deemed as potentially unreliable and/or uncooperative.
- •3\. An ECOG physical status score is ≤ 2 and an expected survival is ≥ 3 months.
- •4\. Relapsed or refractory acute myeloid leukemia (AML) that meets the following criteria will be included in Phase Ⅰa : Patients diagnosed with AML according to the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours: -Myeloid and Histiocytic/Dendritic Neoplasms (Khoury et al., 2022), including any subtype except for acute promyelocytic leukemia (APL). These patients must have received at least one previous treatment and have failed to current standard treatments that provide clinical benefit.
- •Note: The following diagnostic criteria must be met for relapsed/refractory AML: (1) Relapsed AML: Leukemia cells reappear in the peripheral blood or bone marrow blast cells exceed 5% after complete remission (CR) (excluding reasons such as bone marrow regeneration post-consolidation chemotherapy) or there is extramedullary infiltration by leukemia cells. (2) Refractory AML: Initial cases that are unresponsive after two cycles of standard regimen treatment; recurrence within 12 months after CR and consolidation therapy; recurrence beyond 12 months with ineffectiveness of conventional chemotherapy; those who have relapsed twice or more; or persistent extramedullary leukemia.;
- •Phase Ib tentatively includes patients with hematologic malignancies that meet the following criteria: relapsed or refractory AML subjects who have received at least one previous treatment and have failed to current standard treatments that provide clinical benefit, and MDS subjects who are diagnosed according to the 5th edition of the WHO Classification of Haematolymphoid Tumours-Myeloid and Histiocytic/Dendritic Neoplasms (Khoury et al., 2022) and are classified as high-risk or very-high-risk according to the Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al., 2012). The specific tumor type will be determined based on the results of the Phase Ia trial and may be extended to other hematologic malignancies.
- •Note: Subjects with myelodysplastic syndromes with excess blasts (MDS-EBs) type 1 (MDS-EB1) or type 2 (MDS-EB2) may be considered for inclusion. The EB type has a higher risk of transformation to AML than other subtypes and may have greater clinical benefits.
- •6\. The test of CD33 and/or CD123 for Phase Ia and Ib subjects in this study will be required to be positive, and patients with any level of CD33 and/or CD123 positivity were allowed to be included. Note: The positivity and expression levels of CD33 and CD123 were determined by each site.
- •7\. Consent to bone marrow biopsy and aspiration, and consent to implantation of medical devices such as peripherally inserted central catheter (PICC), or venous access port, or central venous catheter (CVC) (if applicable) for long-term intravenous drug administration.
- •8\. Patients have recovered from toxicity of prior first-line therapy, i.e., Grade 1 toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V5.0, with the exception of toxicities such as alopecia, fatigue, and other toxicities deemed by the investigator to be of no safety risk to the patient, as well as hematological toxicities related to the tumor.
Exclusion Criteria
- •1\. APL is suspected or confirmed based on morphology, immunophenotyping, molecular testing, or chromosomal karyotyping, or other hematological tumors, such as myeloid sarcoma, mixed phenotype acute leukemia, accelerated phase and blast phase of chronic myeloid leukemia, etc.;
- •2\. Has received any anticancer therapy or investigational drug within the following specified time period prior to the first dose of RJK-RT2831:
- •Received cytotoxic chemotherapy (except hydroxyurea use for subjects with leukocytosis \>10,000 cells/mm3 or rapid disease progression), radiotherapy (except local palliative radiotherapy), immunotherapy, targeted therapy and other anti-tumor treatments within 14 days;
- •Received adoptive cell therapy, such as autologous or donor natural killer cell or T lymphocyte infusions (e.g., chimeric antigen receptor-T cells), unless \> 60 days prior to the first dose of study treatment and treatment-related toxicities have resolved to at least Grade 1;
- •Received any investigational drug (for any indication) within 5 half-lives of the drug or 14 days, whichever is longer;
- •Received an autologous haematopoietic stem cell transplant within 12 weeks.
- •3\. Subjects with cardiovascular disease, including but not limited to:
- •Resting state, mean QTcF \> 480 ms in men/women derived from 12-lead electrocardiogram (ECG) (repeated 3 times); Note: QTcF = QTcB ×RR\^0.17, QTcB is the corrected QT interval obtained using the Bazetts correction formula;
- •Echocardiogram or multigated acquisition (MUGA) scan showing a left ventricular ejection fraction of less than 50%;
- •Symptomatic or treatment-requiring abnormalities in rhythm, conduction, and resting ECG morphology, such as arrhythmias, degree II or III atrioventricular block, congestive heart failure (New York Heart Association cardiac function class III or IV)
Arms & Interventions
RJK-RT2831
Intervention: RJK-RT2831 dose-escalation phase Ia
RJK-RT2831
Intervention: RJK-RT2831 Dose Expansion Phase Ib
Outcomes
Primary Outcomes
phase Ia and phase Ib: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
Time Frame: The summary of all AEs was dominated by adverse events that occurred during treatment, including any AE that occurred from the first administration of the study drug until 28 ± 7 days after the last administration.
All AEs (except for CRS and TLS) will be graded according to NCI CTCAE V5.0, a common standard term for AE. CRS and TLS will be graded according to ASCTC Consensus (2019) and Cairo-Bishop grading system (Howard revised) respectively.
phase Ia: Maximum Tolerated Dose (MTD)
Time Frame: From the first administration of the study drug until 28 days after the first dose
To assess the safety, tolerability, and maximum tolerated dose (MTD) of RJK-RT2831 in patients with hematologic malignancies.
phase Ia: Recommended Doses for Expansion (RDEs)
Time Frame: From the first administration of the study drug until 28 ±7 days after the last administration and prior to the initiation of a new anti-tumor therapy
To determine the recommended doses for expansion (RDEs) in patients with hematologic malignancies.
phase Ib: Recommended Phase II Dose (RP2D)
Time Frame: From the first administration of the study drug until 28 ±7 days after the last administration and prior to the initiation of a new anti-tumor therapy
To determine the recommended Phase II dose (RP2D) in patients with hematologic malignancies.
Secondary Outcomes
- Volume of distribution (Vd)(The first 6 cycles (28 days/cycle))
- Half-life (t1/2)(The first 6 cycles (28 days/cycle))
- Clearance (CL)(The first 6 cycles (28 days/cycle))
- Cmax(The first 6 cycles (28 days/cycle))
- Tmax(The first 6 cycles (28 days/cycle))
- Area under the concentration-time curve (AUC)(The first 6 cycles (28 days/cycle))
- Total Clearance (CL)(The first 6 cycles (28 days/cycle))
- volume of distribution (Vd）(The first 6 cycles (28 days/cycle))
- elimination rate constant (Kel)(The first 6 cycles (28 days/cycle))
- average concentration (Cave)(The first 6 cycles (28 days/cycle))
- Anti-Drug Antibodies (ADA)(On the first day of each cycle until the last cycle administrated (28 days/cycle))
- overall remission rate (ORR)(On the first day of each cycle until the end of treatment (+ 3 days) and before starting new anti-tumor therapy (28 days/cycle))
- duration of remission (DOR)(Throughout the study (from the first administration of the study drug until 28 ± 7 days after the last dose and before starting new anti-tumor therapy))
- event-free survival (EFS)(Throughout the study (until 28 ± 7 days after the last dose and before starting new anti-tumor therapy))
- overall survival (OS)(Throughout the study (every 3 months ±7 days after discontinuation to assess survival status until subject death or study termination))