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Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

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Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

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Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

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Micronutrients

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Cytarabine

Epinephrine

Methotrexate

Prednisone

Daunorubicin

Pegaspargase

Asparaginase

Racepinephrine

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Consolidation therapy with cranial irradiation in intermediate risk group patients

Consolidation therapy with additional triple intrathecal therapy (N6) and without cranial irradiation in intermediate risk group patients

Consolidation therapy with High-dose Methotrexate 2,000 mg/m2/24 h i.v. biweekly in intermediate risk group patients

Consolidation therapy with Low-dose Methotrexate 30 mg/m2 i.m. weekly in intermediate risk group patients

Consolidation therapy with PEG-L-asparaginase cons 1,000 U/m2 biweekly in standard risk group patients

Consolidation therapy with E.coli L-asparaginase 5,000 U/m2 weekly in standard risk group patients

Induction therapy without PEG-L-asparaginase and with Daunorubicin 45 mg/m2 in standard and intermediate risk group patients

Induction therapy with PEG-L-asparaginase ind (1,000 U/m2 on day 3 of therapy)and daunorubicin 45 mg/m2 in standard and intermediate risk group patients

Induction therapy with PEG-L-asparaginase ind (1,000 U/m2 on day 3 of therapy) without daunorubicin on day 8 in standard risk group patients

1,000 U/m2 on day 3 of induction therapy, intravenously, in 200 ml of saline, during 1 hour

PEG-L-asparaginase ind

1,000 U/m2 intravenously, in 200 ml of saline, during 1 hour, 24 hours after methotrexate on weeks 7, 9, and 11 - days 44, 58, and 72 (phase S1), weeks 15, 17, and 19 - days 100, 114, 128 (phase S2), weeks 23, 25, and 27 - days 156, 170, 184 (phase S3).

PEG-L-asparaginase cons

E.coli L-asparaginase (asparaginase medac) 5,000 U/m2 intramuscularly weekly, 24 hours after methotrexate dose, from week 7 to week 12 - days 44, 51, 58. 65, 72, 79 (phase S1), from week 15 to week 20 - days 100, 107, 114, 121, 128, 135 (phase S2), from week 23 to week 28 - days 156, 163, 170, 177, 184, 191 (phase S3).

E.coli L-asparaginase

2,000 mg/m2 per 24 hours is given at days 43, 57, and 71 (weeks 7, 9, and 11). 1/5 of the total dose is given as slow intravenous bolus over 3-5 minutes. 4/5 of the total dose of methotrexate is injected as continuous 24 hours infusion.

High-dose Methotrexate

30 mg/м2 is given intramuscularly 1 time weekly - days 43, 50, 57, 64, 71, and 78 (weeks 7, 8, 9, 10, 11, and 12).

Low-dose Methotrexate

Intrathecal injection of 3 drugs is additionally given three times during phase S-2 (weeks 15, 17, and 19 - days 99, 113, and 127), and three times during phase S-3 (weeks 23, 25, and 27 - days 155, 169, and 183).

Triple intrathecal therapy

12 Gy cranial irradiation is conducted at weeks 31-32 of the Protocol in patients \>3 years of age

Cranial irradiation

Daunorubicin at a dose of 45 mg/m2 i.v. for 6 hours on day 8 of induction therapy

Alexander I. Karachunskiy, Professor

QUESTIONS AND OBJECTIVES OF ALL-MB-2008 STUDY

1. Whether the early PEG-asparaginase in induction will lead to the earlier achievement of remission, improvement of days 8 and 15 responses leading to an earlier reconstitution of bone marrow and immunocompetence, decrease of severe infections and early mortality rate?
2. Whether the use of PEG-asparaginase in induction will allow to avoid the anthracyclines in standard risk group patients and to reduce treatment myelotoxicity?
3. Whether the administration of 9 doses of PEG-asparaginase 1,000 U/m2 instead of 18 doses of E.coli L-asparaginase 5,000 U/m2 in standard risk patients will improve treatment outcome?
4. Whether the administrations of high dose methotrexate (2 g/m2 in 24 hours) during 1-st consolidation in intermediate risk patients will result in decrease of central nervous system relapse incidence and improvement of event-free and overall survival? Whether the increase of 6-mercaptopurine starting dose up to 50 mg/m2 in 1-st consolidation phase (instead of 25 mg/m2) will decrease in relapse risk, but would not be accompanied with enhanced toxicity?
5. Is it possible to completely avoid the cranial irradiation in intermediate risk patients? In some subgroup of intermediate risk patients? Is it enough to control neuroleukemia in these patients to introduce additional TIT in the consolidation phase of treatment? How will change the possible late effects in these patients according to the third arm of randomization?
6. Will the new risk group stratification to improve overall and event-free survival?

