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

Phase 1

Terminated

• Conditions: Relapsed T-Cell Lymphoblastic Lymphoma; Relapsed T-Cell Acute Lymphoblastic Leukemia
• Interventions: Drug: Nelarabine; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Filgrastim

• Registration Number: NCT00981799
• Lead Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-09-09
• Study First Submitted QC: 2009-09-18
• Study First Posted: 2009-09-22
• Study Start: 2010-06
• Primary Completion: 2015-11
• Study Completion: 2016-07-18
• Status Verified: 2020-09
• Results First Submitted: 2020-09-08
• Results First Submitted QC: 2020-09-08
• Last Update Submitted: 2020-09-08
• Results First Posted: 2020-10-01
• Last Update Posted: 2020-10-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 23

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Nelarabine Dose Level 1	Etoposide	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.
Nelarabine Dose Level 2	Nelarabine	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.
Nelarabine Dose Level 2	Etoposide	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.
Nelarabine Dose Level 2	Filgrastim	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.
Nelarabine Dose Level 3	Nelarabine	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide
Nelarabine Dose Level 3	Etoposide	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide
Nelarabine Dose Level 3	Cyclophosphamide	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide
Nelarabine Dose Level 0	Nelarabine	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 Level 0	Etoposide	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 Level 0	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 Level 1	Nelarabine	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.
Nelarabine Dose Level 1	Cyclophosphamide	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.
Nelarabine Dose Level 1	Methotrexate	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.
Nelarabine Dose Level 1	Filgrastim	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.
Nelarabine Dose Level 2	Cyclophosphamide	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.
Nelarabine Dose Level 2	Methotrexate	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 330 mg/m2 Cyclophosphamide.
Nelarabine Dose Level 3	Filgrastim	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide
Nelarabine Dose Level 3	Methotrexate	Patients in this arm will be administered Nelarabine at 650 mg/m2 (100% of single agent MTD) and 400 mg/m2 Cyclophosphamide
Nelarabine Dose Level 0	Methotrexate	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 Level 0	Filgrastim	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.

Trial Locations

Locations (37)

Childrens Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

University of Texas at Southwestern; 🇺🇸 Dallas, Texas, United States

University of Miami Cancer Center; 🇺🇸 Miami, Florida, United States

Children's Healthcare of Atlanta, Emory University; 🇺🇸 Atlanta, Georgia, United States

Rainbow Babies; 🇺🇸 Cleveland, Ohio, United States

Nationwide Childrens Hospital; 🇺🇸 Columbus, Ohio, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

UCSF School of Medicine; 🇺🇸 San Francisco, California, United States

New York University Medical Center; 🇺🇸 New York, New York, United States

St. Anna Children's Hospital; 🇦🇹 Vienna, Austria

Dana Farber; 🇺🇸 Boston, Massachusetts, United States

Childrens Hospital & Clinics of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

The Children's Hospital, University of Colorado; 🇺🇸 Aurora, Colorado, United States

St. Jude; 🇺🇸 Memphis, Tennessee, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Vanderbilt Children's Hospital; 🇺🇸 Nashville, Tennessee, United States

Sydney Children's Hospital; 🇦🇺 Sydney, Australia

Children's Hospital New York-Presbyterian; 🇺🇸 New York, New York, United States

C.S. Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Bambino Gesù Hospital; 🇮🇹 Rome, Italy

Hospital for Sick Kids; 🇨🇦 Toronto, Ontario, Canada

CHU Lille; 🇫🇷 Lille, France

Cook Children's Hospital; 🇺🇸 Fort Worth, Texas, United States

Royal Children's Hospital, Melbourne; 🇦🇺 Melbourne, Victoria, Australia

British Columbia Children's Hospital; 🇨🇦 Vancouver, Canada

Sainte Justine University Hospital; 🇨🇦 Montreal, Quebec, Canada

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Children's Hospital Orange County; 🇺🇸 Orange, California, United States

Children's Mercy Hospitals and Clinics; 🇺🇸 Kansas City, Missouri, United States

Levine Children's Hospital at Carolinas Medical Center; 🇺🇸 Charlotte, North Carolina, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Children's Hospital at Westmead; 🇦🇺 Westmead, New South Wales, Australia

Erasmus MC - Sophia; 🇳🇱 Rotterdam, Netherlands

Primary Children's; 🇺🇸 Salt Lake City, Utah, United States

Royal Children's Hospital; 🇦🇺 Brisbane, Queensland, Australia

Lurie Children's Hospital; 🇺🇸 Chicago, Illinois, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States