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.
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.
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 ≥ 50.
Any AEs (excluding alopecia and pigmentation) that are due to other anti-tumor therapies have not recovered to CTCAE v5.0 grade 0 - 1.
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).
Single group
Olverembatinib, APG-2575, Dexamethasone
Drug* Period 1: Subjects will orally take olverembatinib 40mg adult equivalent dose alone QOD from Day 1 to Day 14 (D1 - D14) =. The investigator may start the combination therapy in advance based on medical conditions of the subjects, but not earlier than Day 5/the third dose (D5). * Period 2: 1) Subjects will orally take olverembatinib 40mg adult equivalent dose QOD from Day 15 to Day 42 (D15 - D42)). 2\) Subjects will orally take APG-2575 at a ramp up 200mg/400mg/600mg adult equivalent dos QD from D13 to D42 at a dose . In addition, a 3-day dose escalation from D13 to D15 will be needed, and the designated reference dose will be reached on D15. 3\) Subjects will orally take dexamethasone 6 mg/m2/day, QD from D15 to D42 at 6 mg/m2/day.
Dose-limiting toxicity (DLT)
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)
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)
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 .
Area under the plasma concentration versus time curve (AUC)
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 .
Minimal Residual Disease (MRD) negative rate
To observe the proportion of subjects with MRD negative status in bone marrow.
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