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Cytarabine

Mitoxantrone

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Sorafenib

Cladribine

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Enzyme Inhibitors

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Antibiotics, Antitubercular

The patients in this arm will receive SCCLG-M5 2022 regimen for newly dignosed acute monocytic leukemia (M5) ,including two courses of CLAG(cladribine, darubicin and cytarabine) in the induction period and followed by three courses(HA1M, HA2E, HA3) in consolidation therapy prescribed as the NOPHO-AML 2004 protocol.

The targeted drugs sorafenib 200mg/m2/day orally is used for FLT3 positive acute monocytic leukemia until molecular biology remission for 2 years.

5mg/㎡/day d1-5 in 2 hours, before the use of Cytarabine

5ug/kg/day d0-5,if Peripheral blood leukocytes\<20,000/ul

G-CSF

2g/㎡/day d1-5 in 4 hours, after the use of Cladribine

Idarubicin 10mg/m2/day or mitoxantrone 10mg/m2/day on day 1-3 in the induction therapy II

200mg/m2/day was taken orally until molecular biology remission for 2 years

dunhua zhou, M.D

riling chen, M.D

lina wang, M.D

yawei zhou, M.D

huiqin chen, M.D

lihua yang, M.D

beiyan wu, M.D

wuqing wan

changda liang, M.D

qiwen chen, M.D

dunha zhou, M.D

This is a multicenter, single arm, prospective, intervention trial. Since cladribine can enhance the biological activity and self-protection of cytarabine, giving cladribine and cytarabine together may kill more cancer cells. 10 centers from South China Childhood Leukaemia Collaborative Group carry out the SCCLG-M5-2022 regimen including two courses of CLAG(cladribine, darubicin and cytarabine) in the induction period for the treatment of newly dignosed acute monocytic leukemia (M5). The targeted drugs sorafenib is used for FLT3 positive acute monocytic leukemia to inhibit the serine / threonine kinase activity of FLT3.

PRIMARY OBJECTIVES

1.To study the 3 year-overall survival of newly diagnosed monocytic leukemia treated with Cladribine and cytarabine in children.

SECONDARY OBJECTIVES

1. To describe the complete response rate following CLAG (cladribine, cytarabine and granulocyte stimulating factor) in newly diagnosed monocytic leukemia in children for intensive induction therapy.
2. To evaluate the 3-year progression-free survival in response to CLAG in children.
3. To assess the toxicity of CLAG including cumulative infection incidence, cumulative adverse effects and chemotherapy-related mortality (TRD).
4. To study the progression-free survival and overall survival (1 year, 2 year and 3 year) of newly diagnosed monocytic leukemia with positive FLT3 treated with CLAG in children and the side effects of sorafenib.

OUTLINE:

1. The induction phase includes two parts including induction therapy I(CLAG) and induction therpay II(CLAG+I/M).
2. The diagnosis and classified criteria is according to the 2016 WHO classification criteria for hematopoietic and lymphoid tissue tumors, and the consolidation therapy consists the therapeutic phases as the NOPHO-AML 2004 protocol prescribed.

   INDUCTION THERAPY I: Patients receive cladribine intravenously (IV) at a dose of 5mg/m2/day combined with cytarabine 2g/m2/day on day 1-5 and granulocyte stimulating factor 5ug/kg/day on day 0-6. When blood count recover(WBC\>2.0×109/L， ANC1.0×109/L、PLT≥50×109/L) , Patients achieving a morphological leukemia free state (\< 5% blasts) or MRD\< 1% receive a second course treatment as above.

