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

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00981799
• Collaborator: GlaxoSmithKline (Industry), Novartis (Industry)
• Enrollment: 23
• Locations: 37
• Arms: 4
• Duration (Months): 73.6
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed T-Cell Acute Lymphoblastic Leukemia; Relapsed T-Cell Lymphoblastic Lymphoma	Drug: Nelarabine; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Filgrastim	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse): A Joint Study of TACL and POETIC
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Jul 18, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nelarabine Dose Level 1 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.	Drug: 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.; Other Names: Arranon Compound 506U78 ; Drug: Etoposide; 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5; Other Names: VePesid Etopophos VP-16 ; Drug: 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.; Other Names: Cytoxan ; Drug: 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 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; Other Names: MTX Amethopterin Trexall ; Drug: Filgrastim; 5 micrograms/kg/day IV or SC will begin on Day 6 and end when the ANC is > 1000/mm3 for two consecutive days.; Other Names: Neupogen GCSF granulocyte colony stimulating factor
Experimental: Nelarabine Dose Level 2 Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.	Drug: 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.; Other Names: Arranon Compound 506U78 ; Drug: Etoposide; 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5; Other Names: VePesid Etopophos VP-16 ; Drug: 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.; Other Names: Cytoxan ; Drug: 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 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; Other Names: MTX Amethopterin Trexall ; Drug: Filgrastim; 5 micrograms/kg/day IV or SC will begin on Day 6 and end when the ANC is > 1000/mm3 for two consecutive days.; Other Names: Neupogen GCSF granulocyte colony stimulating factor
Experimental: Nelarabine Dose Level 3 Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide	Drug: 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.; Other Names: Arranon Compound 506U78 ; Drug: Etoposide; 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5; Other Names: VePesid Etopophos VP-16 ; Drug: 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.; Other Names: Cytoxan ; Drug: 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 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; Other Names: MTX Amethopterin Trexall ; Drug: Filgrastim; 5 micrograms/kg/day IV or SC will begin on Day 6 and end when the ANC is > 1000/mm3 for two consecutive days.; Other Names: Neupogen GCSF granulocyte colony stimulating factor
Experimental: Nelarabine Dose Level 0 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.	Drug: 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.; Other Names: Arranon Compound 506U78 ; Drug: Etoposide; 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5; Other Names: VePesid Etopophos VP-16 ; Drug: 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.; Other Names: Cytoxan ; Drug: 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 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; Other Names: MTX Amethopterin Trexall ; Drug: Filgrastim; 5 micrograms/kg/day IV or SC will begin on Day 6 and end when the ANC is > 1000/mm3 for two consecutive days.; Other Names: Neupogen GCSF granulocyte colony stimulating factor

Outcome Measures

Primary Outcome Measures

1. 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. [6 months]

   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.

Secondary Outcome Measures

1. 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. [1-3 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients to be enrolled in the dose-escalation portion of this study must have T-cell ALL or T-cell lymphoblastic lymphoma (LL) in first relapse or must have failed primary induction chemotherapy (ie, never attained a complete remission following an initial course of standard therapy for T-ALL or T-LL). Patients to be enrolled in the cohort expansion portion of this study (ie, those treated at the recommended phase 2 dose) must have T-cell ALL in first relapse or must have failed primary induction chemotherapy (ie, never attained a complete remission following an initial course of standard therapy for T-ALL). T-LL patients are not eligible for the cohort expansion phase.

• Patients with T-cell ALL must have greater than 25% blasts in the bone marrow with or without extramedullary disease.

• Patients with T-cell LL must have recurrent disease, documented by clinical or radiographic criteria, as well as histologic verification of the malignancy at original diagnosis. Patients with T-cell LL enrolled in the phase I dose-escalation study are not required to have measurable disease; however, patients enrolled in the phase II cohort expansion at the MTD must have measurable disease.

• Patients may have CNS 1 or CNS 2 disease but not CNS 3.

