Clinical Trials /

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



The purpose of this study is to determine if AR-67 is effective in the treatment for patients with MDS.

Related Conditions:
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Unknown status


Phase 2

Trial Eligibility



  • Brief Title: Study of AR-67 (DB-67) in Myelodysplastic Syndrome (MDS)
  • Official Title: Phase 2 Study of AR-67 (DB-67) in Myelodysplastic Syndrome(MDS)

Clinical Trial IDs

  • NCT ID: NCT00956787
  • NCT ALIAS: NCT00930540


  • Myelodysplastic Syndrome


AR-67 (20S)-7-t-Butyldimethylsilyl-10-hydroxycamptothecin)AR-67, (20S)-7-t-Butyldimethylsilyl-10-hydroxycamptothecin)Treatment with AR-67


The purpose of this study is to determine if AR-67 is effective in the treatment for patients with MDS.

Detailed Description

      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.

Trial Arms

Treatment with AR-67ExperimentalPatients will receive AR-67 at an initial dose of 7.5 mg/m2 IV over 1 hour daily for 5 days.
  • AR-67 (20S)-7-t-Butyldimethylsilyl-10-hydroxycamptothecin)

Eligibility Criteria

        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 document.

          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
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To estimate the efficacy of AR-67 in treating patients with MDS who have failed prior therapies
Time Frame:4 cycles (approximately 16 weeks)
Safety Issue:


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Unknown status
Lead Sponsor:Arno Therapeutics

Trial Keywords

  • Myelodysplastic Syndrome

Last Updated

June 24, 2014