   INDUCTION THERPAY II: Patients receive cladribine intravenously (IV) at a dose of 5mg/m2/day combined with cytarabine 2g/m2/day on day 1-5, mitoxantrone/idarubicin 10mg/m2/day on day 1-3 and granulocyte stimulating factor 5ug/kg/day on day 0-6. Patients achieving blast count≥5% or MRD ≥1% proceed to induction II therpy.
3. For FLT3 positive acute monocytic leukemia children, sorafenib 200mg/m2/day was taken orally until molecular biology remission for 2 years.
4. After two courses of indution phase, patients with incomplete response（MRD≥0.1%）are recommended into hematopoietic stem cell transplantation.
5. After two courses of indution phase, patients with persisting positive adverse prognosis cytogenetic abnormalities are recommended into hematopoietic stem cell transplantation.

Patients must meet one of the following risk criteria:

Standard-risk (SR) group meeting all of the following criteria:

Initial WBC \< 10,000/μL

M1 (\<5%) blasts or MRD\<1% in bone marrow after the first course of induction therapy

M1 (\<5%) blasts or MRD\<0.1% in bone marrow after two courses of induction therapy

Cytogenetic abnormalities with good prognosis

Intermediate-risk (IR) group meeting the following criteria:

Lack of low-risk and high-risk conditions

High-risk (HR) group meeting ≥ 1 of the following criteria:

M2/M3(≥5%) blasts or MRD\>5% in bone marrow after the first course of induction therapy

MRD≥0.1% in bone marrow after two course of induction therapy

Cytogenetic abnormalities with poor prognosis

Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children

Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children： A Prospective Multicenter Study in South China

TOS was defined as time from diagnostic date through the date of death due to any reasons. For all other participants, the last follow-up available was taken as the last control. If the participant had not completed the study, the date of the last visit available was considered.

According to the time point specified in the treatment plan (22 days after the end of induction I, 29-43 days after the end of induction II and before each consolidation scheme) bone marrow puncture and lumbar puncture were performed. The follow-up contents included the detection of the count of primitive / immature lymphocytes and flow MRD. If there was a positive gene at the onset, the quantitative monitoring of the gene should be performed as MRD data at the same time. If the gene cannot be analyzed quantitatively, PCR qualitative analysis should still be performed as the monitoring basis

During treatment, closely monitor relevant laboratory tests, register adverse reaction records, and report the records according to the requirements of CRF form.

EFS was estimated from date of diagnosis until date of one of the following events: relapse, refractory disease, second malignancy or death from any reason.

Third Affiliated Hospital, Sun Yat-Sen University

Maternal and Child Health Hospital of Foshan

The First Affiliated Hospital of Guangzhou Medical University

Second Xiangya Hospital of Central South University

Jiangxi Province Children's Hospital

Southern Medical University, China

The First Affiliated Hospital of Nanchang University

Guangzhou First People's Hospital

First Affiliated Hospital of Shantou University Medical College

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Childhood Acute Lymphoblastic Leukemia

Amino Acids

BCT-100

Arginine

PEG- BCT-100 in patients with Leukaemia Starting dose 1600U/Kg IV infusion weekly

PEG- BCT-100 in patients with Neuroblastoma Starting dose 1600U/Kg IV infusion weekly

PEG- BCT-100 in patients with Sarcomas Starting dose 1600U/Kg IV infusion weekly

PEG- BCT-100 in patients with High Grade Gliomas Starting dose 1600U/Kg IV infusion weekly

PEG- BCT-100

Francis J Mussai, DPhil

PARC is an international phase I/II trial evaluating the safety and activity of pegylated recombinant human arginase (BCT-100) in children and young people with relapsed/refractory leukaemia, neuroblastoma, sarcoma and high grade gliomas (brain cancers).

Currently the outcomes for these patients are poor and the therapeutic options are limited with a significant toxicity burden. Therefore new treatments which work in different ways to standard chemotherapy are urgently needed. Research has shown that arginine (a nutrient) is important in the survival of cancer cells. BCT-100 is a drug which can deplete arginine levels and starve cancer cells - a completely new approach. BCT-100 has been tested in adults and shown to be active with almost no side-effects. This trial will test whether this dose of BCT-100 is also safe and active in children with relapsed/refractory leukaemia, neuroblastoma, sarcoma and high grade glioma. The trial will also study how BCT-100 is broken down in the body and look for new biological markers of treatment response. Up to 64 children with relapsed cancers will be recruited over 2 years.

A Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100)

A Phase I/II Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100) in Relapsed/Refractory Cancers of Children and Young Adults

Safety profile as measured by the occurrence/non-occurrence of DLT within 28 days of treatment with BCT-100.

o Optimal dose as measured by the complete depletion of arginine. This is defined as AAD \<8μM arginine in the blood after 3 doses of BCT-100.

Disease response (Complete Response (CR) or Partial Response (PR)) after 8 weeks of treatment with BCT-100

Incidence and severity of Adverse Events (AEs) defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4

Disease response ( CR / PR) according to Cheson criteria

Disease response ( CR / PR) according to RECIST criteria

Disease response ( CR / PR) according to RANO criteria

Disease response ( CR / PR) according to INCR criteria

BCT-100 concentration in cerebrospinal fluid

University of Birmingham

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Antirheumatic Agents

Anti-Inflammatory Agents

Cyclophosphamide

Prednisone

Vincristine

Thioguanine

Conventional consolidation (CONS) (active comparator) (6-thioguanine 60 mg/m2/d, on days 1 to 43 orally; prednisone 40 mg/m2/d, on days 1 to 28 orally; vincristine 1.5 mg/m2/d, on days 1, 8, 15, 22; idarubicin 7 mg/m2/d, on days 1, 8, 15, 22; cytarabine 75 mg/m2/d, on days 3-6, 10-13, 17-20, 24-27, 31-34, 38-41; intrathecal cytarabine on days 1, 15, 29, 43 \[age-dependent dose\]; cyclophosphamide 500 mg/m2/d, on days 29, 43)

Block Therapy: AI block (randomized; cytarabine 500 mg/m2 as continuous infusion ×4 days and idarubicin 7 mg/m2 on days 3 and 5; intrathecal cytarabine on days 0 and 6), haM block (high-dose cytarabine 1 g/m2 every 12 hours for 3 days and mitoxantrone 10 mg/m2 on days 4 and 5, intrathecal cytarabine days 6 and 15)

Consolidation 6-thioguanine 60 mg/m2/d, 1 to 43 po; prednisone 40 mg/m2/d, on days 1-28 orally; vincristine 1.5 mg/m2/d, days 1, 8, 15, 22; idarubicin 7 mg/m2/d, on days 1, 8, 15, 22; cytarabine 75 mg/m2/d, on days 3-6, 10-13, 17-20, 24-27, 31-34, 38-41; intrathecal cytarabine on days 1, 15, 29, 43; cyclophosphamide 500 mg/m2/d, days 29, 43.

ARM A: Active Comparator Drug

Blocks AI Cytarabine 500 mg/m2 as 24 infusion infusion x 4 d; Idarubicin 7 mg/m2 on days 3 and 5; Intrathecal cytarabine on days 0 and 6.

haM Cytarabine 1 g/m2 every 12 hours for 3 days; Mitoxantrone 10 mg/m2 days 4 and 5; Intrathecal cytarabine days 6 and 15.

ARM B: Blocks Therapy Drug

Alcyra Fynn, Dr.

GATLA 8-AML´07 trial is an multicenter phase III dose-optimization trial for the treatment of acute myeloid leukemias in children and adolescents. Patients are treated with a combination of intensive chemotherapy in combination with intrathecal-injection by CNS and haematopoietic stem cell transplantation.

The patients are stratified in a standard-group (SR) and a high risk-group (HR). SR was defined as FAB (French-American-British) M1/M2 with Auer rods; FAB M4eo or favorable cytogenetics \[t(8;21)/AML1-ETO or inv(16) or t(16;16) and/or CBFB/MYH11)\]; bone marrow blasts ≤5% on day 15. HR was defined as all others. SR patients were reclassified to the HR group if FLT3-ITD positive.

