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Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. 3+3 escalation design.

Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. Patients receive bortezomib at maximum tolerated dose (as established in the Phase 1 portion of the study) and are assessed for response and toxicity.

Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.

10 mg/m2/day divided BID, oral administration for 14 days.

2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22

PEG-asparaginase

Given intrathecally on Day 1 of course 1 at the dose defined by age below.

* 30 mg for patients age 1-1.99
* 50 mg for patients age 2-2.99
* 70 mg for patients \>3 years of age

Given intrathecally to all patients who are CNS 1 at study entry on Day 15 at the dose defined by age below.

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age

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

Triple IT therapy will be given intrathecally on Day 8, 15, and 22 for patients who are CNS 2 and CNS 3 at study entry. Regimen/dosing as follows:

Methotrexate-

* \<2 years: 8 mg
* 2 - \<3 y: 10 mg
* 3 - \<9 y: 12 mg
* \>=9 y: 15 mg

Cytarabine:

* \<2 years: 16 mg
* 2 - \<3 y: 20 mg
* 3 - \<9 y: 24 mg
* \>=9 y: 30 mg

Hydrocortisone:

* \<2 years: 8 mg
* 2 - \<3 y: 10 mg
* 3 - \<9 y: 12 mg
* \>=9 y: 15 mg

Triple IT Therapy

Yoav Messinger, MD

This is a Phase I/II study of a drug called bortezomib given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). Bortezomib is a drug that has been approved by the Food and Drug Administration (FDA) for treating adults with multiple myeloma which is a type of blood cancer. Bortezomib has been shown to cause cancer cells to die in studies done on animals (mice). Studies have been done that have shown that some adults and children with cancer have shown a response to bortezomib when it is used alone. Studies have also been done in adults to evaluate the dose of bortezomib that can be safely given in combination with other chemotherapy drugs.

All patients will receive 1 course of chemotherapy unless medical complications prevent the administration of some of the drugs. Treatment will last about 1 month.

Treatment on this study will consist of a combination of 7 anti-cancer medications. The 7 anti-cancer medicines are bortezomib, vincristine, dexamethasone, PEG-asparaginase, doxorubicin, cytarabine (Ara-C), and methotrexate (MTX).

If you are in the Phase I portion of this study, you will be given an assigned dose of bortezomib. The dose of bortezomib will be based on doses given in previous studies done with adults and children. At each dose level of bortezomib, between 3 and 6 children will receive bortezomib in combination with chemotherapy. If the side effects are not too severe, the next group of children will receive a higher dose. The dose will continue to be increased until we find the dose that causes serious side effects. Your dose of bortezomib will not be increased. If you have bad side effects, your dose may be decreased.

The dose used during the Phase 2 part of this study will be determined by the outcome of the Phase I study. The highest dose used in Phase I that was tolerated without serious side effects will be the one used in Phase 2.

Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)

A Study of Bortezomib With Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

Toxicity will be graded using the CTCAE criteria, version 3.0. Dose-limiting toxicity will be defined as any of the following events that are deemed by the investigator as possibly, probably or definitely attributable to bortezomib: Grade 3 or 4 Sensory Neuropathy; Grade 3 or 4 Neuropathic pain (Neuralgia or peripheral nerve) lasting longer than 24 hours despite medical intervention; Marrow hypoplasia, which continues 6 weeks from the start of each course (less than 10% cellularity); and Grade 4 Non-Hematologic Toxicity excluding the following: Infection (septic shock, typhlitis), Fever/Neutropenia, Fatigue, Electrolyte abnormalities, Hyper/Hypoglycemia, Nausea or Vomiting, AST/ALT/Bilirubin elevations that return to grade 1 by the time of the next course.

