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

This study has been withdrawn prior to enrollment.
(no patients enrolled, decided not to pursue study)
Sponsor:
Information provided by (Responsible Party):
Frank Keller, Emory University
ClinicalTrials.gov Identifier:
NCT00957320
First received: August 11, 2009
Last updated: November 30, 2013
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Drug: Sirolimus
Drug: PEG-asparaginase
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Sirolimus With PEG-Asparaginase in Multiple Recurrent or Refractory Childhood Acute Lymphoblastic Leukemia

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
  • To determine the dose limiting toxicities of sirolimus in combination with PEG-asparaginase in this Phase I Study. [ Time Frame: end of study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • To correlate the signal pathway phosphorylation to clinical response to the chemotherapy regimen used in this study. [ Time Frame: end of study ] [ Designated as safety issue: No ]

Enrollment: 0
Study Start Date: June 2009
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00957320

Locations
United States, Georgia
Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Frank Keller, MD Emory University
  More Information

No publications provided

Responsible Party: Frank Keller, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT00957320     History of Changes
Other Study ID Numbers: IRB00015324, Sirolimus
Study First Received: August 11, 2009
Last Updated: November 30, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Emory University:
leukemia
cancer
oncology
sirolimus
ALL

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pegaspargase
Asparaginase
Sirolimus
Everolimus
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antineoplastic
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 26, 2014