• ECOG 0-2 or Karnofsky ≥ 50% for patients > 16 years of age; Lansky ≥ 50% for patients ≤16 years of age.

• Patients may be enrolled on study regardless of the timing of prior Intrathecal therapy; however, they MAY NOT BEGIN TREATMENT ON THIS PROTOCOL UNTIL A MINIMUM OF 7 DAYS HAS ELAPSED SINCE PRIOR INTRATHECAL THERAPY.

• At least 6 weeks must have elapsed since administration of nitrosureas.

• At least 12 weeks must have elapsed since administration of craniospinal or hemipelvic radiation.

• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

• Female patients with infants must agree not to breastfeed their infants while on this study.

• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

• Adequate renal function defined as serum creatinine ≤ 1.5x upper limit of normal (ULN) for age. If the serum creatinine is above these values, the calculated creatinine clearance or radioisotope GFR must be ≥ 70 mL/min/1.73m2.

• Total bilirubin ≤ 1.5x ULN for age. If the total bilirubin is elevated, patient will still be eligible if the conjugated (direct) serum bilirubin ≤ ULN for age.

• ALT ≤ 5x ULN of normal for age.

• Adequate cardiac function defined as shortening fraction of ≥ 27% by echocardiogram or ejection fraction ≥ 45% by gated radionuclide study.

• No evidence of dyspnea at rest

• No exercise intolerance

• A pulse oximetry ≥ 94% at sea level (≥ 90% at altitude ≥ 5000 feet) if there is clinical indication for determination.

• Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria:

• Patients with Down syndrome are excluded.

• Patients with pre-existing Grade 2 (or greater) peripheral motor or sensory neurotoxicity per the CTCAE 3.0 as determined by the treating physician or a neurologist.

• Patients with a history of prior veno-occlusive disease (VOD) or findings consistent with a diagnosis of VOD, defined as: conjugated serum bilirubin >1.4 mg/dL AND unexplained weight gain greater than 10% of baseline weight or ascites AND hepatomegaly or right upper quadrant pain without another explanation, OR reversal of portal vein flow on ultrasound, OR pathological confirmation of VOD on liver biopsy.

• Previous hematopoetic stem cell transplantation.

• Patients with a prior seizure disorder requiring anti-convulsant therapy are not eligible to receive nelarabine. For the purposes of this study, this includes any patient that has received anticonvulsant therapy to prevent/treat seizures in the prior two years.

• Positive blood culture within 48 hours of study enrollment.

• Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection.

• Plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.

• Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
2	Children's Hospital Orange County	Orange	California	United States
3	UCSF School of Medicine	San Francisco	California	United States	94143-0106
4	The Children's Hospital, University of Colorado	Aurora	Colorado	United States	80045
5	Children's National Medical Center	Washington	District of Columbia	United States
6	University of Miami Cancer Center	Miami	Florida	United States	33136
7	Children's Healthcare of Atlanta, Emory University	Atlanta	Georgia	United States
8	Lurie Children's Hospital	Chicago	Illinois	United States
9	Johns Hopkins University	Baltimore	Maryland	United States
10	Dana Farber	Boston	Massachusetts	United States
11	C.S. Mott Children's Hospital	Ann Arbor	Michigan	United States	48109-0914
12	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota	United States	55404-4597
13	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
14	New York University Medical Center	New York	New York	United States	10016
15	Children's Hospital New York-Presbyterian	New York	New York	United States	10032
16	Levine Children's Hospital at Carolinas Medical Center	Charlotte	North Carolina	United States	28203
17	Rainbow Babies	Cleveland	Ohio	United States
18	Nationwide Childrens Hospital	Columbus	Ohio	United States
19	Oregon Health and Science University	Portland	Oregon	United States
20	St. Jude	Memphis	Tennessee	United States	38105-3678
21	Vanderbilt Children's Hospital	Nashville	Tennessee	United States
22	University of Texas at Southwestern	Dallas	Texas	United States
23	Cook Children's Hospital	Fort Worth	Texas	United States
24	Primary Children's	Salt Lake City	Utah	United States
25	Seattle Children's Hospital	Seattle	Washington	United States	98105
26	Medical College of Wisconsin	Milwaukee	Wisconsin	United States
27	Children's Hospital at Westmead	Westmead	New South Wales	Australia
28	Royal Children's Hospital	Brisbane	Queensland	Australia
29	Royal Children's Hospital, Melbourne	Melbourne	Victoria	Australia
30	Sydney Children's Hospital	Sydney		Australia
31	St. Anna Children's Hospital	Vienna		Austria
32	Hospital for Sick Kids	Toronto	Ontario	Canada
33	Sainte Justine University Hospital	Montreal	Quebec	Canada
34	British Columbia Children's Hospital	Vancouver		Canada
35	CHU Lille	Lille		France
36	Bambino Gesù Hospital	Rome		Italy
37	Erasmus MC - Sophia	Rotterdam		Netherlands

