Trial of Nelarabine, Etoposide and Cyclophosphamide in Relapsed T-cell ALL and T-cell LL
Verified December 2014 by Therapeutic Advances in Childhood Leukemia Consortium
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
First received: September 9, 2009
Last updated: December 3, 2014
Last verified: December 2014
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.
Relapsed T-Cell Acute Lymphoblastic Leukemia
Relapsed T-Cell Lymphoblastic Lymphoma
||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Phase I Trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse): A Joint Study of TACL and POETIC
Primary Outcome Measures:
- To determine the maximum tolerated doses and 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. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- 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. [ Time Frame: 1-3 months ] [ Designated as safety issue: No ]
- To determine the percent of children with T-ALL and 1st BM relapse that have a complete response after therapy on this study and proceed to stem cell transplantation in complete response within 20 weeks of beginning this regimen. [ Time Frame: 5 months ] [ Designated as safety issue: No ]
- To determine minimal residual disease (MRD) levels at the end of each course of treatment. [ Time Frame: 60 days ] [ Designated as safety issue: No ]
- To evaluate the vitamin B12 pathway and metabolites and the potential association of neurotoxicity following nelarabine therapy with alterations in this pathway. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To determine, in a preliminary manner, whether patients with relapsed T-ALL/LL have a distinct signaling signature that distinguishes malignant cells from normal thymocytes. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- To evaluate, in a preliminary manner, whether phospho-flow cytometry can be used to predict clinical response to Nelarabine. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
| Estimated Enrollment:
| Study Start Date:
| Estimated Primary Completion Date:
||December 2016 (Final data collection date for primary outcome measure)
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.
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.
Other Name: Cytoxan
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.
- granulocyte colony stimulating factor
|Ages Eligible for Study:
||1 Year to 21 Years
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- 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.
- 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00981799
Therapeutic Advances in Childhood Leukemia Consortium
||Jim Whitlock, MD
||The Hospital for Sick Children
No publications provided
||Therapeutic Advances in Childhood Leukemia Consortium
History of Changes
|Other Study ID Numbers:
|Study First Received:
||September 9, 2009
||December 3, 2014
||United States: Institutional Review Board
Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Health Canada
Brazil: National Committee of Ethics in Research
Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on October 06, 2015
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Neoplasms by Histologic Type
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Phytogenic
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Topoisomerase II Inhibitors