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

Study Overview
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Brief Summary
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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.

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

Conditions
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Relapsed T-Cell Acute Lymphoblastic Leukemia, Relapsed T-Cell Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: Nelarabine
* Drug: Etoposide
* Drug: Cyclophosphamide
* Drug: Methotrexate
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 1-3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapse, T cell, Lymphoblastic, Leukemia, Lymphoma, Nelarabine, TACL, NECTAR