Sponsors and Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium
• GlaxoSmithKline
• Novartis

Investigators

• Study Chair: Jim Whitlock, MD, The Hospital for Sick Children

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• For more information about this and other clinical trials, please visit the TACL website

Publications

None provided.

• Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
• ClinicalTrials.gov Identifier: NCT00981799
• Other Study ID Numbers: T2008-002
• First Posted: Sep 22, 2009
• Last Update Posted: Oct 1, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium: Relapse; T cell; Lymphoblastic; Leukemia; Lymphoma; Nelarabine; TACL; NECTAR
• Additional relevant MeSH terms: Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Cyclophosphamide; Methotrexate; Etoposide; Lenograstim

Study Results

Participant Flow

Arm/Group Title	Nelarabine Dose Level 1	Nelarabine Dose Level 2	Nelarabine Dose Level 3	Nelarabine Dose Level 0
Arm/Group Description	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	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. 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
Period Title: Overall Study
STARTED	6	7	10	0
COMPLETED	5	6	10	0
NOT COMPLETED	1	1	0	0

Baseline Characteristics

Arm/Group Title	Nelarabine Dose Level 1	Nelarabine Dose Level 2	Nelarabine Dose Level 3	Nelarabine Dose Level 0	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	6	7	10	0	23
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	13	7	10.5	9
Sex: Female, Male (Count of Participants)
Female	2 33.3%	3 42.9%	3 30%	0 NaN	8 34.8%
Male	4 66.7%	4 57.1%	7 70%	0 NaN	15 65.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 16.7%	1 14.3%	0 0%	2 Infinity
Not Hispanic or Latino	4 66.7%	6 85.7%	9 90%	19 Infinity
Unknown or Not Reported	1 16.7%	0 0%	1 10%	2 Infinity
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 NaN
Asian	1 16.7%	2 28.6%	4 40%	7 Infinity
Native Hawaiian or Other Pacific Islander	0 0%	1 14.3%	0 0%	1 Infinity
Black or African American	1 16.7%	0 0%	3 30%	4 Infinity
White	3 50%	4 57.1%	3 30%	10 Infinity
More than one race	0 0%	0 0%	0 0%	0 NaN
Unknown or Not Reported	1 16.7%	0 0%	0 0%	1 Infinity

Outcome Measures

1. Primary Outcome

Title	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.
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Nelarabine Dose Level 1	Nelarabine Dose Level 2	Nelarabine Dose Level 3	Nelarabine Dose Level 0
Arm/Group Description	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.	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.
Measure Participants	5	6	10	0
# of patients with DLT	0 0%	1 14.3%	2 20%	0 NaN
# of patients without DLT	5 83.3%	5 71.4%	8 80%	0 NaN

