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Phase 2 Study of AR-67 (DB-67) in Myelodysplastic Syndrome(MDS)

Phase 2
18 Years
Open (Enrolling)
Myelodysplastic Syndrome

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Trial Information

Phase 2 Study of AR-67 (DB-67) in Myelodysplastic Syndrome(MDS)

The management of MDS has been, until recently, based mostly on supportive care. This
includes transfusion support, hematopoietic growth factors, and management of complications.
With this management, the disease would run its natural course and the patient eventually
died either from progression to acute leukemia or from complications associated with MDS
itself (e.g., infections, hemorrhage). Recently, hypomethylating agents have offered promise
for the management of patients with MDS. Although both agents have shown efficacy in a
subset of patients, responses are usually either partial or hematologic improvement only,
with CR rates <10%. In addition, responses have a median duration of less than 12 months.
Thus, although both of these agents have improved the outcome of patients with MDS and been
approved by the FDA for this purpose, there is clearly need for additional and more
effective agents for this disease.

In vitro data suggested that topoisomerase I inhibitors could have activity in MDS, and a
prolonged exposure appeared to be particularly effective. Topotecan was the first agent of
this class explored for this purpose. A phase I study established the maximum tolerated dose
(MTD) at 2 mg/m2/day as a continuous infusion for 5 days. Using this dose, a phase II study
in patients with MDS and CMML, a complete remission rate of 31% was achieved. These agents
are now considered the most effective available to date in the treatment of MDS and
constitute standard therapy. Because of the different times when the studies were conducted
and the different eligibility criteria used (e.g., patients with secondary MDS not eligible
for decitabine, only patients with high-risk MDS eligible for topotecan), comparisons are
somehow limited. However, results with topotecan compare favorably to those obtained with
both 5-azacytidine and decitabine. The CR rate is the highest achieved with any of these
agents. Response duration is shorter than that reported for AZA, but the remission duration
for AZA includes hematologic improvements which constitute most of the responses with AZA.
In addition, the AZA study continued therapy until the response was lost, while the
topotecan study (as well as the decitabine study) administered by design only 4-6 cycles of
therapy. Survival was shorter for patients treated with topotecan, but this is not
unexpected considering that this population included 50% of patients with CMML and 32% with
secondary MDS, both important adverse prognostic characteristics in MDS. The AZA study had
the best survival, but it included 37% patients with RA or RAES and only 20% with
intermediate-2 or high IPSS. Because the eligibility included patients with greater than
10% blasts, all MDS patients would have had a score of at least 1.5 and thus be classified
in the intermediate-2 risk group.

Based on the favorable activity of topotecan as a single agent, topotecan was also used in
combination with cytarabine in high-risk MDS (i.e., RAEB with >10% blasts or RAEBt). A CR
rate of 56% was achieved, with a low rate of induction mortality (7%) in a population with a
median age of 68 years. These results were at least equivalent to those achieved with an
idarubicin and cytarabine combination both in a retrospective comparison of two different
trials, and in a prospective randomized trial.

Overall, these results suggest that additional exploration of topoisomerase I inhibitors in
myelodysplastic syndrome is warranted.

Inclusion Criteria:

1. Patients with either of the following diagnoses:

- MDS and >5% blasts, or IPSS risk group intermediate-1, intermediate-2 or high

- Chronic myelomonocytic leukemia (CMML)

2. Patients must have failed prior therapy with either a hypomethylating agent (e.g.,
azacytidine, decitabine) alone or in combination with other agents. Patients with
abnormalities in chromosome 5q, should have failed either a hypomethylating agent or

- Patients intolerant or unable to receive these agents will be considered

3. Age > 18 years. Because no dosing or adverse event data are currently available on
the use of AR-67 in patients < 18 years of age, children are excluded from this study
but will be eligible for future pediatric single-agent trials, if applicable.

4. ECOG performance status 0-2.

5. Patients must have normal organ function as defined below:

- Total bilirubin: < 1.5 x institutional upper limit of normal

- ALT (SGPT): < 2.5 X institutional upper limit of normal

- Creatinine: < 1.5 x institutional upper limit of normal

6. The effects of AR-67 on the developing human fetus at the recommended therapeutic
dose are unknown. For this reason women of child-bearing potential (i.e., not
post-menopausal for at least 12 months and not surgically sterile) and men must agree
to use effective methods of contraception. Women of childbearing potential (any women
who is not surgically sterile or > 2 years post menopause) must give consent for
using a reliable method of contraception (e.g. double-barrier, tubal ligation or
stable hormonal contraception) throughout the duration of study participation.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.

7. Ability to understand and the willingness to sign a written informed consent

8. Patients must have been off chemotherapy for 2 weeks prior to entering this study
unless there is evidence of rapidly progressive disease. Patients must have recovered
from the toxic effects of prior therapy to grade ≤1. The use of hydroxyurea is
allowed to control counts up to 24 hrs prior to the start of therapy with AR-67.

Exclusion Criteria:

1. Nursing or pregnant females or females who plan pregnancy during the duration of the

2. Active and uncontrolled systemic infections.

3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, or
psychiatric illness/social situations that would limit compliance with study

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To estimate the efficacy of AR-67 in treating patients with MDS who have failed prior therapies

Outcome Time Frame:

4 cycles (approximately 16 weeks)

Safety Issue:


Principal Investigator

Jorge Cortes, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The University of Texas MD Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2009

Completion Date:

July 2010

Related Keywords:

  • Myelodysplastic Syndrome
  • Myelodysplastic Syndrome
  • Myelodysplastic Syndromes
  • Preleukemia



The University of Texas MD Anderson Cancer Center Houston, Texas  77030-4009