A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
- Conditions
- Lymphoblastic Leukemia, Acute, ChildhoodPeripheral T-cell LymphomaLymphoblastic Lymphoma
- Interventions
- Registration Number
- NCT01614197
- Lead Sponsor
- Therapeutic Advances in Childhood Leukemia Consortium
- Brief Summary
This is a phase I study of temsirolimus (Torisel) combined with dexamethasone, cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).
- Detailed Description
Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL cell lines in vitro and in ALL xenograft models. The MTI temsirolimus was chosen for use in this study due to its weekly intravenous dosing, its more predictable blood levels, and availability of a single-agent pediatric MTD and its sustained biologic effect due to conversion to sirolimus. This study will determine the maximum tolerated dose of temsirolimus that can given in combination with dexamethasone, cyclophosphamide and etoposide in relapsed ALL, LL or PTL. A standard 3-patient cohort dose-escalation design will be used. Response to treatment will be evaluated. Biology tests will be done to evaluate minimal residual disease (MRD), temsirolimus' effect on glucocorticoid resistance, and mTOR inhibition.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 16
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Level 1 Temsirolimus This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 1 Etoposide This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 1 Cyclophosphamide This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 1 Methotrexate This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 1 Hydrocortisone This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 1 Cytarabine This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 2 Temsirolimus If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 2 Etoposide If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 2 Hydrocortisone If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 2 Cyclophosphamide If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 2 Methotrexate If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 2 Cytarabine If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 3 Temsirolimus If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 3 Etoposide If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 3 Cyclophosphamide If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 3 Methotrexate If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 3 Hydrocortisone If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 4 Etoposide If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4. Dose Level 3 Cytarabine If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Dose Level 4 Temsirolimus If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4. Dose Level 4 Cyclophosphamide If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4. Dose Level 4 Methotrexate If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4. Dose Level 4 Cytarabine If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4. Dose Level 4 Hydrocortisone If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.
- Primary Outcome Measures
Name Time Method Number of Patients That Experienced DLT During Cycle 1 of Therapy Cycle 1 (a minimum of 4 weeks and a max of 8 weeks) The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy. All these analyses will be descriptive and exploratory and hypotheses generating in nature.
- Secondary Outcome Measures
Name Time Method Minimum Residual Disease (MRD) Levels Present at End of Cycle 1 Therapy in Patients Cycle 1 (a minimum of 4 weeks and a max of 8 weeks) MRD positive is defined as \> or = to 0.1% MRD MRD negative is define as \< 0.1% MRD
All these analyses will be descriptive and exploratory and hypotheses generating in nature.Response Rate at the Completion of 1 Cycle of Study Treatment Cycle 1 (a minimum of 4 weeks and a max of 8 weeks) CR = Complete remission defined as attainment of bone marrow with \<5% blasts with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (absolute neutrophil counts (ANC) \> or = to 500/uL and platelet count \> or = to 50,000 microliters) CRi = Complete remission with incomplete blood count recovery defined as attainment of bone marrow with \>5% blasts with no evidence of circulating blasts or extramedullary disease but insufficient recovery of ANC \< 500/uL or platelets \< 50,000 microliters PR = partial remission defined as complete disappearance of circulating blasts and achievement of 5-25% blasts if greater than 25% blasts originally without new sites of extramedullary disease and with recovery of ANC.
SD = stable disease defined as not satisfying criteria for PD, or has recovery of ANC \> or = to 500/uL and fails to qualify for CR, CRi, or PR PD = progressive disease defined as an increase of at least 25% in bone marrow leukemic cells
Trial Locations
- Locations (32)
Childrens Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's Healthcare of Atlanta, Emory University
🇺🇸Atlanta, Georgia, United States
Lurie Children's Hospital
🇺🇸Chicago, Illinois, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Dana Farber
🇺🇸Boston, Massachusetts, United States
Rainbow Babies
🇺🇸Cleveland, Ohio, United States
University of Texas at Southwestern
🇺🇸Dallas, Texas, United States
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
The Children's Hospital, University of Colorado
🇺🇸Aurora, Colorado, United States
UCSF School of Medicine
🇺🇸San Francisco, California, United States
University of Miami Cancer Center
🇺🇸Miami, Florida, United States
C.S. Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Childrens Hospital & Clinics of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Levine Children's Hospital at Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
Children's Hospital New York-Presbyterian
🇺🇸New York, New York, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Nationwide Childrens Hospital
🇺🇸Columbus, Ohio, United States
St. Jude
🇺🇸Memphis, Tennessee, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Primary Children's
🇺🇸Salt Lake City, Utah, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Royal Children's Hospital
🇦🇺Brisbane, Queensland, Australia
Hospital for Sick Kids
🇨🇦Toronto, Ontario, Canada
Sydney Children's Hospital
🇦🇺Sydney, Australia
Royal Children's Hospital, Melbourne
🇦🇺Melbourne, Victoria, Australia
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States