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Single Agent Chemotherapy. TSPA or DTC101. 3-Drug Combination Chemotherapy plus Triple Intrathecal Therapy. DM/DNR/VCR; plus TIT. 2-Drug Combination Chemotherapy plus Triple Intrathecal Therapy. ARA-C/ASP; plus TIT. 4-Drug Combination Chemotherapy with Leucovorin Rescue plus Triple Intrathecal Therapy. CTX/MP/MTX/VP-16; with CF; plus TIT. 3-Drug Combination Chemotherapy plus Triple Intrathecal Therapy. DM/DNR/VCR; plus TIT. 6-Drug Combination Chemotherapy with Leucovorin Rescue plus Triple Intrathecal Therapy. ARA-C/ASP/CTX/MP/MTX/VP-16; with CF; plus TIT. Radiotherapy plus 3-Drug Combination Chemotherapy. Craniospinal irradiation using x-rays with energies of 4-6 MV (electrons acceptable for spinal cord irradiation); plus ASP/DM/VCR. 2-Drug Combination Chemotherapy Alternating with 2-Drug Combination Chemotherapy. MP/MTX; alternating with CTX/VCR.

filgrastim

asparaginase

cyclophosphamide

daunorubicin hydrochloride

dexamethasone

etoposide

leucovorin calcium

liposomal cytarabine

mercaptopurine

mesna

methotrexate

therapeutic hydrocortisone

thiotepa

vincristine sulfate

low-LET electron therapy

low-LET photon therapy

Julio C. Barredo, MD

Phase II trial to study the effectiveness of radiation therapy following chemotherapy in treating children with CNS relapse from acute lymphoblastic leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with radiation therapy may kill more cancer cells.

OBJECTIVES:

I. Determine the efficacy and toxicity of intensified systemic treatment with delayed central nervous system (CNS) irradiation in children with acute lymphoblastic leukemia and isolated CNS disease.

II. Determine the efficacy of systemic thiotepa in reducing or clearing blasts in the cerebrospinal fluid of these patients.

III. Evaluate the toxicity of single dose thiotepa followed by dexamethasone, vincristine, daunorubicin, and triple intrathecal therapy in these patients.

IV. Determine the response rate of intrathecal sustained release cytarabine (DTC101) in patients with first bone marrow remission with first isolated CNS relapse.

V. Assess the safety and toxicity of DTC101 in these patients.

OUTLINE:

Patients with significant neurologic symptoms (e.g., seizures, cranial nerve palsy, paresis, mental status changes) are entered directly on the Induction regimen and do not receive the Therapeutic Window. The following acronyms are used: ARA-C Cytarabine, NSC-63878 ASP Asparaginase, NSC-109229 (E. coli) or 106977 (Erwinia) CF Leucovorin calcium, NSC-3590 CTX Cyclophosphamide, NSC-26271 DM Dexamethasone, NSC-34521 DNR Daunorubicin, NSC-82151 DTC101 Sustained release cytarabine G-CSF Granulocyte Colony-Stimulating Factor (Amgen), NSC-614629 HC Hydrocortisone, NSC-10483 Mesna Mercaptoethane sulfonate, NSC-113891 MP Mercaptopurine, NSC-755 MTX Methotrexate, NSC-740 TIT Triple Intrathecal Therapy, IT MTX/IT HC/IT ARA-C TMP-SMX Trimethoprim-sulfamethoxazole TSPA Thiotepa, NSC-6396 VCR Vincristine, NSC-67574 VP-16 Etoposide, NSC-141540

THERAPEUTIC WINDOW: Single Agent Chemotherapy. TSPA or DTC101. \*\* Thiotepa window closed as of 7/6/98 \*\* \*\* DTC101 window opened 11/15/99 \*\*

INDUCTION: 3-Drug Combination Chemotherapy plus Triple Intrathecal Therapy. DM/DNR/VCR; plus TIT.

CONSOLIDATION: 2-Drug Combination Chemotherapy plus Triple Intrathecal Therapy. ARA-C/ASP; plus TIT.

INTENSIFICATION I: 4-Drug Combination Chemotherapy with Leucovorin Rescue plus Triple Intrathecal Therapy. CTX/MP/MTX/VP-16; with CF; plus TIT.

RE-INDUCTION: 3-Drug Combination Chemotherapy plus Triple Intrathecal Therapy. DM/DNR/VCR; plus TIT.