Based on the experience of the BFM group, it was decided to randomly evaluate whether the six-drug conventional consolidation stage can be replaced with the use of a consolidation based by block therapy on drugs of proven efficacy in AML with the aim of reducing residual disease, and the toxicity of this stage. Patients are randomized once the double induction is completed into those who will receive the conventional consolidation phase and those who will receive consolidation with the combination of high doses cytarabine and two different anthracyclines sequentially.

All patients in the trial, whether standard risk (SR) or high risk (HR), receive 2 Induction courses: AIE and HAM and then are randomized to continue with the consolidation phase: a conventional consolidation (Arm A) with 6 drugs vs 2 blocks of chemotherapy that are incorporated in this protocol (AI and haM) (Arm B) and then an Intensification phase with high doses of cytarabine and etoposide. The difference between the SR and AR groups is that the former don't continue with the maintenance phase, while those in HR receive 1 year of Maintenance if they don't have a histoidentical family donor. SR patients according to cytogenetics and with \< 5% blasts in the bone marrow on day 15, haven´t indication for TCHP in 1st CR. HR patients, with a histoidentical family donor, will be transplanted in the 1st. CR after the Consolidation phases or the AI and haM blocks, according to the treatment arm that corresponded to them by randomization

It is a randomized model, the evaluation is based on event time (overall survival, event free survival, cumulative incidence relapse with treatment related mortality as competitive event). Comparator log rank test.

Comparison of Consolidation Strategies for Pediatric Patients With Acute Myeloid Leukemia

Comparison of Consolidation Strategies for Pediatric Patients With Acute Myeloid Leukemia - Results of the Randomized GATLA 8-LMA-P'07 Trial

The GATLA 8-LMA-P'07 was a randomized trial including pediatric AML children in Argentina; the design was based on AML-BFM 98 with minor modifications.(10) Similar to AML-BFM 98, the trial compared two approaches to consolidation. The standard regimen was a 6-week consolidation phase (CONS), which was also used in AML-BFM 93 vs. the comparator regimen of two short chemotherapy cycles (two-cycle) with cytarabine plus idarubicin (AI) and high dose cytarabine plus mitoxantrone (haM). AML-BFM 98 previously demonstrated that haM was tolerable.10 We hypothesized that the two-cycle consolidation (two-cycle) would be associated with lower relapse rates related to dose intensification compared to the standard CONS approach.

EFS was calculated from date of randomization to first event (death, resistant leukemia, relapse or secondary malignancy) or date of last follow-up.

OS was also calculated from date of randomization to date of death or date of last follow-up.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children	NCT05313958	Leukemia, Monoc... Pediatric AML	Cladribine G-CSF Cytarabine Idarubicin Mitoxantrone Sorafenib	1 Month - 14 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
A Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100)	NCT03455140	Cancer Pediatric Solid... Pediatric AML Pediatric ALL	PEG- BCT-100	1 Year - 25 Years	University of Birmingham
Comparison of Consolidation Strategies for Pediatric Patients With Acute Myeloid Leukemia	NCT06211452	AML Pediatric AML	ARM A: Active C... ARM B: Blocks T...	- 18 Years	Grupo Argentino de Tratamiento de la Leucemia Aguda
Treateament of Newly Diagnosed Acute Monocytic Leukemia in Children	NCT05313958	Leukemia, Monoc... Pediatric AML	Cladribine G-CSF Cytarabine Idarubicin Mitoxantrone Sorafenib	1 Month - 14 Years	Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
A Study Evaluating the Safety and Activity of Pegylated Recombinant Human Arginase (BCT-100)	NCT03455140	Cancer Pediatric Solid... Pediatric AML Pediatric ALL	PEG- BCT-100	1 Year - 25 Years	University of Birmingham

Spots Global Cancer Trial Database for pediatric aml