ADVL1114: A Phase I Study of Temsirolimus (CCI-779, IND# 61010) in Combination With Intensive Re-Induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma
What is the purpose of this study?
This phase I trial studies the side effects and the best dose of temsirolimus when given together with dexamethasone, mitoxantrone hydrochloride, vincristine sulfate, and pegaspargase in treating young patients with relapsed acute lymphoblastic leukemia or non-Hodgkin lymphoma.
Who can participate?
Disease Characteristics:
- Patients must have second or greater relapse of pre-B-cell acute lymphoblastic leukemia (ALL), T-cell ALL, lymphoblastic lymphoma, or peripheral T-cell lymphoma
- Patients with ALL, lymphoblastic lymphoma, or peripheral T-cell lymphoma refractory to first relapse therapy are eligible for enrollment
- Patients with leukemia must have had histologic verification of the malignancy at the most recent relapse, including immunophenotyping to confirm diagnosis
Disease status:
Leukemia: Patients with leukemia must have an M3 marrow with or without extramedullary site of relapse OR an M2 bone marrow with an extramedullary site of relapse
Lymphoma: Patients with non-Hodgkin lymphoma must have either measurable or evaluable disease
Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
Patients with known Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome are not eligible
Patients with known optic nerve and/or retinal involvement are not eligible; patients presenting with visual disturbances should have an ophthalmological exam and MRI within 14 days prior to enrollment to determine whether there is optic nerve or retinal involvement
Patient Characteristics:
- Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age
- Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
Platelet count ≥ 20,000/mm³ (may receive platelet transfusions) to initiate therapy
Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73m2 OR a serum creatinine based on age/gender as follows:
0.6 mg/dL ( 1 to < 2 years of age)
0.8 mg/dL (2 to < 6 years of age)
1.0 mg/dL (6 to < 10 years of age)
1.2 mg/dL (10 to < 13 years of age)
1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
SGPT (ALT) ≤ 225 U/L (ULN = 45 U/L)
Serum albumin ≥ 2 g/dL
Shortening fraction of ≥ 27% by echocardiogram OR ejection fraction of ≥ 50% by gated radionuclide study
Pulse oximetry > 94% on room air
Baseline chest x-ray; patients with active infectious disease or pneumonitis are not eligible
Serum triglyceride level ≤ 300 mg/dL and serum cholesterol level ≤ 300 mg/dL
Random or fasting blood glucose within the upper normal limits for age; if the initial blood glucose is a random sample that is above the upper normal limits, then a follow-up fasting blood glucose can be obtained and must be within the upper normal limits for age
Pregnant or breast-feeding women will not be entered on this study
Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
Patients who have an uncontrolled infection are not eligible
Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible
Prior Concurrent Therapy:
- See Disease Characteristics
- Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy
- Patients with leukemia or lymphoma who relapse while receiving standard maintenance chemotherapy with steroid, vincristine sulfate pulses, and oral outpatient chemotherapy will not be required to have a waiting period before enrollment onto this study
- Patients who relapse while they are not receiving standard maintenance therapy must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy, with the exception of hydroxyurea
- Cytoreduction with hydroxyurea in patients can be initiated and continued for up to 24 hours prior to the start of protocol therapy
At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
At least 42 days after the completion of any type of immunotherapy, e.g., tumor vaccines
At least 3 half-lives of the antibody after the last dose of a monoclonal antibody
At least 14 days after local palliative radiotherapy (XRT) (small port)
No evidence of active graft-versus-host disease and at least 84 days must have elapsed after transplant or stem cell infusion
Patient may not have received prior therapy with an mammalian target of rapamycin (mTOR) inhibitor
Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible (excluding pulsed steroids used for maintenance chemotherapy)
Patients who are currently receiving another investigational drug are not eligible
Patients who are currently receiving other anticancer agents are not eligible (except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
Patients who are receiving cyclosporine, tacrolimus, or other agents to prevent graft-versus-host disease post-bone marrow transplant are not eligible for this trial
Patients who cannot receive asparaginase are not permitted on trial; substitution with Erwinia L-asparaginase is acceptable
Cumulative prior anthracycline exposure must not exceed 400 mg/m² (each 10 mg/m² of idarubicin should be calculated as the isotoxic equivalent of 30 mg/m² of daunorubicin hydrochloride or doxorubicin hydrochloride)
Patients who are currently receiving therapeutic anticoagulants (including aspirin, low-molecular-weight heparin, and others) are not eligible
Patients who are currently receiving angiotensin-converting enzyme (ACE) inhibitors are not eligible
Patients who have received a prior solid organ transplantation are not eligible
The use of enzyme-inducing anticonvulsants or antifungals is not permitted while on study
No concurrent anticancer therapy including chemotherapy, radiotherapy, immunotherapy, or biologic therapy
No other concurrent investigational agents
Conditions
- Cancer - Leukemia and Lymphoma
What is involved?
This is a multicenter, dose-escalation study of temsirolimus.
Patients receive dexamethasone orally (PO) or IV on days 1-5 and 15-19; mitoxantrone hydrochloride IV over 30 minutes on days 1-2; temsirolimus IV over 30 minutes on days 1, 8, and 15; vincristine sulfate IV on days 1, 8, 15, and 22; and pegaspargase IV over 1 hour on days 3 and 17. Some patients may also receive methotrexate intrathecally (IT) up to 72 hours prior to or on day 1 and on day 8.
Patients undergo blood and bone marrow collection (patients with ALL only) at baseline, during, and after completion of study for in vitro and in vivo pharmacodynamic studies.
After completion of study therapy, patients are followed up for 30 days.
What are the benefits?
Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, mitoxantrone hydrochloride, vincristine sulfate, and pegaspargase work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus together with combination chemotherapy may kill more cancer cells.
Will I get all the facts about the study?
N/A
Do participants receive pay, compensation or reimbursement?
N/A
Who should I contact for more information?
For more information contact:
Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org
Principal Investigator
N/A