INTENSIFICATION II: 6-Drug Combination Chemotherapy with Leucovorin Rescue plus Triple Intrathecal Therapy. ARA-C/ASP/CTX/MP/MTX/VP-16; with CF; plus TIT.

CHEMORADIOTHERAPY: Radiotherapy plus 3-Drug Combination Chemotherapy. Craniospinal irradiation using x-rays with energies of 4-6 MV (electrons acceptable for spinal cord irradiation); plus ASP/DM/VCR.

MAINTENANCE: 2-Drug Combination Chemotherapy Alternating with 2-Drug Combination Chemotherapy. MP/MTX; alternating with CTX/VCR.

Radiation Therapy and Chemotherapy in Treating Children With CNS Relapse From Acute Lymphoblastic Leukemia

TREATMENT OF ISOLATED CNS RELAPSE OF ACUTE LYMPHOBLASTIC LEUKEMIA -- A PEDIATRIC ONCOLOGY GROUP-WIDE PHASE II STUDY

National Cancer Institute (NCI)

BB 1101

Pegaspargase

Adjuvants, Immunologic

All patients receive common induction (vincristine sulfate, dexamethasone, daunorubicin hydrochloride \& intrathecal triple therapy (ITT: MTX, therapeutic hydrocortisone and cytarabine)), consolidation (cytarabine, pegaspargase, filgrastim, re-induction (vincristine, dexamethasone, daunorubicin), and intensification chemotherapy (MTX, leucovorin calcium, mercaptopurine, etoposide, cyclophosphamide \& ITT.

All patients receive common induction (vincristine sulfate, dexamethasone, daunorubicin hydrochloride \& intrathecal triple therapy (ITT: MTX, therapeutic hydrocortisone and cytarabine)), consolidation (cytarabine, pegaspargase, filgrastim, testicular radiation therapy, re-induction (vincristine, dexamethasone, daunorubicin), and intensification chemotherapy (MTX, leucovorin calcium, mercaptopurine, etoposide, cyclophosphamide \& ITT.

cytarabine

pegaspargase

Patients with isolated testicular relapse will start Induction with a single dose of high-dose methotrexate (HDMTX) and will not receive either testicular or cranial radiation. Patients with isolated CNS relapse will NOT receive the initial dose of HDMTX prior to Induction, but will receive 1200 cGy of cranial radiation after completing the initial 12 months of intensive systemic chemotherapy.

radiation therapy

Caroline A. Hastings, MD

RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells.

PURPOSE: This clinical trial is studying how well giving chemotherapy together with radiation therapy works in treating patients with acute lymphoblastic leukemia that has relapsed in the CNS and/or testes.

OBJECTIVES:

Primary

* Determine the efficacy of intensified systemic chemotherapy with reduced-dose CNS radiotherapy in patients with acute lymphoblastic leukemia and late isolated CNS relapse.
* Determine the efficacy of intensive systemic chemotherapy without testicular radiotherapy in patients with acute lymphoblastic leukemia and late isolated testicular relapse.
* Determine the toxicity of these regimens in these patients.

Secondary

* Determine whether bone marrow involvement is present at the time of extramedullary relapse in patients treated with these regimens.
* Correlate pretreatment minimal residual disease with outcomes in patients treated with these regimens.
* Correlate the role of host gene polymorphisms with toxicity of these regimens and incidence and outcome in these patients.
* Determine the neuropsychological sequelae associated with isolated CNS relapse and these treatment regimens in these patients.

OUTLINE: This is a pilot, multicenter study. All patients receive common induction, consolidation, re-induction, and intensification chemotherapy. Patients are stratified to maintenance therapy according to site of extramedullary relapse (CNS vs testicular).

* Induction therapy (weeks 1-4): Patients receive vincristine IV on days 1, 8, 15, and 22; oral dexamethasone twice daily on days 1-28; daunorubicin\* IV over 15 minutes on days 1, 8, and 15; and intrathecal triple therapy\*\* (ITT) comprising methotrexate, hydrocortisone, and cytarabine on days 1, 8, 15, and 22.

NOTE: \*The total dose of anthracyclines on this study is capped at 450 mg/m2. Once this dose is reached, all subsequent doses of daunorubicin are omitted.

NOTE: \*\*Patients with isolated testicular relapse receive ITT on day 1 only.

