search
Back to results

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

Primary Purpose

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

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Nelarabine
Etoposide
Cyclophosphamide
Methotrexate
Filgrastim
Sponsored by
Therapeutic Advances in Childhood Leukemia Consortium
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsed T-Cell Acute Lymphoblastic Leukemia focused on measuring Relapse, T cell, Lymphoblastic, Leukemia, Lymphoma, Nelarabine, TACL, NECTAR

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Childrens Hospital Los Angeles
  • Children's Hospital Orange County
  • UCSF School of Medicine
  • The Children's Hospital, University of Colorado
  • Children's National Medical Center
  • University of Miami Cancer Center
  • Children's Healthcare of Atlanta, Emory University
  • Lurie Children's Hospital
  • Johns Hopkins University
  • Dana Farber
  • C.S. Mott Children's Hospital
  • Childrens Hospital & Clinics of Minnesota
  • Children's Mercy Hospitals and Clinics
  • New York University Medical Center
  • Children's Hospital New York-Presbyterian
  • Levine Children's Hospital at Carolinas Medical Center
  • Rainbow Babies
  • Nationwide Childrens Hospital
  • Oregon Health and Science University
  • St. Jude
  • Vanderbilt Children's Hospital
  • University of Texas at Southwestern
  • Cook Children's Hospital
  • Primary Children's
  • Seattle Children's Hospital
  • Medical College of Wisconsin
  • Children's Hospital at Westmead
  • Royal Children's Hospital
  • Royal Children's Hospital, Melbourne
  • Sydney Children's Hospital
  • St. Anna Children's Hospital
  • Hospital for Sick Kids
  • Sainte Justine University Hospital
  • British Columbia Children's Hospital
  • CHU Lille
  • Bambino Gesù Hospital
  • Erasmus MC - Sophia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Nelarabine Dose Level 1

Nelarabine Dose Level 2

Nelarabine Dose Level 3

Nelarabine Dose Level 0

Arm 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. 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.

Outcomes

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.
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.
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.

Full Information

First Posted
September 9, 2009
Last Updated
September 8, 2020
Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
Collaborators
GlaxoSmithKline, Novartis
search

1. Study Identification

Unique Protocol Identification Number
NCT00981799
Brief Title
Trial of Nelarabine, Etoposide and Cyclophosphamide in Relapsed T-cell ALL and T-cell LL
Official Title
A Phase I Trial of NECTAR (Nelarabine, Etoposide and Cyclophosphamide in T-ALL Relapse): A Joint Study of TACL and POETIC
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual rate
Study Start Date
June 2010 (undefined)
Primary Completion Date
November 2015 (Actual)
Study Completion Date
July 18, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
Collaborators
GlaxoSmithKline, Novartis

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed T-Cell Acute Lymphoblastic Leukemia, Relapsed T-Cell Lymphoblastic Lymphoma
Keywords
Relapse, T cell, Lymphoblastic, Leukemia, Lymphoma, Nelarabine, TACL, NECTAR

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jim Whitlock, MD
Organizational Affiliation
The Hospital for Sick Children
Official's Role
Study Chair
Facility Information:
Facility Name
Childrens Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's Hospital Orange County
City
Orange
State/Province
California
Country
United States
Facility Name
UCSF School of Medicine
City
San Francisco
State/Province
California
ZIP/Postal Code
94143-0106
Country
United States
Facility Name
The Children's Hospital, University of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
Country
United States
Facility Name
University of Miami Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Children's Healthcare of Atlanta, Emory University
City
Atlanta
State/Province
Georgia
Country
United States
Facility Name
Lurie Children's Hospital
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
Country
United States
Facility Name
Dana Farber
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
C.S. Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0914
Country
United States
Facility Name
Childrens Hospital & Clinics of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404-4597
Country
United States
Facility Name
Children's Mercy Hospitals and Clinics
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Children's Hospital New York-Presbyterian
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Levine Children's Hospital at Carolinas Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Facility Name
Rainbow Babies
City
Cleveland
State/Province
Ohio
Country
United States
Facility Name
Nationwide Childrens Hospital
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
Country
United States
Facility Name
St. Jude
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105-3678
Country
United States
Facility Name
Vanderbilt Children's Hospital
City
Nashville
State/Province
Tennessee
Country
United States
Facility Name
University of Texas at Southwestern
City
Dallas
State/Province
Texas
Country
United States
Facility Name
Cook Children's Hospital
City
Fort Worth
State/Province
Texas
Country
United States
Facility Name
Primary Children's
City
Salt Lake City
State/Province
Utah
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
Country
United States
Facility Name
Children's Hospital at Westmead
City
Westmead
State/Province
New South Wales
Country
Australia
Facility Name
Royal Children's Hospital
City
Brisbane
State/Province
Queensland
Country
Australia
Facility Name
Royal Children's Hospital, Melbourne
City
Melbourne
State/Province
Victoria
Country
Australia
Facility Name
Sydney Children's Hospital
City
Sydney
Country
Australia
Facility Name
St. Anna Children's Hospital
City
Vienna
Country
Austria
Facility Name
Hospital for Sick Kids
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
Sainte Justine University Hospital
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
British Columbia Children's Hospital
City
Vancouver
Country
Canada
Facility Name
CHU Lille
City
Lille
Country
France
Facility Name
Bambino Gesù Hospital
City
Rome
Country
Italy
Facility Name
Erasmus MC - Sophia
City
Rotterdam
Country
Netherlands

12. IPD Sharing Statement

Links:
URL
http://www.tacl.us
Description
For more information about this and other clinical trials, please visit the TACL website

Learn more about this trial

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

We'll reach out to this number within 24 hrs