Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

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 together with combination chemotherapy may kill more cancer cells.

Further Study Information

PRIMARY OBJECTIVES:

I. To estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose of temsirolimus administered weekly for 3 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 mTOR inhibition using in vitro and in vivo pharmacodynamic assessment of the response of ALL blasts to temsirolimus.

OUTLINE: 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 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.

Patients undergo blood and bone marrow collection 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.

Eligibility Criteria

Inclusion Criteria:

• Diagnosis:

• Patients must have 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 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; patients with 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

• Myelosuppressive chemotherapy:

• Patients with leukemia or lymphoma who relapse while receiving standard maintenance chemotherapy with steroid, vincristine 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

• Note: Cytoreduction with hydroxyurea in patients can be initiated and continued for up to 24 hours prior to the start of protocol therapy

• Hematopoietic growth factors: 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

• Biologic (anti-neoplastic agent): 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

• Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines

• Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody with the exception of blinatumomab; patients must have been off blinatumomab infusion for at least 7 days and all drug-related toxicity must have resolved to Grade 1 or lower as outline in the inclusion and exclusion criteria

• XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have elapsed if prior TBI, craniospinal XRT or if >= 50% radiation of pelvis; At least 42 days must have elapsed if other substantial BM radiation

• Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant or stem cell infusion

• Study specific limitations on prior therapy: Patient may not have received prior therapy with an mTOR inhibitor

• Platelet count >= 20,000/mm^3 (may receive platelet transfusions) to initiate therapy

• Patients must not be known to be refractory to red cell or platelet transfusion

• Creatinine clearance or radioisotope GFR >= 70ml/min/1.73 m^2

• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age

• SGPT (ALT) =< 225 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

• GGT =< ULN for age

• 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; iIf 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

• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

• 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)

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study

• 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 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 asparginase 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/m2 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 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, phenobarbitol, or carbamazepine) are not eligible

• Patients with CNS 3 status at enrollment are not eligible

• Patients must have no pre-existing Grade 1 or higher ulcerations, fistulas, mucosal lesions, or skin barrier breakdown

• Patients who have an uncontrolled infection are not eligible

• Patients with known optic nerve and/or retinal involvement (because it may not be possible to safely delay irradiation) are not eligible; patients presenting with visual disturbances by history or physical exam should have an ophthalmological exam and MRI within 14 days prior to enrollment to determine whether there is optic nerve or retinal involvement

• Patients with known Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome are not eligible

• Patients who have received a prior solid organ transplantation 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

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Susan Rheingold

Principal Investigator

U.S.A.
Alabama
	Birmingham
	Children's Hospital of Alabama at University of Alabama at Birmingham
		Joseph G Pressey	Ph: 205-934-0309
California
	Arcadia
	Children's Oncology Group
		Susan R Rheingold	Ph: 215-590-3079
			Email: rheingold@email.chop.edu
	San Diego
	Rady Children's Hospital - San Diego
		William D Roberts	Ph: 858-966-5934
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Steven G DuBois	Ph: 877-827-3222
Georgia
	Atlanta
	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
		Howard M Katzenstein	Ph: 888-785-1112
Indiana
	Indianapolis
	Riley's Children Cancer Center at Riley Hospital for Children
		James M Croop	Ph: 317-274-2552
Missouri
	Kansas City
	Children's Mercy Hospital
		Keith J August	Ph: 816-234-3265
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Robert J Hayashi	Ph: 800-600-3606
			Email: info@siteman.wustl.edu
North Carolina
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Stuart H Gold	Ph: 877-668-0683
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		John P Perentesis	Ph: 513-636-2799
	Cleveland
	Seidman Cancer Center at University Hospitals/Case Medical Center
		Yousif (Joe) H Matloub	Ph: 216-844-5437
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Linda C. Stork	Ph: 503-494-1080
			Email: trials@ohsu.edu
Pennsylvania
	Pittsburgh
	Children's Hospital of Pittsburgh of UPMC
		Regina I Jakacki	Ph: 412-692-5573
Tennessee
	Nashville
	Vanderbilt-Ingram Cancer Center
		Valerie I Brown	Ph: 215-590-2810
Texas
	Houston
	Dan L. Duncan Cancer Center at Baylor College of Medicine
		Lisa R Bomgaars	Ph: 713-798-1354
			Email: burton@bcm.edu

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01403415
Information obtained from ClinicalTrials.gov on March 26, 2013

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