Study of Sirolimus With PEG-Asparaginase in Acute Lymphoblastic Leukemia (ALL)

November 30, 2013 updated by: Frank Keller, Emory University

A Phase I Study of Sirolimus With PEG-Asparaginase in Multiple Recurrent or Refractory Childhood Acute Lymphoblastic Leukemia

The goal of this study is to find a safe dose of sirolimus that can be used with a standard dose of L-asparaginase. To find the safe dose, the investigators will give the first patient a very small dose of sirolimus (smaller than the dose used in organ transplant children) and the standard dose of L-asparaginase. The investigators will then look for side effects. If side effects develop, the investigators will decrease the dose of sirolimus. If they do not, the investigators will increase the dose of sirolimus in the next patient on the study. The investigators will continue this method until fewer than one-third of patients have a side effect that would require stopping the drug or changing the dose.

The investigators plan to enroll up to 15 children with relapsed ALL. The enrolled patients must have recovered from other treatment before starting this study. Also, they cannot have severe side effects from their earlier therapy that will possibly make these drugs less safe.

The investigators will collect information on whether these drugs help to cure the ALL, but the purpose will be to find a dose of sirolimus that does not cause too many side effects when combined with L-asparaginase. This will be explained to the families and they will sign a written consent. The patients will provide either verbal or written assent when appropriate.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Multiple relapsed acute lymphoblastic leukemia (ALL) has a very poor cure rate, and there is no standard of care for treatment of these patients. Therefore, we want to combine two chemotherapy drugs to see if they are safe and will help treat these patients. The first agent, L-asparaginase, is used in most patients during their initial treatment for ALL. The second agent, sirolimus, causes death in human leukemia cells in the laboratory. Sirolimus is also used in children who have received kidney or heart transplants to prevent organ rejection. Therefore, the safety and side effects are well known in children.

There are many steps that allow cancer cells to grow in humans. L-asparaginase and sirolimus block two different steps in cell growth. Because of this, we anticipate that these two drugs will work together to lead to more cancer cell death.

The first part of the study will last 1 month for each patient. If the patients have a good response to these two drugs, they will be allowed to continue these drugs for up to 12 months. They will continue on the dose of sirolimus that they received during the first month for the remaining time on the study.

We will also look at the way leukemia cells are responding to these medications in the laboratory. We will not draw any blood or bone marrow samples from the patient unless they already need the procedure done for other tests. The amount of extra blood or bone marrow drawn will not cause the patients any harm. As we do not know what these laboratory tests mean, we will not tell the patients the results during the study.

Study Type

Interventional

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
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Children's Healthcare of Atlanta

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

No older than 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Less than 21 years old.
  2. Acute lymphoblastic leukemia.
  3. Second or greater bone marrow relapse or 1st relapse and refractory to at least 2 Attempts at re-induction.
  4. Life expectancy of at least 8 weeks.
  5. Fully recovered from the acute toxic effects of all prior therapy.
  6. Appropriate organ function.

Exclusion Criteria:

  1. Patients with a documented history of ≥ grade 3 local or systemic reactions to PEG-asparaginase.
  2. Patients with a documented history of anti-E. coli asparaginase antibodies.
  3. Patients with a history of ≥ grade 3 pancreatitis.
  4. Patients with an active and uncontrolled infection.
  5. Patients s/p allogeneic bone marrow transplantation, who are still on immunosuppressants.
  6. Pregnant or lactating females. Women of childbearing age will agree to use contraception during the protocol.
  7. Patients currently receiving other investigational agents, medications, or supplements with a known anti-leukemic effect.
  8. Other concomitant medications that may alter the metabolism of Sirolimus (See section 7.2).
  9. Patients who, in the opinion of the investigator, will not be able to comply with safety monitoring requirements of the study.
  10. Patients with a history of a documented thrombus from previous asparaginase 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: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1

Subjects will receive PEG-asparaginase at a fixed weekly dose, as per published reports in relapsed childhood ALL. The dose of sirolimus will be dose escalated following standard phase 1 statistical methods.

For patients with active CNS leukemia, intrathecal methotrexate, hydrocortisone and cytarabine (triple IT) will be administered weekly, with leucovorin rescue at the treating physician's discretion.
Drug: Sirolimus
Sirolimus daily po days 1 through 28, Dose level 0: 0.25 mg/m2 po daily Dose level 1: 0.5 mg/m2 po daily Dose level 2: 1 mg/m2 po daily Dose level 3 1.5 mg/m2 po daily Dose level 4 2 mg/m2 po daily
Drug: PEG-asparaginase
Subjects will receive PEG-asparaginase at a fixed weekly dose, as per published reports in relapsed childhood ALL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To estimate the maximum tolerated dose (MTD) of sirolimus in children with refractory or recurrent acute lymphoblastic leukemia (ALL) who are concurrently receiving PEG-asparaginase.
Time Frame: end of study
end of study
To determine the dose limiting toxicities of sirolimus in combination with PEG-asparaginase in this Phase I Study.
Time Frame: end of study
end of study

Secondary Outcome Measures

Outcome Measure
Time Frame
To use phospho-flow to measure the degree of phosphorylation of signaling pathway proteins in response to specific stimulating events in bone marrow derived leukemia cells obtained at the time of study entry and at day 15 and 29.
Time Frame: end of study
end of study
To correlate the signal pathway phosphorylation to clinical response to the chemotherapy regimen used in this study.
Time Frame: end of study
end of study

Collaborators and Investigators

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

Sponsor

Emory University

Investigators

  • Principal Investigator: Frank Keller, MD, Emory University

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

June 1, 2009

Primary Completion (Actual)

August 1, 2012

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

August 11, 2009

First Submitted That Met QC Criteria

August 11, 2009

First Posted (Estimate)

August 12, 2009

Study Record Updates

Last Update Posted (Estimate)

December 3, 2013

Last Update Submitted That Met QC Criteria

November 30, 2013

Last Verified

November 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB00015324
  • Sirolimus (Other Identifier: Other)

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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