Childhood Acute Lymphoblastic Leukemia Treatment Protocol Moscow-Berlin 2008

Moscow-Berlin 2008 Multicenter Randomised Study for Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents

Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Deputy director of Research Institute of Pediatric Hematology, Oncology and Immunology

Hypersensitivity

Antiemetics

Gastrointestinal Agents

Cardiotonic Agents

Dexamethasone

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Doxorubicin

Liposomal doxorubicin

Vincristine

Dexamethasone acetate

BB 1101

Dexrazoxane

Razoxane

Dexamethasone 21-phosphate

HIV Protease Inhibitors

Protease Inhibitors

Tubulin Modulators

Antimitotic Agents

Protective Agents

All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22.

The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses.

Erwinase will be administered as a 2-hour intravenous infusion.

Erwinase

1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22

10 mg/m2/day divided BID. Give by mouth days 1-14.

Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3 and older

Given Intrathecally to all patients who are CNS 1 or 2 at study entry. Dose defined by age. Given on day 15 8mg for age 1-1.99 10 mg for age 2-2.99 12 mg for age 3-8.99 15 mg for age 9 and older

Methotrexate, Cytarabine and Hydrocortisone given Intrathecally on day 8, 15 and 22 for patients who are CNS 3 at study entry. Doses determined by age.

Triple Intrathecal Therapy

Due to the limited availability of Dexrazoxane (Zinecard®), treatment will be at the discretion of the treating physician. Dose should be 600 mg/m2 as a IV push immediately prior to anthracycline dose (the elapsed time from the beginning of the dexrazoxane dose to the end of the anthracycline infusion should be 30 minutes or less).

Heather Grossman, MD

Paul Gaynon, MD

This is a phase I study using the Erwinia form of asparaginase in place of the E. coli form using a standard re-induction regimen (Vincristine, Dexamethasone, Doxorubicin) for patients with relapsed ALL who have developed an allergy to the E. coli formulation. This study will administer the drug intravenously instead of the usual intramuscular route. The dose of Erwinia will be escalated in the absence of dose limiting toxicity. Patients must have first or second relapse ALL with a history of prior systemic reaction to E. coli asparaginase.

Significance

1. Substitution of Erwinase after E.coli asparaginase allergy has been standard practice despite the paucity of evidence regarding its efficacy and uncertainty about dose. Definition of an appropriate dose and schedule of Erwinase that provides reliable asparagine depletion may be useful for patients with clinical allergy to E. coli asparaginase, both in first remission or after relapse.
2. Patients in relapse may have a different level of asparagine synthesis than patients maintaining remission and require different asparaginase dosing.5
3. Intravenous administration provides more rapid and predictable asparagine depletion with less discomfort and danger of bleeding for often thrombocytopenic patients than intramuscular administration.
4. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically relevant for a population with first marrow relapse.
5. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically relevant for a population with second marrow relapse, if the duration of CR2 \> 18 months year.

Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) (IND 104224)

Intravenous Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia and Allergy to E. Coli Asparaginase (IND 104224)

The MTD in each stratum will be the highest dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.

Disease response evaluated by examination and labs. MRD evaluated from marrow samples.

Activity levels assessed from PK sampling

Therapeutic Advances in Childhood Leukemia Consortium

The definition of AE and SAE do not differ from the clinicaltrials.gov definitions.

All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22.

Erwinase: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses.

Erwinase will be administered as a 2-hour intravenous infusion.

Vincristine: 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22

Dexamethasone: 10 mg/m2/day divided BID. Give by mouth days 1-14.

Doxorubicin: 60 mg/m2/day IV over 15 minutes on day 1

Cytarabine: Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3

Single Arm

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The study closed early due to lack of accrual and insufficient funding. Only one patient was enrolled. This patient completed the protocol therapy.

Peggy Romano, BA, CCRP

Occurrence of a Dose-Limiting Toxicity

Study closed early due to lack of accrual, and insufficient data were collected for performing this analysis.

Response Rate and Minimum Residual Disease

Study closed early due to lack of accrual and insufficient data were collected to perform this analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Childhood Acute Lymphoblastic Leukemia Treatment Protocol Moscow-Berlin 2008	NCT01953770	Childhood Acute...	PEG-L-asparagin... PEG-L-asparagin... E.coli L-aspara... High-dose Metho... Low-dose Methot... Triple intrathe... Cranial irradia... Daunorubicin	1 Year - 18 Years	Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) (IND 104224)	NCT00928200	Relapsed Acute ... Allergy to PEG ... Allergy to Nati...	Erwinase Vincristine Dexamethasone Doxorubicin Cytarabine Methotrexate Triple Intrathe... Dexrazoxane	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

Spots Global Cancer Trial Database for triple intrathecal therapy