Newly-diagnosed Pediatric Ph-positive B-ALL Protocol

Official title

A Phase 3, Multicenter Trial for Pediatric Philadelphia Chromosome-positive B-Acute Lymphoblastic Leukemia -2025 Project

Overview

This prospective clinical trial evaluates the effectiveness and safety of "chemotherapy-light" regimen incorporating the third-generation TKI olverembatinib, the bi-specific CD3/CD19 T cell engager blinatumomab, and the BCL-2 selective inhibitor venetoclax for newly diagnosed pediatric/adolescent patients with Ph+ ALL. The CCCG-Ph+ B-ALL-2025 protocol will be modified as following compared to the CCCG-ALL-2020 protocol

Detailed description

1. All Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen. 2. OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol. 3. Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity. 4. All patients will receive two cycles of HDMTX+Blina-14 and 4 times of triple intrathecal therapy (TIT) throughout the consolidation 1 phase. 5. To decrease the toxicities of high-dose AraC, the dosage will be reduced to 1 g/m2 in the consolidation 2 phase in contrast to 2 g/m2 in 2020 protocol. 6. Throughout the early Maintenance Therapy, dexamethasone and vincristine combination will be added with either venetoclax or daunorubicin alternatively for five cycles, given after MTX and 6-MP. 7. Cyclophosphamide and asparaginase are totally omitted from the entire treatment to mitigate toxicities. 8. Olverembatinib concentrations are recommended to be examined (cerebrospinal fluid and peripheral blood in parallel) before OVB given, after full dosing of OVB, and/or Blina+OVB, best to match lumbar puncture assessments timepoints. 9. IgH rearrangement by NGS MRD will be added as an evaluation indicator, with testing frequency matching bone marrow aspiration assessments. 10. Pharmarcotyping studies are recommended at baseline if condition permits. 11. For patients who cannot use full-dose blinatumomab, we will adopt the CCCG-Ph+ALL2020 protocol. complications.

Interventions

• Drug olverembatinib
  All Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen. OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol. Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity. All patients will receive two cycles of HDMTX+Blina-14 and 4 times of tripl

Primary outcome measures

• Day 48 end-of-induction measurable residual diseases (MRD48) after induction remission with olverembatinib and blinatumomab, compared to MRD46 of those treated with dasatinib plus chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts . [Time frame: Up to approximately 4.5 years.]

Secondary outcome measures (4)

• Day 19 measurable residual diseases (MRD19) during induction remission with olverembatinib plus VP (VOP), compared to MRD19 of those treated with dasatinib plus 4-drug chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts [Time frame: Approximately 4.5 years.]
• Event-free survival (EFS) of patients treated with this therapy, in comparison to historical regimens. [Time frame: Approximately 7 years.]
• Overall survival (OS) of patients treated with this therapy, in comparison to historical regimens [Time frame: Approximately 7 years.]
• Cumulative incidence of relapse (CIR) of this therapy, in comparison to historical regimens. [Time frame: Approximately 7 years.]

Eligibility criteria

Inclusion criteria

Must meet all items below:

• Age older than 1 month to younger 18 years.
• Newly diagnosed Philadelphia chromosome-positive or BCR::ABL1-positive B-ALL.
• Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.

Exclusion criteria

Should be excluded if had any item below:

• ALL evolved from CML.
• Known underlying congenital immunodeficiency or metabolic disease.
• Congenital heart disease with cardiac insufficiency.
• Gastrointestinal dysfunction or gastrointestinal diseases that may significantly alter the absorption of study drug.
• Severe malnutrition, uncontrolled active infections, or serious cardiovascular diseases.
• Subjects with significant CNS disorder (e.g., uncontrolled seizure disorder, autoimmune disease involving CNS).
• Treated with glucocorticoids for ≥14 days, or targeted inhibitor for > 7 days within one month before enrollment, or any chemotherapy or any systemic anticancer therapy (including but not limited to any TKI) or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression).
• Any significant comorbidities or psychiatric disorders that may impact patient safety, compliance, informed consent, study participation, follow-up, or the interpretation of study results. In such cases, all participating sites must report directly to the PI to determine whether the patient meets exclusion criteria.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 23 centers

• Anhui Medical University Second Affiliated Hospita — Hefei
• Chongqing Medical University Affiliated Children's Hospital — Chongqing
• Fujian Medical University Union Hospital — Fuzhou
• Guangzhou Women and Children's Medical Center — Guangzhou
• Nanfang Hospital, Southern Medical University — Guangzhou
• The First Affiliated Hospital, Sun Yat-sen University — Guangzhou
• The Affiliated Hospital of Guizhou Medical University — Guiyang
• Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology — Wuhan
• … and 15 more centers

Hong Kong · 1 center

• Hong Kong Children's Hospital, The Chinese University of Hong Kong — Hong Kong

Publications

• Manabe A, Kawasaki H, Shimada H, Kato I, Kodama Y, Sato A, Matsumoto K, Kato K, Yabe H, Kudo K, Kato M, Saito T, Saito AM, Tsurusawa M, Horibe K. Imatinib use immediately before stem cell transplantation in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Results from Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph(+) ALL04. Cancer Med. 2015 May;4(5):6 PMID 25641907
• Hum RM, Deambrosis D, Lum SH, Davies E, Bonney D, Guiver M, Turner A, Wynn RF, Hiwarkar P. Molecular monitoring of adenovirus reactivation in faeces after haematopoietic stem-cell transplantation to predict systemic infection: a retrospective cohort study. Lancet Haematol. 2018 Sep;5(9):e422-e429. doi: 10.1016/S2352-3026(18)30130-3. PMID 30172346
• Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, Pieters R, Stary J, Escherich G, Campbell M, Li CK, Vora A, Arico M, Rottgers S, Saha V, Valsecchi MG. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012 Sep;13(9):936-45. PMID 22898679
• Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Zheng HW, Davies SM, Gaynon PS, Trigg M, Rutledge R, Jorstad D, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B; Children's Oncology Group. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia. 2014 PMID 24441288
• Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Wang C, Davies SM, Gaynon PS, Trigg M, Rutledge R, Burden L, Jorstad D, Carroll A, Heerema NA, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009 Nov 1;27(31):5 PMID 19805687
• Arico M, Schrappe M, Hunger SP, Carroll WL, Conter V, Galimberti S, Manabe A, Saha V, Baruchel A, Vettenranta K, Horibe K, Benoit Y, Pieters R, Escherich G, Silverman LB, Pui CH, Valsecchi MG. Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol. 2010 Nov 1;28(31):4755-61. doi: 10.1200/JCO.2010.3 PMID 20876426

Identifiers

NCT: NCT07152041 · IIT2025041

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