Everolimus and Combination Chemotherapy in Treating Younger Patients with Relapsed Acute Lymphoblastic Leukemia

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IBiomarker/Laboratory analysis, TreatmentActive18 months to 21 years11-237
NCI-2012-00118, CRAD001NUS175T, NCT01523977

Trial Description


This phase I trial studies the side effects and best dose of everolimus when given together with combination chemotherapy in treating younger patients with acute lymphoblastic leukemia that has returned after a period of improvement. Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) together with everolimus may be a better treatment for acute lymphoblastic leukemia.

Further Study Information


I. To determine the safety and feasibility of treatment with everolimus in combination with vincristine sulfate (vincristine), prednisone, pegaspargase (PEG-asparaginase) and doxorubicin hydrochloride (doxorubicin) in patients with relapsed acute lymphoblastic leukemia (ALL).


I. To investigate the clinical activity (complete remission rate and levels of end-reinduction minimal residual disease [MRD]) of everolimus in combination with vincristine, prednisone, PEG-asparaginase and doxorubicin in patients with ALL.

II. To assess the impact of everolimus therapy when given in combination with vincristine, prednisone, PEG-asparaginase and doxorubicin on biologic markers of glucocorticoid resistance including levels of v-akt murine thymoma viral oncogene homolog 1 (AKT), myeloid cell leukemia sequence 1 (MCL1) and phosphorylated S6 ribosomal protein (PS6).

III. To explore possible determinants of response (as measured by peripheral blast clearance, MRD levels and complete remission [CR] status) to everolimus in combination with multi-agent therapy including measurements of anti-apoptotic proteins (B-cell chronic lymphocytic leukemia/lymphoma 2 [BCL2], BCL2-like 1 [BCLxL], and MCL1), genome-wide gene expression profiling, BCL-2 homology domain 3 (BH3) profiling and OncoMap profiling.

OUTLINE: This is a dose-escalation study of everolimus.

Patients receive everolimus orally (PO) once daily (QD) on days 1-32, cytarabine intrathecally (IT) on day 1, prednisone PO thrice daily (TID) on days 4-32, vincristine sulfate intravenously (IV) on days 4, 11, 18, and 25, doxorubicin hydrochloride IV over 15 minutes and dexrazoxane hydrochloride IV over 15 minutes on days 4 and 5, pegaspargase IV over 1 hour on days 5 and 18. Patients who are central nervous system (CNS) positive at the time of relapse also receive cytarabine IT on day 4 and methotrexate IT, cytarabine IT, and hydrocortisone sodium succinate IT on days 11, 18, 25, and 32. Patients who are CNS negative at the time of relapse also receive methotrexate IT, cytarabine IT, and hydrocortisone sodium succinate IT on days 18 and 32.

After completion of study treatment, patients are followed up at 30 days, 1 year, and 2 years.

Eligibility Criteria

Inclusion Criteria:

ALL in first bone marrow relapse occurring > 18 months (> 540 days) from initial diagnosis; marrow must have >= 25% blasts (M3 marrow), either on an aspirate or biopsy sample, as assessed by morphology, flow cytometry, and/or immunohistochemistry; individuals with CNS, testicular or other extramedullary involvement are eligible as long as they also meet marrow involvement criteria

No prior therapy for recurrent ALL is allowed prior to study entry with the exception of intrathecal (IT) chemotherapy; participants who have relapsed while receiving up-front therapy are eligible, but must have recovered from adverse effects from any previously administered agents

Patients who underwent stem cell transplant (SCT) in first complete remission are eligible, as long as all of the following criteria are met:

At least 100 days have elapsed since stem cell infusion

At least 14 days off of all medications for graft-versus-host-disease (GVHD) prophylaxis or treatment

No evidence of acute GVHD

Performance status: Lansky >= 50 for individuals 18 months to < 10 years old; Karnofsky > 50% for individuals 10-21 years old

Direct bilirubin =< 1.5 X institutional upper limit of normal (ULN)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X institutional upper limit of normal

Creatinine less than the institutional upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal

Serum lipase < 3 X institutional upper limit of normal

Shortening fraction >= 28% on screening echocardiogram

Fasting serum cholesterol =< 300 mg/dL or =< 7.75 mmol/L AND fasting triglycerides =< 300 mg/dL or 3.42 mmol/L

NOTE: non-fasting cholesterol/triglyceride levels that meet these criteria are acceptable; if these thresholds are exceeded in non-fasting samples, then fasting samples should be obtained

NOTE: if one or both of these thresholds are exceeded in fasting samples, the patient can only be included after initiation of appropriate lipid lowering medication

International normalized ratio (INR) =< 1.5

Maximum prior cumulative doxorubicin dose of =< 360 mg/m^2 or equivalent

Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Ability of participant (or parent/guardian for participants who are minors) to understand and the willingness to sign the written informed consent document

Exclusion Criteria:

Individuals with a known t(9;22)/breakpoint cluster region-Abelson (BCR-ABL) fusion based on testing at either initial diagnosis or at relapse

Individuals whose lymphoblasts have surface immunoglobulin by flow cytometry and/or known t(8;14), t(2;8), or t(8;22); absence of surface immunoglobulin by flow cytometry at time of initial diagnosis or relapse is sufficient to rule out mature B-cell leukemia; karyotype or fluorescent in situ hybridization (FISH) results documenting absence of t(8;14), t(2;8), or t(8;22) are not necessary prior to enrollment if absence of surface of immunoglobulin is documented by flow cytometry

Individuals with Down syndrome

Prior therapy with mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus, temsirolimus)

Individuals who have had a stem cell transplant and are still receiving treatment for GVHD or GVHD prophylaxis, or who have evidence of acute GVHD, or who are less than 100 days from stem cell infusion

Individuals who have received any investigational drug within 4 weeks

Individuals with a history of asparaginase-associated pancreatitis

Individuals with a history of allergic reactions to any of the agents being used in this trial, with the exception of PEG asparaginase; participants with a history of allergy to PEG asparaginase are allowed on study but should receive Erwinia asparaginase instead of PEG asparaginase; individuals with a history of allergy to both PEG and Erwinia asparaginase are excluded from the study

Individuals receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) enzyme(s) are eligible only if principal investigator approves subject enrollment prior to registration; participants who have received a medication or substance listed may be enrolled on study as long as they have discontinued its use at least 48 hours prior to registration

Individuals with active lung disease as defined by presence of pulmonary infiltrates on screening chest x-ray or baseline room air oxygen saturation of < 92%

Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g. ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption or small bowel resection)

Individuals with severe and/or uncontrolled intercurrent illness including, but not limited to:

Active (acute or chronic) or uncontrolled severe infections

Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C)

Unstable angina pectoris, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia or other clinically significant cardiac disease

Uncontrolled diabetes as defined by fasting serum glucose >= 200 mg/dL (note: participants with history of hyperglycemia receiving medical management whose fasting serum glucose is < 200 mg/dL with that management are eligible for enrollment)

Psychiatric illness/social situations that would limit compliance with study requirements

Individuals with a documented history of previous or current hepatitis B or C infection; hepatitis B or C serologic screening is not required prior to enrollment, except in participants with any of the following high-risk features:

Suspected (but not documented) previous hepatitis B or C infection

Blood transfusion(s) prior to 1990

Current or prior IV drug use

Current or prior dialysis

Household contact with hepatitis B or C infected individual

Mother with known hepatitis B or C infection

Current or prior high-risk sexual activity

For participants with any of the above high risk features: study enrollment will only be allowed if hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) or hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV)-ribonucleic acid (RNA) polymerase chain reaction (PCR) are negative within 14 days prior to study enrollment; any patient with a positive result on any of these screening tests is ineligible

Pregnant women are excluded from this study; breastfeeding is not allowed during study treatment

Individuals with a history of a different malignancy (other than ALL) are ineligible except for the following circumstances: individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin

Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible

Participants who have received immunizations with attenuated live vaccines within one week of study entry are not eligible; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Dana-Farber Harvard Cancer Center

  • National Cancer Institute
Lewis Barry Silverman, Principal Investigator

Trial Sites


San Francisco

UCSF Medical Center-Mount Zion

Mignon Lee-Cheun Loh
Ph: 415-502-4372
Email: lohm@peds.ucsf.edu

Mignon Lee-Cheun Loh
Principal Investigator


Children's Hospital Colorado

Lia Gore
Ph: 720-777-6772
Email: lia.gore@ucdenver.edu

Lia Gore
Principal Investigator


Children's Healthcare of Atlanta - Egleston

Melinda Gordon Pauly
Ph: 404-785-1200
Email: Melinda.Pauly@choa.org

Melinda Gordon Pauly
Principal Investigator


Lurie Children's Hospital-Chicago

Nobuko Hijiya
Ph: 312-227-4090
Email: nhijiya@luriechildrens.org

Nobuko Hijiya
Principal Investigator


Boston Children's Hospital

Lewis Barry Silverman
Ph: 617-632-6191
Email: lewis_silverman@dfci.harvard.edu

Lewis Barry Silverman
Principal Investigator

Dana-Farber Cancer Institute

Lewis Barry Silverman
Ph: 617-632-6191
Email: lewis_silverman@dfci.harvard.edu

Lewis Barry Silverman
Principal Investigator

New York
New York

Columbia University/Herbert Irving Cancer Center

Maria Luisa Sulis
Ph: 212-305-5808
Email: mls95@columbia.edu

Maria Luisa Sulis
Principal Investigator


Seattle Children's Hospital

Todd Michael Cooper
Ph: 206-987-2106
Email: Todd.Cooper@seattlechildrens.org

Todd Michael Cooper
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifier NCT01523977

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.