* Complete Remission (CR): M1 (\< 5% blasts) BM with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC\>750/uL and platelet count \>75 000/uL);
* Complete Remission without Platelet Recovery (CRp): M1 BM with no circulating blasts or extramedullary disease and recovery of ANC (\>750/uL) but insufficient recovery of platelets (\<75 000/uL).
* Partial Remission (PR): the disappearance of circulating blasts and achievement of M2 (5%-25% blasts) marrow status, without new sites of extramedullary disease, and with recovery of ANC (\>750/uL).
* Stable disease (SD): not satisfying the criterion for progressive disease (PD), or a recovery of ANC (\>750/uL) but fails to qualify for CR, CRp, or PR.
* Progressive Disease (PD): increase of at least 25% in the absolute number of circulating leukemia cells, development of new sites of extramedullary disease, or other lab or clinical evidence of PD, with or without recovery of ANC or platelets.

Therapeutic Advances in Childhood Leukemia Consortium

The definition of adverse event used for data collection does not differ from that in the clinicaltrials.gov Definitions.

For the purpose of reporting SAEs, all Grade 3 and 4 toxicities (CTCAE) are reported in this study record.

Patients were evaluated regularly by the treating physician.

Patients receiving a 1 mg/m2 dose of bortezomib (known as Dose Level 1 in the Phase 1 portion). All patients in this group were from the Phase 1 portion of the study.

1 mg/m2 Dose Group

Patients receiving a 1.3 mg/m2 dose of bortezomib (known as Dose Level 2 in the Phase 1 portion). This group includes patients from both the Phase 1 and Phase 2 portions of the study.

1.3 mg/m2 Dose Group

Bortezomib (Velcade): Intravenous on days 1, 4, 8 and 11, dose-escalation

Dexamethasone: Intravenous or oral administration for 14 days.

PEG-asparaginase: Intramuscular injection

Doxorubicin: Intravenous infusion

Cytarabine: Intrathecal administration on day 1

Methotrexate: Intrathecal administration

Vincristine: Intravenous push on days 1, 8, 15, 22

The starting dose level of bortezomib will be 1 mg/m2/day given 2x week for 2 weeks on Days 1, 4, 8, and 11. The dose will be escalated to 1.3 mg/m2/day assuming that the maximum tolerated dose (MTD) is not exceeded. If the MTD is exceeded, the study will back down to the next whole dose level.

Phase 1 Dose Level 1

If the MTD is not exceeded at Dose Level 1, the next group of patients enrolled will escalate to Dose Level 2 of bortezomib at 1.3 mg/m2/day given on Days 1, 4, 8, and 11. This dose level is the highest possible dose level

Phase 1 Dose Level 2

After the MTD of bortezomib is defined with Phase 1, Phase 2 will enroll patients to receive bortezomib on Day 1, 4, 8 and 11 to evaluate activity of the regimen.

Bortezomib (Velcade): Intravenous on days 1, 4, 8 and 11 at 1.3 mg/m2/day

Dexamethasone: Intravenous or oral administration for 14 days.

PEG-asparaginase: Intramuscular injection

Doxorubicin: Intravenous infusion

Cytarabine: Intrathecal administration on day 1

Methotrexate: Intrathecal administration

Vincristine: Intravenous push on days 1, 8, 15, 22

Phase 2 Efficacy

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Patients in the dose escalation group were not stratified by lineage

Lineage

Prior Treatment Attempts

Patients in the dose escalation group not stratified by previous BM transplant.

Previous Bone Marrow Transplant

Patients in the dose escalation group not stratified by leukemic blast status

Bone Marrow M3 at study entry

31 unique individual participants were enrolled into the study collectively for both Phase 1 and 2. The breakdown is as follows: 10 in the Phase I study and 21 in the Phase II study. There was, however, one patient that started on Phase I, Cohort 2 that was later eligible and rolled into the Phase II study.