2. Secondary Outcome

Title	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.
Description	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.
Time Frame	1-3 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Nelarabine Dose Level 1	Nelarabine Dose Level 2	Nelarabine Dose Level 3	Nelarabine Dose Level 0
Arm/Group Description	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.	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. 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
Measure Participants	5	6	10	0
# of patients not with complete remission	3 50%	4 57.1%	9 90%	0 NaN
# of patients with complete remission	2 33.3%	2 28.6%	1 10%	0 NaN

Adverse Events

Time Frame	From date of first dose of Nelarabine, Etoposide, and Cyclophosphamide until 30 days following the last dose of protocol therapy (approximately from Day 0 to Day 66)
Adverse Event Reporting Description	The definitions of AE and SAE do not differ from the clinicaltrials.gov definitions
Arm/Group Title	Nelarabine Dose Level 1		Nelarabine Dose Level 2		Nelarabine Dose Level 3		Nelarabine Dose Level 0
Arm/Group Description	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.		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.
All Cause Mortality
	Nelarabine Dose Level 1		Nelarabine Dose Level 2		Nelarabine Dose Level 3		Nelarabine Dose Level 0
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		7/7 (100%)		8/10 (80%)		0/0 (NaN)
Serious Adverse Events
	Nelarabine Dose Level 1		Nelarabine Dose Level 2		Nelarabine Dose Level 3		Nelarabine Dose Level 0
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		5/7 (71.4%)		7/10 (70%)		0/0 (NaN)
Blood and lymphatic system disorders
Febrile Neutropenia	0/6 (0%)	0	1/7 (14.3%)	1	4/10 (40%)	4	0/0 (NaN)	4
Cardiac disorders
HLH-Syndrome-Other	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Endocrine disorders
hyponatremia	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Gastrointestinal disorders
diarrhea	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
GI bleed	0/6 (0%)		1/7 (14.3%)	1	0/10 (0%)	1	0/0 (NaN)	1
Immune system disorders
Allergic reaction	0/6 (0%)	0	0/7 (0%)	0	2/10 (20%)	2	0/0 (NaN)	2
Sepsis	0/6 (0%)		1/7 (14.3%)	1	0/10 (0%)	1	0/0 (NaN)	1
Infections and infestations
Infection, Parainfluenza	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Herpes Zoster Infection	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Infection Oral cavity	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Infection, vulva	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Infection, perianal	0/6 (0%)	0	0/7 (0%)	0	2/10 (20%)	2	0/0 (NaN)	2
catheter infection	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Infection	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Investigations
Hypoalbuminemia	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
elevated bilirubin	0/6 (0%)		1/7 (14.3%)	1	0/10 (0%)	1	0/0 (NaN)	1
Musculoskeletal and connective tissue disorders
musculoskeletal pain	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Nervous system disorders
Neuropathy- Peripheral Motor	0/6 (0%)	0	0/7 (0%)	0	2/10 (20%)	2	0/0 (NaN)	2
Neuropathy- Peripheral Sensory	0/6 (0%)	0	1/7 (14.3%)	1	1/10 (10%)	1	0/0 (NaN)	1
Hydrocephalus	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Oral Mucositis	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
Pleural Effusion	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	0/0 (NaN)	1
dyspnea	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
Vascular disorders
Hypotension	0/6 (0%)	0	0/7 (0%)	0	2/10 (20%)	2	0/0 (NaN)	2
Other (Not Including Serious) Adverse Events
	Nelarabine Dose Level 1		Nelarabine Dose Level 2		Nelarabine Dose Level 3		Nelarabine Dose Level 0
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		7/7 (100%)		10/10 (100%)		0/0 (NaN)
Blood and lymphatic system disorders
Febrile Neutropenia	1/6 (16.7%)	1	3/7 (42.9%)	3	3/10 (30%)	3	3/0 (Infinity)	3
