Study for Safety and Efficacy Evaluation of Olverembatinib Combined With APG-2575 in Children With Relapsed/Refractory Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (R/R Ph + ALL）
Overview
- Phase
- Phase 1
- Intervention
- Olverembatinib, APG-2575, Dexamethasone
- Conditions
- Lymphoblastic Leukemia, Acute, Childhood
- Sponsor
- Institute of Hematology & Blood Diseases Hospital, China
- Enrollment
- 22
- Locations
- 4
- Primary Endpoint
- Area under the plasma concentration versus time curve (AUC)
- Status
- Recruiting
- Last Updated
- 3 years ago
Overview
Brief Summary
This is an open-label, multicenter, phase 1b study, which is designed to explore the safety, efficacy and PK of olverembatinib, a third-generation tyrosine kinase inhibitor (TKI) marketed in China, in combination with APG-2575 in treating R/R Ph+ALL children, and to preliminarily establish the recommended dose of olverembatinib and APG-2575 for children based on the above results.
Detailed Description
Eligible patients will receive a 6-week core treatment after screening, including a 2-week olverembatinib monotherapy and a 4-week combination therapy with olverembatinib, APG-2575 and dexamethasone, and based on the remission of leukemia after 2, 4, and 6 weeks of treatment, these patients will either continue olverembatinib alone/in combination with APG-2575 and dexamethasone as maintenance therapy or switch to other anti-tumor therapy. Toxicities of this study will be graded according to NCI CTCAT (Version 5.0). The investigator will interrupt, reduce or discontinue the dose of the investigational drug according to the correlation and grade of toxicities. The study drug can be resumed when the drug related toxicities resolve to grade 1 or below.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Eligible patients must meet all of the following criteria:
- •Children under 18 years of age on the day of signing the informed consent form, and able to swallow the oral drugs during the study period.
- •Subjects who are diagnosed with Ph+ALL, and are resistant or intolerant to at least one TKI. If the subject has BCR-ABL1 T315I mutation, prior use of TKIs will not be considered.
- •Drug resistance includes disease recurrence and refractory disease. Relapse: Presence of blasts \> 5% in peripheral blood or bone marrow or presence of extramedullary disease following CR. Refractory disease: Failure to have CR or incomplete remission (CRi) at the end of induction therapy. Intolerance refers to ≥ grade 3 non-hematological toxicity or ≥ grade 4 hematological toxicity in subjects which is at least possibly related to the last TKI treatment, lasts for \> 2 weeks, and leads to TKI withdrawal.
- •Informed consent of parents or legal guardians should be obtained before any study activities.
- •For patients \>16 years of age, Karnofsky performance status score ≥ 50; for patients ≤ 16 years of age, Lansky performance status score ≥
- •Life expectancy of ≥ 3 months.
- •For female patients of childbearing potential, urine β-HCG is negative.
- •The following laboratory values must be met (reference ranges based on age and gender of children):
- •Estimated glomerular filtration rate (eGFR) or radioisotope glomerular filtration rate (GFR) ≥70 mL/min/1.73 m2 based on Schwartz formula, or normal serum creatinine determined based on age and gender
Exclusion Criteria
- •The subject who meets any of the following criteria cannot be enrolled in this study:
- •Any AEs (excluding alopecia and pigmentation) that are due to other anti-tumor therapies have not recovered to CTCAE v5.0 grade 0 -
- •Gastrointestinal dysfunction or gastrointestinal diseases that may significantly alter absorption of study drug.
- •Uncontrollable or serious cardiovascular diseases.
- •Subjects with symptomatic CNS disorder (e.g., convulsion caused by CNS disorder).
- •Patients who have significant bleeding unrelated to Ph+ ALL.
- •Patients who are known to have hypersensitivity to any component of the study drug.
- •Patients with uncontrolled systemic infection, or there is laboratory or clinical evidence for infection with active human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or SARS-CoV-
- •Vaccination with attenuated live vaccines within 28 days prior to study treatment.
- •Patients who have any conditions that, in the opinion of the investigator, would jeopardize the patient safety or interfere with the evaluation of safety and efficacy of the study drug.
Arms & Interventions
Olverembatinib + APG-2575 combinational therapy
* Period 1: Olverembatinib alone period (2 weeks): * Period 2: olverembatinib in combination with APG-2575 and dexamethasone (4 weeks):
Intervention: Olverembatinib, APG-2575, Dexamethasone
Outcomes
Primary Outcomes
Area under the plasma concentration versus time curve (AUC)
Time Frame: 42 days
Area under the plasma concentration versus time curve (AUC) will be assessed on all participantsof each dose group on the first day of olverembatinib monotherapy in period 1, and on the first and last days of olverembatinib in combination with APG-2575 in period 2 .
R2PD of Olverembatinib and APG-2575
Time Frame: 42 days
To confirm the recommended doses of olverembatinib and APG-2575 in children with Ph+ ALL
Dose-limiting toxicity (DLT)
Time Frame: 42 days
DLT evaluation is defined as adverse events or laboratory abnormalities that occur within 6 weeks after investigational drug administration, are unrelated to external causes such as progressive disease, concomitant disease, and concomitant medications, including hematologic and non-hematologic adverse events (grade according to NCI CTCAE 5.0).
Objective Response Rate (ORR)
Time Frame: 132 days
ORR is defined by Complete Remission (CR)+ CR with incomplete marrow recovery (CRi) + Partial Remission (PR).Response will be evaluated every period till complete treatment and three months after last dose.
Maximum plasma concentration (Cmax)
Time Frame: 42 days
Maximum plasma concentration (Cmax) will be assessed on all participants of each dose group on the first day of olverembatinib monotherapy in period 1, and on the first and last days of olverembatinib in combination with APG-2575 in period 2 .
Secondary Outcomes
- Minimal Residual Disease (MRD) negative rate(132 days)