CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children

NCT04224571 | Completed Phase 2 DMC

• 1 other identifier: HKCH-REC-2019-006
• Study Type: interventional
• Target: 208
• Locations: 1 country
• Sites: 1

Brief Summary

Relapsed acute lymphoblastic leukaemia (ALL) has a poorer outcome than newly diagnosed ALL patients with only about 40% overall survival after re-treatment. The study CCCG Relapsed ALL 2017 study will adopt the UK R3 study stratification and treatment backbone with two new agents added. There will be a 4-week induction, followed by two consolidation courses. High-risk patients will receive allogeneic stem cell transplant. While intermediate and standard risk groups will continue maintenance treatment for another 2 years or one year. New agents will be added aiming at improving survival outcome.

1. 1.Study of adding anti-CD20 antibody (rituximab) with chemotherapy: CD20 is found to be expressed in 40-50% of B-lineage ALL, and rituximab has been studied in adult ALL with superior survival (75% vs 47%,). There is little experience of using rituximab in pediatric ALL thus a CCCG Relapsed ALL 2017 Study will perform the study assessing the remission rate and MRD response of CD20+ ALL treated with rituximab. Six doses of rituximab and will be monitored the week 5 MRD and relapse rate as study outcome.
2. 2.Adding bortezomid during the induction: The very early or early bone marrow relapse has low remission rate. Previous case studies showed that Bortezomib, a proteasome inhibitor, may achieve remission in refractory ALL, 80% remission in B-ALL with combination of chemotherapy and bortezomib. Thus adding bortezomib, may improve the remission rate, thus bridging to allogeneic stem cell transplant. Adding bortezomib in the relapsed chemotherapy protocol may increase the toxicity and even treatment related mortality. In this protocol, we suggested to add during the induction therapy.

Conditions

Acute Lymphoblastic Leukemia, in Relapse

Keywords

Relapsed ALL

Outcome Measures

Primary Outcomes (1)

• remission rate

  bone marrow blast count \< 5% and MRD \<0.01%

  week 5 MRD and relapse rate

Secondary Outcomes (2)

• event-free survival rates

  2-year

• overall survival

  5 years

Study Arms (1)

rituximab and bortezomib

EXPERIMENTAL

to test whether adding rituximab in CD20 positive patients will have improvement in remission rate. (this arm terminated in October 2020) to add bortezomib in high risk patients at Induction to improve remission rate.

Drug: Bortezomib Injection; Drug: rituximab injection

Interventions

Bortezomib Injection DRUG

Bortezomib: patients with BM relapsed, add for 4 doses on D1,4,7, 11 in induction; dosage 1.3 mg/m2/dose as per parenteral;

Also known as: Velcade

rituximab and bortezomib

rituximab injection DRUG

Add rituximab in patients with CD20 positive ALL, rituximab: 6 doses of on D8,11of induction, D1,15 of consolidation1 and 2 with dosage 375 mg/m2 as parenteral (Terminated in Oct 2020)