In addition to the above, patients with isolated testicular relapse also receive high-dose methotrexate IV continuously over 24 hours on day -14. Patients with clinical signs of disease at the end of induction undergo testicular biopsy.

Patients with CNS disease who do not achieve CNS remission after induction therapy receive additional ITT as above on days 29 and 36.

* Consolidation therapy (weeks 5-10): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-2 and 22-23 and pegaspargase intramuscularly (IM) on days 2 and 23. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on days 3 and 24 and continuing until blood counts recover.

Patients with isolated testicular relapse with positive biopsy results at the end of induction undergo testicular radiotherapy once daily for a total of 12 fractions during consolidation therapy.

* Intensification I (weeks 11-22): Patients receive high-dose methotrexate with leucovorin calcium rescue IV over 24 hours on days 1, 22, 43, and 64 and oral mercaptopurine once daily on days 2-6, 23-27, 44-48, and 65-69. Patients also receive etoposide IV over 1 hour and cyclophosphamide IV over 15-30 minutes on days 8, 29, 50, and 71. Patients receive ITT\* on days 15, 36, 57, and 78.

NOTE: \*Patients with isolated testicular relapse receive ITT on days 36 and 78 only.

* Reinduction therapy (weeks 23-26): Patients receive vincristine IV on days 1, 8, 15, and 22; oral dexamethasone twice daily on days 1-7 and 15-21, and daunorubicin IV over 15 minutes on days 1, 8, and 15.
* Intensification II (weeks 27-50): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-2, 43-44, 85-86, and 127-128; pegaspargase IM on days 2, 44, 86, and 128; ITT\* on days 22, 64, 106, and 148; high-dose methotrexate IV continuously over 24 hours on days 29, 71, 113, and 155; oral mercaptopurine on days 30-34, 72-76, 114-118, and 156-160; and etoposide IV over 1 hour and cyclophosphamide IV over 15-30 minutes on days 36, 78, 120, and 162. Patients also receive G-CSF SC beginning on days 3, 45, 87, and 129 and continuing until blood counts recover.

NOTE: \*Patients with isolated testicular relapse receive ITT on days 22 and 106 only.

* Chemotherapy and radiotherapy (weeks 51-54): Patients receive oral dexamethasone twice daily on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, and pegaspargase IM on days 1 and 15.

Patients with isolated CNS relapse also undergo cranial radiotherapy once daily, 5 days a week, for a total of 12 fractions.

* Maintenance therapy for isolated CNS relapse: (weeks 55-104): Patients receive dexamethasone PO orIV twice daily on days 1-5; oral mercaptopurine once daily on days 1-42; methotrexate IM on days 1, 8, 15, 22, 29, and 36; and vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 10 weeks for 5 courses.
* Maintenance therapy for isolated testicular relapse:

  * (Weeks 55-74): Patients receive ITT on day 1 and dexamethasone, mercaptopurine, methotrexate, vincristine, and cyclophosphamide as in maintenance therapy for isolated CNS relapse. Treatment repeats every 10 weeks for 2 courses.
  * (Weeks 75-106): Patients receive vincristine IV on day 1; dexamethasone orally or IV on days 1-5; oral mercaptopurine on days 1-28; and methotrexate IM on days 1, 8, 15, and 22. Treatment repeats every 28 days for 8 courses. Patients also receive ITT on day 1 every 12 weeks for 3 doses.

Patients with combined testicular and CNS relapse receive high-dose methotrexate IV continuously over 24 hours on day -14 in addition to the same chemotherapy and radiotherapy administered during the induction, consolidation, intensification I, reinduction, intensification II, and maintenance phases of therapy as isolated CNS relapse patients.

All patients undergo neuropsychological assessment within 3 months after completion of induction therapy (before cranial radiotherapy) and at 2 years after completion of treatment.

Patients are followed for survival.

Combination Chemotherapy and Radiation Therapy in Treating Patients With Acute Lymphoblastic Leukemia That Has Relapsed in the CNS or Testes

Treatment of Late Isolated Extramedullary Relapse From Acute Lymphoblastic Leukemia (ALL) (Initial CR1≥ 18 Months)

Monitoring of efficacy results will be performed in comparison with historical results.

Children's Oncology Group

SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs. The 2 ineligible patients in the CNS group are not included in the adverse event reporting.

