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

NCT ID: NCT01403415

Last Updated: 2015-07-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Given PO or IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Methotrexate

Intervention Type: DRUG

Given IT

Mitoxantrone Hydrochloride

Intervention Type: DRUG

Given IV

Pegaspargase

Intervention Type: DRUG

Given IV

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Temsirolimus

Intervention Type: DRUG

Given IV

Vincristine Sulfate

Intervention Type: DRUG

Given IV

Interventions

Dexamethasone

Given PO or IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Methotrexate

Given IT

Intervention Type: DRUG

Mitoxantrone Hydrochloride

Given IV

Intervention Type: DRUG

Pegaspargase

Given IV

Intervention Type: DRUG

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Temsirolimus

Given IV

Intervention Type: DRUG

Vincristine Sulfate

Given IV

Intervention Type: DRUG

Other Intervention Names

Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; Visumetazone; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate; Mexate-AQ; MTX; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan; L-Asparaginase with Polyethylene Glycol; Oncaspar; PEG-Asparaginase; PEG-L-Asparaginase; PEG-L-Asparaginase (Enzon - Kyowa Hakko); PEGLA; Polyethylene Glycol L-Asparaginase; Polyethylene Glycol-L-Asparaginase; CCI-779; CCI-779 Rapamycin Analog; Cell Cycle Inhibitor 779; Rapamycin Analog; Rapamycin Analog CCI-779; Torisel; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Oncovin; Vincasar; Vincosid; Vincrex; Vincristine, sulfate

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:

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
• 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 age
• 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 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
• 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

• 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susan Rheingold

Role: PRINCIPAL_INVESTIGATOR

COG Phase I Consortium

Locations

Children's Hospital of Alabama

Birmingham, Alabama, United States

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Childrens Hospital of Orange County

Orange, California, United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Rady Children's Hospital - San Diego

San Diego, California, United States

UCSF Medical Center-Parnassus

San Francisco, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota, United States

University of Minnesota Medical Center-Fairview

Minneapolis, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

The Childrens Mercy Hospital

Kansas City, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

Columbia University Medical Center

New York, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital

Cleveland, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

Midwest Children's Cancer Center

Milwaukee, Wisconsin, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Countries

United States; Canada

Other Identifiers

NCI-2011-02679

Identifier Type: REGISTRY

Identifier Source: secondary_id

COG-ADVL1114

Identifier Type: -

Identifier Source: secondary_id

CDR0000703889

Identifier Type: -

Identifier Source: secondary_id

ADVL1114

Identifier Type: OTHER

Identifier Source: secondary_id

ADVL1114

Identifier Type: OTHER

Identifier Source: secondary_id

U01CA097452

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2011-02679

Identifier Type: -

Identifier Source: org_study_id