Also known as: Mab Thera

rituximab and bortezomib

Eligibility Criteria

• Age: 3 Months - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age at relapse less than 21 years and the age at initial diagnosis of ALL of Pre-B or T-lineage less than 18 years.
• Confirmed diagnosis of relapse of leukemia according to definition as below:
• Definitions of Relapse
• RELAPSE: Any recurrence of disease whether in marrow or extramedullary.
• (1) ISOLATED Bone Marrow Relapse: Patients with an M3 marrow (\>25% blast) at any point after achieving remission without involvement of the CNS and/or testicles and/or other extramedullary sites. Relapsed should be confirmed by morphology, flow cytometry, FISH and/or cytogenetics. M2 marrow should have a repeat of bone marrow in 1-2 weeks to confirm M3 status unless the original cytogenetic clone reappears.
• (2) CNS Relapse: Positive cytomorphology and WBC ≥ 5/μL OR clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome that are compatible with recurrent CNS leukemia than to alternative causes (e.g., viral infection with facial nerve palsy or chemotherapy toxicity). If any CSF evaluation shows positive cytomorphology and WBC \< 5/μL, a second CSF evaluation is recommended within 2 - 4 weeks. While identification of a leukemic clone in CSF by flow cytometry (TdT, CD19, CD10, etc.) or FISH for diagnostic karyotypic abnormality may be useful, definitive evidence of CNS involvement (i.e. WBC ≥ 5/μL OR clinical signs of CNS leukemia) is required for the diagnosis of a CNS relapse.
• (3) TESTICULAR Relapse: Must be documented by testicular biopsy, if not associated with a marrow relapse.
• (4) ISOLATED Extramedullary (IEM) relapse: CNS and/or testicular relapse and/or other extramedullary sites such as skin with an M1 marrow. The presence of MRD in the bone marrow does NOT exclude IEM.
• (5) COMBINED Relapse: M2 or M3 marrow at any time after achieving remission with concomitant CNS and/or testicular relapse.
• CNS Status:
• CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless of the number of white blood cells (WBCs).
• CNS 2: In CSF, presence \< 5/μL WBCs and cytospin positive for blasts, or ≥ 5/μL WBCs but negative by Steinherz/Bleyer algorithm:
• CNS 2a: \< 10/μL RBCs; \< 5/μL WBCs and cytospin positive for blasts; CNS 2b: ≥ 10/μL RBCs; \< 5/μL WBCs and cytospin positive for blasts; and CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm (see below).
• CNS3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or clinical signs of CNS leukemia:
• CNS 3a: \< 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer algorithm (see below); CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome).

You may not qualify if:

• Mature B ALL,
• Poor Karnosky score

Sponsors & Collaborators

• Chinese University of Hong Kong: lead
• Shanghai Children's Medical Center: collaborator

Study Sites (1)

Hong Kong Children's Hospital

Hong Kong, 852, Hong Kong

Location

Related Publications (6)

• Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011 Feb 10;29(5):551-65. doi: 10.1200/JCO.2010.30.7405. Epub 2011 Jan 10.

  PMID: 21220611 BACKGROUND

• Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, Ebell W, Escherich G, Schrappe M, Klingebiel T, Fengler R, Henze G, von Stackelberg A. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010 May 10;28(14):2339-47. doi: 10.1200/JCO.2009.25.1983. Epub 2010 Apr 12.

  PMID: 20385996 BACKGROUND

• Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Revesz T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. doi: 10.1016/S0140-6736(10)62002-8. Epub 2010 Dec 3.

  PMID: 21131038 BACKGROUND

• Bertaina A, Vinti L, Strocchio L, Gaspari S, Caruso R, Algeri M, Coletti V, Gurnari C, Romano M, Cefalo MG, Girardi K, Trevisan V, Bertaina V, Merli P, Locatelli F. The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood. Br J Haematol. 2017 Feb;176(4):629-636. doi: 10.1111/bjh.14505. Epub 2017 Jan 24.

  PMID: 28116786 BACKGROUND

• Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, Hess U, Vey N, Pignon JM, Braun T, Marolleau JP, Cahn JY, Chalandon Y, Lheritier V, Beldjord K, Bene MC, Ifrah N, Dombret H; for GRAALL. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia. N Engl J Med. 2016 Sep 15;375(11):1044-53. doi: 10.1056/NEJMoa1605085.

  PMID: 27626518 BACKGROUND

• Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.

  PMID: 35622074 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Bortezomib; Rituximab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Chi Kong LI, Professor

  Chinese University of Hong Kong

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Prospective and Non-randomized controlled trial

Study Record Dates

• First Submitted: January 8, 2020
• First Posted: January 13, 2020
• Study Start: September 14, 2018
• Primary Completion: February 15, 2023
• Study Completion: February 15, 2023
• Last Updated: August 30, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

HK (1)