Peggy Romano, BA, CCRP

Phase 1 patients receiving 1 mg/m2 dose of bortezomib

Ph 1, Dose Level 1 (1 mg/m2)

Phase 1 patients receiving 1.3 mg/m2 dose of bortezomib

Ph 1, Dose Level 2 (1.3 mg/m2)

Occurrence of a Dose-Limiting Toxicity (Phase 1)

Patients enrolled into the Phase 1 portion of the study

Ph 1 Dose Escalation

Patients enrolled into the Phase 2 portion of the study having B-Precursor ALL

Ph 2 B-Precursor ALL Patients

Patients enrolled into the Phase 2 portion of the study having T-Cell ALL

Ph 2 T-Cell ALL Patients

One Ph 1 patient received incorrect doses of Dexamethasone, so not evaluable for response. One Phase 2 patient achieved BM M1 but was treated with additional chemotherapy before peripheral recovery, so response to protocol treatment could not be evaluated.

Achievement of Complete Remission (CR)

M1: Less than 5% blasts in a bone marrow aspirate and at least 200 cells counted.

M2: 5-25% blasts in a bone marrow aspirate with at least 200 cells counted. M3: Greater than 25% blasts in a bone marrow aspirate with at least 200 cells counted.

Phase 2 B-Precursor ALL Patients

Phase 2 T-cell ALL Patients

All patients who enrolled and treated under Phase 2 will be evaluated at the end of Course 1 for treatment response as indicated by measure of bone marrow (M1, M2, or M3) or patient survival if death occurred.

Bone Marrow Response

The starting dose level of bortezomib will be 1 mg/m2/day given 2x week for 2 weeks on Days 1, 4, 8, and 11. The dose will be escalated to 1.3 mg/m2/day assuming that the maximum tolerated dose (MTD) is not exceeded. If the MTD is exceeded, the study will back down to the next whole dose level.

Phase 1: Cohort 1 Bortezomib 1mg/m2/Day (Dose Level 1)

If the MTD is not exceeded at Dose Level 1, the next group of patients enrolled will escalate to Dose Level 2 of bortezomib at 1.3 mg/m2/day given on Days 1, 4, 8, and 11. This dose level is the highest possible dose level.

Phase 1: Cohort 2 Bortezomib 1.3 mg/m2/Day (Dose Level 2)

After the MTD of bortezomib is defined with Phase 1, Phase 2 will enroll patients to receive bortezomib on Day 1, 4, 8 and 11 to evaluate activity of the regimen.

Phase 2: Bortezomib 1.3 mg/m2/Day (Efficacy)

Phase 1

Phase 2

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Leukemia-Lymphoma, Adult T-Cell

Adult T-cell Leukemia/lymphoma

Etoposide

Cyclophosphamide

Lenograstim

Etoposide phosphate

Antineoplastic Agents, Alkylating

Alkylating Agents

Adjuvants, Immunologic

The study will begin at Dose Level 1 at 480 mg/m2 Nelarabine (75% of single agent maximum tolerated dose) and 330 mg/m2 Cyclophospamide and will escalate to the next Dose Level if the maximum tolerated dose (MTD) is not exceeded. The first 3 patients will be enrolled into Dose Level 1. If 0/3 experiences dose limiting toxicity (DLT) at a given dose level, then the dose is escalated to the next higher level and 3 more patients are enrolled. If 1/3 experiences DLT at current dose, the up to 3 more patients are accrued at the same dose level. If 2 or more DLTs are observed in a 3-patient or 6-patient cohort at a given dose level, then the MTD has been exceeded, dose escalation will be stopped, and up to 3 additional patients will be enrolled at the next lower dose level (unless 6 patients have already been treated at that prior dose). If the MTD is exceeded at Dose Level 0, the study will be closed.

Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.

Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide

Patients in this arm will be administered Nelarabine 325 mg/m2 (50% of single agent MTD) and 330 mg/2 Cyclophosphamide. Patients will only enter this arm if the MTD at Dose Level 1 has been exceeded. If the MTD is exceeded at Dose Level 0, the study will be closed.

Dose will be assigned at study entry. Nelarabine will be given IV over 60 minutes (given at hours 0 to 1) on days 1 through 5.

