An Open-Label, Multi-Center, Phase Ib/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of YK012 in Participants With B-cell Acute Lymphoblastic Leukemia
Overview
- Phase
- Phase 1
- Intervention
- YK012
- Conditions
- B-cell Acute Lymphoblastic Leukemia
- Sponsor
- Excyte Biopharma Ltd
- Enrollment
- 46
- Locations
- 12
- Primary Endpoint
- The Incidence and Profile of Dose-limiting Toxicity (DLT)
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
The purpose of this study is to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of YK012 administered as monotherapy in participants with B-cell acute lymphoblastic leukemia (B-ALL).
Detailed Description
YK012 is a bispecific antibody designed to link B cells and T cells resulting in T-cell activation and a cytotoxic T-cell response against cluster of differentiation (CD)19 expressing cells. Relapsed/refractory B-ALL in adult patients is an aggressive malignant disease with dismal prognosis. This study is designed in 2 parts as described below: Phase Ib (dose escalation) and Phase II (dose expansion). If in Phase Ib it is observed in adult subjects at doses with manageable risk and antitumor activity, studies in pediatric subjects can be initiated to explore safety and efficacy in pediatric subjects, as well as pharmacokinetic profiles.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants or their legally acceptable representative must sign an ICF indicating that the participants understand the purpose of, and procedures required for the study and are willing to participate in the study.
- •Eastern Cooperative Oncology Group Performance Status (ECOG) of 0-
- •An estimated survival time of more than 12 weeks.
- •A definitive diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with any of the following conditions:
- •Ph-negative B-ALL with any of the following: i. Failure to achieve complete remission after initial induction therapy. ii. Failure to achieve complete remission after salvage treatment. iii. Relapse with first remission duration ≤12 months. iv. Second or later relapse. v. Relapse after hematopoietic stem cell transplantation (HSCT).
- •Ph-positive B-ALL: failure to 1 or more tyrosine kinase inhibitors (TKIs), or intolerance to treatment with TKIs, or with the T315I mutation.
- •≥ 5% blasts in the bone marrow by morphologic assessment.
- •Recovery to Grade 0-1 (Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0) from adverse events related to prior therapy except alopecia.
- •Adequate hematological and organ function.
- •Female participants of childbearing potential must have a negative serum pregnancy test at screening. Female patients who are sexually active must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.
Exclusion Criteria
- •Burkitt´s Leukemia according to World Health Organization (WHO) classification.
- •History of antitumor therapy as follows, before the first dose of study drug:
- •Targeted therapy with small molecule drug within 2 weeks or 5 half-lives, whichever is longer
- •Targeted therapy with macromolecular drug or Immunomodulatory agent therapy within 3 weeks
- •Radiotherapy or chemotherapy (except for intrathecal chemotherapy and dexamethasone), or treatment with Chinese traditional/patent medicine that has definite antitumor effect within 2 weeks
- •Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is shorter
- •Receipt of any live attenuated vaccines or live virus vaccine within 4 weeks
- •Autologous stem cell transplantation within 6 weeks
- •History of organ transplant, or allogeneic stem cell transplantation within 12 weeks.
- •Any active acute graft-versus-host disease (GvHD), grade 2-4 (according to Glucksberg criteria) or active chronic GvHD requiring systemic treatment.
Arms & Interventions
YK012
Participants will be assigned to a dose level of YK012 based on when the participants join this study. Participants will receive YK012 by intravenous infusion (IV), once per week, four weeks per treatment cycle.
Intervention: YK012
Outcomes
Primary Outcomes
The Incidence and Profile of Dose-limiting Toxicity (DLT)
Time Frame: 28 days after the first dose
The toxicities occurring within 28 days (i.e., DLT observation period) after the first dose will be defined as DLTs in the discretion of the investigator as related to the IMP (Investigational Medicinal Product). This outcome measure is applicable for dose escalation phase only. The MTD dose will be calculated by the statistician upon completion of the dose escalation study.
Maximum Tolerated dose (MTD) or The Recommended Dose for Future Clinical Study
Time Frame: Through study completion, 20 weeks
This outcome measure is applicable for dose escalation phase only. The MTD dose will be calculated by the statistician upon completion of the dose escalation study.
Number of Participants with Adverse Events
Time Frame: From the time the participant signs the ICF until the end of the safety visit period, assessed up to 24weeks.
An AE is defined as any untoward medical event that occurs after a subject receives the investigational drug, which may be manifested as symptoms, signs, diseases, or laboratory abnormalities, but may not necessarily have a causal relationship with the investigational drug.
Number of Participants with Serious Adverse Events
Time Frame: From the time the participant signs the ICF until the end of the safety visit period, assessed up to 24weeks.
An SAE refers to an untoward medical occurrence such as death, life-threatening event, permanent or serious disability or loss of function, need for hospitalization or prolongation of hospitalization after the subject receives the IMP, and congenital abnormalities or birth defects.
Dose Expansion Phase: Objective Response Rate (ORR)
Time Frame: From the time the participant signs the ICF until hematological relapse, assessed up to 1 year
ORR is defined as percentage of participants achieving either a complete response (CR) or complete remission with partial hematological recovery (CRi). The MTD dose will be calculated by the statistician upon completion of the dose escalation study. This outcome measure is applicable for dose expansion phase only.
Secondary Outcomes
- Area Under the Concentration-time Curve (AUC)(Up to 20 weeks)
- Maximum Observed Concentration (Cmax)(Up to 20 weeks)
- Time to Reach Maximum Concentration (Tmax)(Up to 20 weeks)
- Half Life (t1/2) of YK012(Up to 20 weeks)
- Clearance (CL) of YK012(Up to 20 weeks)
- Trough Plasma Concentration (Ctrough)(Up to 20 weeks)
- Percentage of Participants with Anti-Drug Antibody (ADA) and Neutralizing Antibody (Nab) Against YK012(Up to 20 weeks)
- Dose Escalation Phase: Objective Response Rate (ORR)(From the time the participant signs the ICF until hematological relapse, assessed up to 1 year)
- Relapse-free Survival (RFS)(From the time the participant signs the ICF until hematological relapse, assessed up to 1 year)
- Overall survival (OS)(From the date of first dose until loss of follow-up, death, withdrawal of informed consent, or the end of study, whichever occurs first, assessed up to 1 year.)
- Number of B cells and T cells in peripheral blood after administration(Up to 20 weeks)