CRAD001NUS175T: Everolimus With Multiagent Re-Induction Chemotherapy in Pediatric Patients With ALL

Sponsor

Dana-Farber Cancer Institute (Other)

Overall Status

Completed

CT.gov ID

NCT01523977

Collaborator

Novartis (Industry)

Enrollment

Locations

Duration (Months)

2.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Laboratory and other studies suggest that, the study drug, Everolimus (RAD001), may prevent tumor cell growth and also may increase the efficacy of other chemotherapy drugs. Everolimus is approved for use in the United States for certain types of cancer, such as kidney cancer. It has been extensively studied in people with various types of cancer as a single agent (a drug that is used alone to treat the cancer) or in combination with a number of other drugs. Studies in adults with cancer have also evaluated Everolimus in combination with other anti-tumor drugs. Information from lab studies and some other clinical trials suggests that Everolimus may kill leukemia cells on its own, and also make it more likely that steroids (such as prednisone) are able to kill leukemia cells.

In this research study, we are looking to learn more about how Everolimus works in combination with other drugs which are commonly used to treat relapsed acute lymphoblastic leukemia (prednisone, vincristine, PEG-asparaginase, and doxorubicin). The main goal of the study is to evaluate the side effects of this treatment combination in order to determine a safe dose of Everolimus which can be given with these other 4 drugs.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Drug: Everolimus Drug: Prednisone Drug: Vincristine Drug: PEG-Asparaginase Drug: Doxorubicin Drug: Dexrazoxane	Phase 1

Detailed Description

Study Treatment: The study treatment lasts 32 days during which time you will be taking the study drug Everolimus daily for 32 days in addition to standard chemotherapy drugs. Below lists the study drug as well as the other drugs you will be receiving to treat your leukemia during this research study.

Chemotherapy drugs:

Everolimus (RAD001): By mouth Daily 1-32
Prednisone: By mouth or in the vein Three times daily on days 4-32
Vincristine: In the vein Daily on days 4, 11, 18, and 25
Doxorubicin: In the vein Once per day on days 4 and 5. A drug called dexrazoxane will be given with each dose of Doxorubicin to protect the heart from any damage that might be caused by Doxorubicin.
PEG-asparaginase: In the vein Once per day on days 5 and 18

If you have or have had an allergy to PEG-asparaginase, we will give another form of asparaginase (Erwinia asparaginase). Four doses of Erwinia asparaginase will be given in the muscle twice a week beginning on Day 5 and then another 4 doses will be given in the muscle twice a week beginning on Day 15 in place of the scheduled doses of PEG-asparaginase.

In addition to the medications listed above, you will also be receiving intrathecal (IT) chemotherapy that is given directly into your spinal fluid to treat the leukemia that may have spread to your brain and spinal fluid. The medicines we will be giving in your spinal fluid are listed below. The number of times we give chemotherapy into the spinal fluid will depend on whether or not we see leukemia cells in your spinal fluid on the sample we take on the first day of the study.

Cytarabine on Day 1 (also Day 4 if we see leukemia cells in your spinal fluid on the screening spinal tap)
Triple intrathecal therapy (cytarabine, methotrexate and hydrocortisone)on Days 18 and 32 (if we do not see leukemia cells in your spinal fluid on the screening spinal tap), or on Days 11, 18, 25 and 32 (if we see leukemia cells in your spinal fluid on the screening spinal tap)

A drug called leucovorin will be given by mouth or by vein after each dose of triple intrathecal therapy. Leucovorin is given to prevent mouth sores which might occur after you get methotrexate in the spinal fluid. Leucovorin will be given three times a day for 24 hours beginning one day after you receive a dose of triple intrathecal therapy.

Portions of this treatment are "routine" or "standard" ways of treating recurrent ALL. Receiving vincristine, prednisone, PEG asparaginase and doxorubicin along with chemotherapy in the spinal fluid is a standard treatment for relapsed leukemia. The research part of the treatment involves giving Everolimus at the same time as these drugs.

Clinical and Lab Exams: During the study, you will have a physical examinations and you will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking. You will also have blood work to check for any side effects to your organs from the study drug and other chemotherapy drugs. Bone marrow studies will be done at the end of the 32-day treatment period to assess how you responded to treatment. If you are in remission, a special minimal residual disease (MRD) test will also be performed from the marrow sample as part of the study.

Study Design

Study Type:

Interventional

Actual Enrollment :

22 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Feasibility Trial of Everolimus (RAD001),an mTOR Inhibitor, Given in Combination With Multiagent Re-Induction Chemotherapy in Pediatric Patients With Relapsed Acute Lymphoblastic Leukemia (ALL)

Study Start Date :

Nov 1, 2011

Actual Primary Completion Date :

Jan 1, 2017

Actual Study Completion Date :

Nov 1, 2018

Outcome Measures

Primary Outcome Measures

Safety and Feasibility [2 years]
To determine the safety and feasibility of treatment with everolimus in combination with vincristine, prednisone, PEG-asparaginase and doxorubicin in patients with relapsed acute lymphoblastic leukemia (ALL)

Secondary Outcome Measures

Clinical Activity [2 years]
To investigate the clinical activity (complete remission rate and levels of end-reinduction MRD) of everolimus in combination with vincristine, prednisone, PEG-asparaginase and doxorubicin in patients with ALL.
Impact on biologic markers [2 years]
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 AKT, MCL1 and phosphorylated S6 ribosomal protein (PS6).
Determinants of Response [2 years]
To explore possible determinants of response (as measured by peripheral blast clearance, MRD levels and CR status) to everolimus in combination with multi-agent therapy including measurements of anti-apoptotic proteins (BCL2, BCLxL and MCL1), genome-wide gene expression profliling, BH3 profiling and OncoMap profiling.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Months to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

ALL in first bone marrow relapse occuring > 18 months from initial diagnosis
Normal organ function
Maximum prior cumulative doxorubicin dose of </= 360 mg/m2 or equivalent

Exclusion Criteria:

Prior therapy for ALL except for intrathecal (IT) chemotherapy
Pregnant or lactating
Individuals whose relapsed ALL harbors a t(9;22)/BCR-ABL fusion
Individuals whose lymphoblasts have surface immunoglobulin by flow cytometry and/or t(8;14), t(2;8), or t(8;22)
Down syndrome
Prior stem cell transplant
History of asparaginase-associated pancreatitis
Active lung disease
Impairment of gastrointestinal function or gastrointestinal disease
Severe and/or uncontrolled intercurrent illness
Documented history of previous or current Hepatitis B or C infection
History of a different malignancy (other than ALL) unless disease-free for at 5 years and deemed by the investigators to be at low risk for recurrence of that malignancy
HIV positive on combination antiretroviral therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF	San Francisco	California	United States	94143
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
4	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
5	Boston Children's Hospital	Boston	Massachusetts	United States	02115
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Columbia University Medical Center	New York	New York	United States	12549
8	Seattle Children's Hospital	Seattle	Washington	United States	98105