Nelarabine

100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5

Dose will be assigned at study entry, IV as a 30-60 minute infusion (given at hours 3 to 4) on days 1 through 5.

Give between day 29 and 36 or when ANC\>750 and PLTS\>75,000 - whichever comes first (but not prior to day 22) at the dose defined by age below, ideally in conjunction with BM evaluation.

Given intrathecally at the dose defined by age below. 8 mg for patients age greater than or equal to 1, but \<2 years of age 10 mg for patients age greater than or equal to 2, but \<3 years of age 12 mg for patients greater than or equal to 3, but \< 9 years of age 15 mg for patients greater than or equal to \>9 years of age

5 micrograms/kg/day IV or SC will begin on Day 6 and end when the ANC is \> 1000/mm3 for two consecutive days.

Filgrastim

Jim Whitlock, MD

Nelarabine has shown significant activity in patients with T-cell malignancies. This study will determine the safety and maximum tolerated dose of the combination of nelarabine, cyclophosphamide and etoposide in patients with first bone marrow relapse of T-ALL, or first relapse of T-LL.

Trial of Nelarabine, Etoposide and Cyclophosphamide in Relapsed T-cell ALL and T-cell LL

A Phase I Trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse): A Joint Study of TACL and POETIC

Patients will be evaluated based on Dose Level and total courses taken at each dose level and for presence of dose limiting toxicities. Not all patients enrolled at each dose level has been assessed to be evaluable for DLTs. Only those that have met criteria for being evaluable for DLT will be counted in the Overall Number of Participants Analyzed.

Patients will be evaluated at each dose level and for assessment of response to treatment. Not all patients enrolled at each dose level has been assessed to be evaluable for response. Only those that have met criteria for being evaluable for response will be counted in the Overall Number of Participants Analyzed.

GlaxoSmithKline

Novartis

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

The study will begin at Dose Level 1 at 480 mg/m2 Nelarabine (75% of single agent maximum tolerated dose) and 330 mg/m2 Cyclophospamide and will escalate to the next Dose Level if the maximum tolerated dose (MTD) is not exceeded. The first 3 patients will be enrolled into Dose Level 1.

Nelarabine Dose Level 1

Nelarabine Dose Level 2

Nelarabine Dose Level 3

Nelarabine Dose Level 0

The study will begin at Dose Level 1 at 480 mg/m2 Nelarabine (75% of single agent MTD) and 330 mg/m2 Cyclophosphamide. The first 3 patients will be enrolled into Dose Level 1.

If 0/3 experiences dose limiting toxicity (DLT) at a given dose level, then the dose is escalated to the next higher level and 3 more patients are enrolled. If 1/3 experiences DLT at current dose, the up to 3 more patients are accrued at the same dose level. If 2 or more DLTs are observed in a 3-patient or 6-patient cohort at a given dose level, then the MTD has been exceeded, dose escalation will be stopped, and up to 3 additional patients will be enrolled at the next lower dose level (unless 6 patients have already been treated at that prior dose). If the MTD is exceeded at Dose Level 0, the study will be closed.

Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.

This is the second dose level of this dose escalation study. If 1 or fewer patients at Dose Level 1 experiences a DLT, patients will be accrued at Dose Level 2.

If 0/3 experiences dose limiting toxicity (DLT) at a given dose level, then the dose is escalated to the next higher level and 3 more patients are enrolled. If 1/3 experiences DLT at current dose, the up to 3 more patients are accrued at the same dose level. If 2 or more DLTs are observed in a 3-patient or 6-patient cohort at a given dose level, then the MTD has been exceeded, dose escalation will be stopped, and up to 3 additional patients will be enrolled at the next lower dose level (unless 6 patients have already been treated at that prior dose). If the MTD is exceeded at Dose Level 0, the study will be closed.

Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide This is the third and final dose level of this dose escalation study. If 1 or fewer patients at Dose Level 2 experiences a DLT, patients will be accrued at Dose Level 3.

If 0/3 experiences dose limiting toxicity (DLT) at a given dose level, then the dose is escalated to the next higher level and 3 more patients are enrolled. If 1/3 experiences DLT at current dose, the up to 3 more patients are accrued at the same dose level. If 2 or more DLTs are observed in a 3-patient or 6-patient cohort at a given dose level, then the MTD has been exceeded, dose escalation will be stopped, and up to 3 additional patients will be enrolled at the next lower dose level (unless 6 patients have already been treated at that prior dose). If the MTD is exceeded at Dose Level 0, the study will be closed.

Age, Continuous

Dose Level 0 did not accrue any subjects as the criteria to accrue at Dose Level 0 was not met

Clinical Research Coordinator, Consortia

# of patients with DLT

# of patients without DLT

The study will begin at Dose Level 1 at 480 mg/m2 Nelarabine (75% of single agent maximum tolerated dose) and 330 mg/m2 Cyclophospamide and will escalate to the next Dose Level if the maximum tolerated dose (MTD) is not exceeded.

There are 0 patients for Dose Level 0 as no patients met the criteria to be enrolled

To Determine the Presence of Dose-limiting Toxicities (DLTs) of Nelarabine, Etoposide and Cyclophosphamide When Given in Combination to Children With T-ALL and Bone Marrow Relapse or T-LL.

# of patients not with complete remission

# of patients with complete remission

Patients in this arm will be administered Nelarabine 325 mg/m2 (50% of single agent MTD) and 330 mg/2 Cyclophosphamide. Patients will only enter this arm if the MTD at Dose Level 1 has been exceeded. If the MTD is exceeded at Dose Level 0, the study will be closed.

Nelarabine: Dose will be assigned at study entry. Nelarabine will be given IV over 60 minutes (given at hours 0 to 1) on days 1 through 5.

Etoposide: 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5

Cyclophosphamide: Dose will be assigned at study entry, IV as a 30-60 minute infusion (given at hours 3 to 4) on days 1 through 5.

Methotrexate: Give between day 29 and 36 or when ANC\>750 and PLTS\>75,000 - whichever comes first (but not prior to day 22) at the dose defined by age below, ideally in conjunction with BM evaluation.

Given intrathecally at the dose defined by age below. 8 mg for patients age greater than or equal to 1, but \<2 years of age 10 mg for patients age greater than

No patients met the criteria to be enrolled at Dose Level 0.

To Determine the Complete Remission Rate After 1 and 2 Courses of This Therapy in Children With T-ALL and Bone Marrow Relapse or T-LL.

The study will begin at Dose Level 1 at 480 mg/m2 Nelarabine (75% of single agent maximum tolerated dose) and 330 mg/m2 Cyclophospamide and will escalate to the next Dose Level if the maximum tolerated dose (MTD) is not exceeded.

Nelarabine: Dose will be assigned at study entry. Nelarabine will be given IV over

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)	NCT00440726	Acute Lymphobla...	Bortezomib Dexamethasone PEG-asparaginas... Doxorubicin Cytarabine Methotrexate Vincristine Triple IT Thera...	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
Trial of Nelarabine, Etoposide and Cyclophosphamide in Relapsed T-cell ALL and T-cell LL	NCT00981799	Relapsed T-Cell... Relapsed T-Cell...	Nelarabine Etoposide Cyclophosphamid... Methotrexate Filgrastim	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
Trial of Nelarabine, Etoposide and Cyclophosphamide in Relapsed T-cell ALL and T-cell LL	NCT00981799	Relapsed T-Cell... Relapsed T-Cell...	Nelarabine Etoposide Cyclophosphamid... Methotrexate Filgrastim	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

Spots Global Cancer Trial Database for tacl

Every month we try and update this database with for tacl cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for tacl

Every month we try and update this database with for tacl cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for tacl cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.