Study for Safety and Efficacy of Olverembatinib Combined With APG-2575 in Children With Relapsed/Refractory Ph + ALL

NCT05495035 | Unknown Phase 1

• 1 other identifier: HQP1351ACE01
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 4

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.

Conditions

Lymphoblastic Leukemia, Acute, Childhood; Leukemia, Lymphoblastic, Acute, Philadelphia-Positive; Relapsed Leukemia; Refractory Leukemia

Outcome Measures

Primary Outcomes (5)

• 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).

  42 days

• 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.

  132 days

• 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 .

  42 days

• 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 .

  42 days

• R2PD of Olverembatinib and APG-2575

  To confirm the recommended doses of olverembatinib and APG-2575 in children with Ph+ ALL

  42 days

Secondary Outcomes (1)

• Minimal Residual Disease (MRD) negative rate

  132 days

Study Arms (1)

Olverembatinib + APG-2575 combinational therapy

EXPERIMENTAL

* Period 1: Olverembatinib alone period (2 weeks): * Period 2: olverembatinib in combination with APG-2575 and dexamethasone (4 weeks):

Drug: Olverembatinib, APG-2575, Dexamethasone

Interventions

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.

Olverembatinib + APG-2575 combinational therapy

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 ≥ 50.
• 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
• Serum albumin ≥ 3.0 g/dL
• Total bilirubin \< 1.5 × upper limit of normal (ULN)
• ALT and AST \< 5 × ULN
• Serum amylase and lipase ≤ 2 × ULN
• Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN

You may not qualify if:

• 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 - 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).
• 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-2.
• 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.

Sponsors & Collaborators

• Institute of Hematology & Blood Diseases Hospital, China: lead

Study Sites (4)

The Second Affiliated Hospital of Anhui Medical University

Hefei, Anhui, China

NOT YET RECRUITING

Qilu Hospital of Shandong University

Jinan, Shandong, China

NOT YET RECRUITING

Department of Pediatrics, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences

Tianjin, Tianjin Municipality, 300020, China

RECRUITING

Department of Hematology/Oncology, Shanghai Jiaotong University School of Medicine Affiliated Shanghai Children's Medical Center

Shanghai, China

NOT YET RECRUITING

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia

Interventions

olverembatinib; Lisaftoclax; Dexamethasone

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Xiaofan Zhu, MD

  Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jingliao Zhang, MD

CONTACT

+86 22 23909196; zhangjingliao@ihcams.ac.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 8, 2022
• First Posted: August 10, 2022
• Study Start: September 1, 2022
• Primary Completion: August 31, 2024
• Study Completion: December 1, 2024
• Last Updated: March 2, 2023

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (4)