L-Ascorbic Acid Depletion to Treat Acute Myeloid Leukemia and Myelodysplastic Syndromes

October 25, 2006 updated by: Samsung Medical Center

Manipulation of L-Ascorbic Acid Level For The Treatment of Selected Cases Of Acute Myeloid Leukemia and Myelodysplastic Syndromes

To document therapeutic gain achieved by cyclic application of L-ascorbic acid (LAA) supplementation and depletion, while confirming safety and avoidance of clinically significant scurvy, in chemorefractory patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

Study Overview

Status

Suspended

Conditions

Intervention / Treatment

Detailed Description

The seminal discovery that the in vitro growth of malignant cells could be absolutely dependent on L-ascorbic acid (LAA) was originally published in Sciene. The cell culture assay used with a mouse plasmacytoma model in this discovery was based on colony formation, and was essentially the same as the one used to grow normal hemopoietic colonies, such as CFU-GM and CFU-G, from normal bone marrow specimens. Subsequent analysis of the growth factors for these CFUs using this same culture system eventually led to the discovery of colony stimulating factors, such as GM-CSF and G-CSF, now widely used clinically. Human leukemia, specifically acute myeloid leukemia (AML), cell colonies also grow well in this culture system, as shown by extensive cell biology studies. In addition, cells from patients with myelodysplastic syndrome (MDS), a significant proportion of them progressing to AML behave similarly to AML cells in this culture system . In particular both AML and MDS are identical in that the growth of colonies is enhanced by addition of LAA to the cell culture media in a high proportion of these patients.

The large volume of in vitro data thus generated, including correlations with direct clinical relevance is increasingly convincing that lowering of LAA levels could potentially be developed and utilized as a treatment for specific hemopoeitic malignancies. This was particularly attractive in view of the fact that the growth of normal hemopoietic colonies, such as CFU-GM and CFU-G, is never enhanced by LAA. Such an absolute selectivity would predict a lack of clinical adverse hemopoetic events from an intervention which lowered LAA levels. We also had seemingly-contradictory data that the growth of colonies from AML and MDS patients could be suppressed by addition of LAA, infrequently but sometimes profoundly. However, detailed dose response analysis later clarified this: low physiologic doses enhance and high pharmacologic doses suppress formation of leukemic colonies. From a therapeutic perspective, we would have greater expectations for a depletion strategy than for supplementation, because 1) leukemic suppression by addition of LAA is often accompanied by some mild suppression of the normal CFU and therefore is not absolutely selective; and 2) LAA supplementation has been clinically tested in a variety of solid tumors, with controversial outcomes.

Therefore, our original protocol was developed primarily to accomplish lowering of LAA levels, with a subsequent oral LAA supplementation used primarily to prevent scurvy and only secondarily for possible benefit. However, with the first patient there was a strong indication of antileukemic effects during both the LAA depletion and supplementation phases. Based on this encouragement, the protocol was amended to formally alternate depletion with supplementation, and to utilize intravenous (IV) administration of LAA to achieve high dose supplementation. With 17 subsequent subjects having been treated, this study of the safety and efficacy of cyclic manipulation of LAA levels has demonstrated beneficial outcome in a high proportion of refractory and terminal patients with AML or MDS. Moreover, growing laboratory evidence being produced provides a molecular basis for these clinical outcomes.

Study Type

Interventional

Enrollment

25

Phase

  • Phase 2

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

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

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients should have AML or MDS according to new WHO classification, with minimum of 5% blasts in peripheral blood.
  • There must be a clear and acceptable reason for not receiving standard treatments (chemotherapy and/or stem cell transplantation); or standard treatments have already been given and this option exhausted with evidence of refractory disease.
  • Prior treatments of any forms are allowed provided there is no potential residual beneficial effect and the patients are off treatment for at least 4 weeks, with estimated life expectancy of at least 2 months.
  • Adequate amount (4 ml) of bone marrow sent to the laboratory for cell culture studies.
  • There are no restrictions based on age, sex, or ethnicity except that adequate contraception must be practiced in women of childbearing ages. Although AML is rare in children, pediatric patients will be accepted.
  • There is no deficiency of G6PD (RBC).
  • Asymptomatic patients with disease progression and symptomatic patients.

Exclusion Criteria:

-

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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Efficacy
Safety, clinically

Secondary Outcome Measures

Outcome Measure
Correlative studies between the modulation of the growth of leukemic colony-forming-cells(CFC) by L-ascorbic acid (LAA) in cell-culture and clinical response.

Collaborators and Investigators

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

Sponsor

Samsung Medical Center

Collaborators

Jin Yang Pharmaceutical

Investigators

  • Principal Investigator: Won Seog Kim, MD, Samsung Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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

May 1, 1998

Study Completion

August 1, 2005

Study Registration Dates

First Submitted

May 22, 2006

First Submitted That Met QC Criteria

May 23, 2006

First Posted (Estimate)

May 24, 2006

Study Record Updates

Last Update Posted (Estimate)

October 26, 2006

Last Update Submitted That Met QC Criteria

October 25, 2006

Last Verified

October 1, 2006

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SMCIRB-98-04-02

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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