Hemoglobin	4/6 (66.7%)	4	3/7 (42.9%)	3	10/10 (100%)	10	10/0 (Infinity)	10
Hypoalbuminemia	1/6 (16.7%)	1	0/7 (0%)	0	2/10 (20%)	2	2/0 (Infinity)	2
Leukopenia NOS	3/6 (50%)	3	5/7 (71.4%)	6	5/10 (50%)	5	5/0 (Infinity)	5
Lymphopenia	1/6 (16.7%)	1	0/7 (0%)	0	6/10 (60%)	8	6/0 (Infinity)	8
hypoxia	0/6 (0%)	0	1/7 (14.3%)	1	2/10 (20%)	2	2/0 (Infinity)	2
Platelet count decrease	0/6 (0%)	0	6/7 (85.7%)	8	10/10 (100%)	11	10/0 (Infinity)	11
Cardiac disorders
Pericardial effusion	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
Ear and labyrinth disorders
Epistaxis	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
Endocrine disorders
lymphopenia	0/6 (0%)	0	4/7 (57.1%)	5	6/10 (60%)	6	6/0 (Infinity)	6
Gastrointestinal disorders
diarrhea NOS	0/6 (0%)	0	2/7 (28.6%)	2	0/10 (0%)	0	0/0 (NaN)	0
Hemorrhage, Upper GI NOS	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
General disorders
Pain NOS	1/6 (16.7%)	1	0/7 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1
constitutional symptoms	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Headache	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
nausea	0/6 (0%)	0	2/7 (28.6%)	2	1/10 (10%)	1	1/0 (Infinity)	1
Pain other	0/6 (0%)	0	1/7 (14.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1
vomiting	0/6 (0%)	0	1/7 (14.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1
Immune system disorders
Allergy/Immunology- Other	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1
Infections and infestations
Infection	1/6 (16.7%)	1	0/7 (0%)	0	2/10 (20%)	3	2/0 (Infinity)	3
clostridial infection NOS	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Infection, blood	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Influenza like illness	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Pyrexia	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
sepsis	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Catheter-related infection	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1
Investigations
Alanine aminotransferase increased	1/6 (16.7%)	1	0/7 (0%)	0	2/10 (20%)	4	2/0 (Infinity)	4
Hypocalcemia	3/6 (50%)	3	1/7 (14.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1
Hypokalemia	3/6 (50%)	3	2/7 (28.6%)	2	3/10 (30%)	3	3/0 (Infinity)	3
Neutrophil count	1/6 (16.7%)	1	6/7 (85.7%)	7	4/10 (40%)	4	4/0 (Infinity)	4
Blood alkaline phosphatase increased	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
Hyperuricemia	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
aspartate aminotransferase increased	0/6 (0%)	0	2/7 (28.6%)	2	1/10 (10%)	1	1/0 (Infinity)	1
blood bilirubin increased	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Hyperkalemia	0/6 (0%)	0	2/7 (28.6%)	2	0/10 (0%)	0	0/0 (NaN)	0
Hypernatremia	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Hyponatremia	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
lipase increased	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
metabolic lab -other	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
CD4 lymphocytes decreased	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Back pain	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
Muscle weakness, lower extremity	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
Nervous system disorders
hydrocephalus	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
peripheral sensory neuropathy	0/6 (0%)	0	1/7 (14.3%)	1	1/10 (10%)	1	1/0 (Infinity)	1
Psychiatric disorders
Anorexia	0/6 (0%)	0	1/7 (14.3%)	1	2/10 (20%)	2	2/0 (Infinity)	2
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/6 (16.7%)	1	0/7 (0%)	0	2/10 (20%)	2	2/0 (Infinity)	2
Pulmonary	1/6 (16.7%)	1	0/7 (0%)	0	0/10 (0%)	0	0/0 (NaN)	0
pulmonary hypertension NOS	0/6 (0%)	0	1/7 (14.3%)	1	0/10 (0%)	0	0/0 (NaN)	0
Acute respiratory distress syndrome	0/6 (0%)	0	0/7 (0%)	0	1/10 (10%)	1	1/0 (Infinity)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.