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

September 19, 2023 updated by: Lewis B. Silverman, MD, Dana-Farber Cancer Institute

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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:

  1. Everolimus (RAD001): By mouth Daily 1-32
  2. Prednisone: By mouth or in the vein Three times daily on days 4-32
  3. Vincristine: In the vein Daily on days 4, 11, 18, and 25
  4. 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.
  5. 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.

  1. Cytarabine on Day 1 (also Day 4 if we see leukemia cells in your spinal fluid on the screening spinal tap)
  2. 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 Type

Interventional

Enrollment (Actual)

22

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • UCSF
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Children's Hospital Colorado
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Children's Healthcare of Atlanta
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Ann & Robert H. Lurie Children's Hospital of Chicago
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Dana-Farber Cancer Institute
      • Boston, Massachusetts, United States, 02115
        • Boston Children's Hospital
    • New York
      • New York, New York, United States, 12549
        • Columbia University Medical Center
    • Washington
      • Seattle, Washington, United States, 98105
        • Seattle Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety and Feasibility
Time Frame: 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)
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Activity
Time Frame: 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.
2 years
Impact on biologic markers
Time Frame: 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).
2 years
Determinants of Response
Time Frame: 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.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dana-Farber Cancer Institute

Collaborators

Novartis

Investigators

  • Principal Investigator: Lewis Silverman, MD, Dana-Farber Cancer Institute

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2011

Primary Completion (Actual)

January 1, 2017

Study Completion (Actual)

November 1, 2018

Study Registration Dates

First Submitted

January 30, 2012

First Submitted That Met QC Criteria

January 30, 2012

First Posted (Estimated)

February 1, 2012

Study Record Updates

Last Update Posted (Actual)

September 21, 2023

Last Update Submitted That Met QC Criteria

September 19, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-237

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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