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Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma

Intervention: Dexamethasone (Drug); Laboratory Biomarker Analysis (Other); Methotrexate (Drug); Mitoxantrone Hydrochloride (Drug); Pegaspargase (Drug); Pharmacological Study (Other); Temsirolimus (Drug); Vincristine Sulfate (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Susan Rheingold, Principal Investigator, Affiliation: COG Phase I Consortium


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.

Clinical Details

Official title: A Phase 1 Study of Temsirolimus in Combination With Intensive Re-induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Dose-limiting toxicity of temsirolimus in combination with intensive re-induction chemotherapy graded according to the NCI CTCAE v4.0

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

Secondary outcome:

CR rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria

MRD levels present at the end of induction

mTOR inhibitor effects on downstream signaling in patient lymphoblasts In vitro and in vivo

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.


Minimum age: 1 Year. Maximum age: 21 Years. Gender(s): Both.


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

- 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

- Radiation therapy (XRT): at least 14 days after local palliative XRT (small

port); at least 84 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation

- Stem cell infusion: no evidence of active graft versus (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

- Note: intrathecal (IT) methotrexate (MTX) that is given up to 72 hours prior to

initiation of systemic chemotherapy per ADVL1114 counts as protocol therapy and not prior anti-cancer therapy; IT MTX given > 72 hours prior does not count as protocol therapy

- 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 glomerular filtration rate (GFR) >=

70ml/min/1. 73 m^2 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 (sum of conjugated + unconjugated) =< 1. 5 x upper limit of normal (ULN) for


- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225

U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- Gamma-glutamyl transpeptidase (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


- 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

- 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 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

- 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 magnetic resonance imaging (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

Locations and Contacts

Children's Hospital of Alabama, Birmingham, Alabama 35233, United States

Phoenix Childrens Hospital, Phoenix, Arizona 85016, United States

Childrens Hospital of Orange County, Orange, California 92868, United States

Lucile Packard Children's Hospital Stanford University, Palo Alto, California 94304, United States

Rady Children's Hospital - San Diego, San Diego, California 92123, United States

UCSF Medical Center-Parnassus, San Francisco, California 94143, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

Children's Healthcare of Atlanta - Egleston, Atlanta, Georgia 30322, United States

Lurie Children's Hospital-Chicago, Chicago, Illinois 60611, United States

Riley Hospital for Children, Indianapolis, Indiana 46202, United States

C S Mott Children's Hospital, Ann Arbor, Michigan 48109, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

University of Minnesota Medical Center-Fairview, Minneapolis, Minnesota 55455, United States

University of Mississippi Medical Center, Jackson, Mississippi 39216, United States

The Childrens Mercy Hospital, Kansas City, Missouri 64108, United States

Washington University School of Medicine, Saint Louis, Missouri 63110, United States

Columbia University Medical Center, New York, New York 10032, United States

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Rainbow Babies and Childrens Hospital, Cleveland, Ohio 44106, United States

Nationwide Children's Hospital, Columbus, Ohio 43205, United States

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Oregon Health and Science University, Portland, Oregon 97239, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, United States

Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee 37232, United States

UT Southwestern/Simmons Cancer Center-Dallas, Dallas, Texas 75390, United States

Baylor College of Medicine, Houston, Texas 77030, United States

Primary Children's Hospital, Salt Lake City, Utah 84113, United States

Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: September 2011
Last updated: July 9, 2015

Page last updated: August 23, 2015

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