Trial of Nelarabine, Etoposide and Cyclophosphamide in Relapsed T-cell ALL and T-cell LL
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| ClinicalTrials.gov Identifier: NCT00981799 |
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Recruitment Status :
Terminated
(Slow accrual rate)
First Posted : September 22, 2009
Results First Posted : October 1, 2020
Last Update Posted : October 1, 2020
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Sponsor:
Therapeutic Advances in Childhood Leukemia Consortium
Collaborators:
GlaxoSmithKline
Novartis
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
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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 Type : | Interventional (Clinical Trial) |
| 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 : | June 2010 |
| Actual Primary Completion Date : | November 2015 |
| Actual Study Completion Date : | July 18, 2016 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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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.
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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:
Drug: Etoposide 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5
Other Names:
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 Name: 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:
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:
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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.
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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:
Drug: Etoposide 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5
Other Names:
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 Name: 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:
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:
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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
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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:
Drug: Etoposide 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5
Other Names:
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 Name: 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:
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:
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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.
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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:
Drug: Etoposide 100 mg/m2/day IV over 2 hours (given at hours 1 to 3) on days 1 through 5
Other Names:
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 Name: 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:
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:
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Primary Outcome Measures :
- 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. [ Time Frame: 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 :
- 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 ]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.
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| Ages Eligible for Study: | 1 Year to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00981799
Locations
Show 37 study locations
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
GlaxoSmithKline
Novartis
Investigators
| Study Chair: | Jim Whitlock, MD | The Hospital for Sick Children |
Additional Information:
| Responsible Party: | Therapeutic Advances in Childhood Leukemia Consortium |
| ClinicalTrials.gov Identifier: | NCT00981799 |
| Other Study ID Numbers: |
T2008-002 |
| First Posted: | September 22, 2009 Key Record Dates |
| Results First Posted: | October 1, 2020 |
| Last Update Posted: | October 1, 2020 |
| Last Verified: | September 2020 |
Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
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Relapse T cell Lymphoblastic Leukemia |
Lymphoma Nelarabine TACL NECTAR |
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Leukemia Leukemia, Lymphoid Cyclophosphamide Methotrexate Etoposide Lenograstim Sargramostim |
Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Antimetabolites, Antineoplastic Antimetabolites Dermatologic Agents |