All patients receive common induction (vincristine sulfate, dexamethasone, daunorubicin hydrochloride \& intrathecal triple therapy (ITT: methotrexate, therapeutic hydrocortisone and cytarabine)), consolidation (cytarabine, pegaspargase, filgrastim, re-induction (vincristine, dexamethasone, daunorubicin), and intensification chemotherapy (methotrexate, leucovorin calcium, mercaptopurine, etoposide, cyclophosphamide \& ITT.

CNS Patients - Treatment (Combination Chemotherapy)

All patients receive common induction (vincristine sulfate, dexamethasone, daunorubicin hydrochloride \& intrathecal triple therapy (ITT: methotrexate, therapeutic hydrocortisone and cytarabine)), consolidation (cytarabine, pegaspargase, filgrastim, testicular radiation therapy, re-induction (vincristine, dexamethasone, daunorubicin), and intensification chemotherapy (methotrexate, leucovorin calcium, mercaptopurine, etoposide, cyclophosphamide \& ITT.

Testicular Relapse Patients (Combination Chemotherapy)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The COG SDC reviewed the NLM notification related to ct.gov AE/SAE reporting. The information in 'Additional Description' is accurate with respect to data supplied to ct.gov.COG plans to submit data AE/SAE data consistent with the text in this field.

Results Reporting Coordinator

The CNS-treatment cohort includes 126 patients with 120 CNS pre-B, 2 CNS+ITR pre-B and 4 T-AL. The primary analysis was restricted to CNS pre-B and ITR pre-B patients, respectively. Both CNS+ITR and T-ALL patients had to be excluded from the primary analysis. That is how we came to 120 in the CNS-treatment cohort for outcome analysis.

Event-free Survival

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Radiation Therapy and Chemotherapy in Treating Children With CNS Relapse From Acute Lymphoblastic Leukemia	NCT00002704	Leukemia	filgrastim asparaginase cyclophosphamid... daunorubicin hy... dexamethasone etoposide leucovorin calc... liposomal cytar... mercaptopurine mesna methotrexate therapeutic hyd... thiotepa vincristine sul... low-LET electro... low-LET photon ...	- 20 Years	National Cancer Institute (NCI)
Radiation Therapy and Chemotherapy in Treating Children With CNS Relapse From Acute Lymphoblastic Leukemia	NCT00002704	Leukemia	filgrastim asparaginase cyclophosphamid... daunorubicin hy... dexamethasone etoposide leucovorin calc... liposomal cytar... mercaptopurine mesna methotrexate therapeutic hyd... thiotepa vincristine sul... low-LET electro... low-LET photon ...	- 20 Years	National Cancer Institute (NCI)
Combination Chemotherapy and Radiation Therapy in Treating Patients With Acute Lymphoblastic Leukemia That Has Relapsed in the CNS or Testes	NCT00096135	Leukemia	filgrastim cyclophosphamid... cytarabine daunorubicin hy... dexamethasone etoposide leucovorin calc... mercaptopurine methotrexate pegaspargase therapeutic hyd... vincristine sul... radiation thera...	18 Months - 29 Years	Children's Oncology Group
Combination Chemotherapy and Radiation Therapy in Treating Patients With Acute Lymphoblastic Leukemia That Has Relapsed in the CNS or Testes	NCT00096135	Leukemia	filgrastim cyclophosphamid... cytarabine daunorubicin hy... dexamethasone etoposide leucovorin calc... mercaptopurine methotrexate pegaspargase therapeutic hyd... vincristine sul... radiation thera...	18 Months - 29 Years	Children's Oncology Group
Combination Chemotherapy and Radiation Therapy in Treating Patients With Acute Lymphoblastic Leukemia That Has Relapsed in the CNS or Testes	NCT00096135	Leukemia	filgrastim cyclophosphamid... cytarabine daunorubicin hy... dexamethasone etoposide leucovorin calc... mercaptopurine methotrexate pegaspargase therapeutic hyd... vincristine sul... radiation thera...	18 Months - 29 Years	Children's Oncology Group
Radiation Therapy and Chemotherapy in Treating Children With CNS Relapse From Acute Lymphoblastic Leukemia	NCT00002704	Leukemia	filgrastim asparaginase cyclophosphamid... daunorubicin hy... dexamethasone etoposide leucovorin calc... liposomal cytar... mercaptopurine mesna methotrexate therapeutic hyd... thiotepa vincristine sul... low-LET electro... low-LET photon ...	- 20 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for tdt positive childhood acute lymphoblastic leukemia