A Phase 1 Study of Temsirolimus in Combination With Intensive Re-induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Temsirolimus
- Conditions
- Childhood B Acute Lymphoblastic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 13
- Locations
- 31
- Primary Endpoint
- Dose-limiting toxicity of temsirolimus in combination with intensive re-induction chemotherapy graded according to the NCI CTCAE v4.0
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
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. 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 with combination chemotherapy may be and effective treatment for acute lymphoblastic leukemia or non-Hodgkin lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. To estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of temsirolimus administered weekly for 2 doses in combination with intensive re-induction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). II. To define and describe the toxicities of temsirolimus in combination with intensive re-induction chemotherapy in children with relapsed ALL or NHL administered on this schedule. SECONDARY OBJECTIVES: I. To compare minimal-residual disease (MRD) levels present at end of induction to historical control in patients with relapsed ALL or NHL with bone marrow involvement of disease. II. To determine the complete remission (CR) rate in patients with ALL or NHL who receive this regimen. III. To evaluate responsiveness of patient ALL cells to mammalian target of rapamycin (mTOR) inhibition using in vitro and in vivo pharmacodynamic assessment of the response of ALL blasts to temsirolimus. OUTLINE: This is a dose-escalation study of temsirolimus. Patients receive dexamethasone orally (PO) or intravenously (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 and 8; 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. After completion of study therapy, patients are followed up for 30 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis:
- •Patients must have second (2nd) or greater relapse of pre-B ALL, T-cell ALL, lymphoblastic lymphoma, or peripheral T-cell lymphoma; patients may not have refractory disease
- •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; patients with central nervous system (CNS) 3 status are not eligible for enrollment
- •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
- •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
- •Prior Therapy:
- •Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy, defined as resolution of all such toxicities to =\< grade 2 or per the inclusion/exclusion criteria
Exclusion Criteria
- •Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
- •Patients receiving stable or decreasing doses of corticosteroids for =\< 7 days prior to enrollment, or who are receiving increasing doses of corticosteroids, are not eligible for enrollment; the exception to this is pulsed steroids used for maintenance chemotherapy
- •Patients who are currently receiving another investigational drug are not eligible
- •Patients who are currently receiving other anti-cancer 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 Asparaginase Erwinia Chrysanthemi is acceptable
- •Cumulative prior anthracycline exposure must not exceed 400 mg/m\^2 (each 10 mg/m\^2 of idarubicin or mitoxantrone should be calculated as the isotoxic equivalent of 30 mg/m\^2 of daunorubicin or doxorubicin)
- •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 due to the development of angioneurotic edema-type reactions in some subjects who received concurrent treatment with temsirolimus + ACE inhibitors
- •Enzyme-Inducing anti-convulsants: patients who are currently receiving enzyme-inducing anti-convulsants (i.e., phenytoin, phenobarbital, or carbamazepine) are not eligible
Arms & Interventions
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Temsirolimus
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Vincristine Sulfate
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Dexamethasone
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Laboratory Biomarker Analysis
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Methotrexate
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Mitoxantrone Hydrochloride
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Pegaspargase
Treatment (temsirolimus, combination chemotherapy)
Patients receive dexamethasone 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 and 8; 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 IT up to 72 hours prior to or on day 1 and on day 8.
Intervention: Pharmacological Study
Outcomes
Primary Outcomes
Dose-limiting toxicity of temsirolimus in combination with intensive re-induction chemotherapy graded according to the NCI CTCAE v4.0
Time Frame: Up to 30 days post-treatment
A descriptive summary of all toxicities will be reported.
MTD and/or recommended phase II dose defined as the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
Time Frame: Up to day 36
A descriptive summary of all toxicities will be reported.
Secondary Outcomes
- MRD levels present at the end of induction(Up to 30 days post-treatment)
- mTOR inhibitor effects on downstream signaling in patient lymphoblasts In vitro and in vivo(Up to 30 days post-treatment)
- CR rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria(Up to 30 days post-treatment)