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Myelodysplastic SyndromesPhase 2NCT00531232

A Dose Confirmation Study of Oral Clofarabine for Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)

A Phase 2 study testing Clofarabine in people with Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia (AML), run by Genzyme, a Sanofi Company at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

There was no well accepted standard of care for participants who failed or were intolerant to any of the currently approved therapies for myelodysplastic syndromes (MDS). In this study, participants were initially assigned to receive 55 or 35 milligrams (mg) of oral clofarabine daily for 5 days. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Clofarabine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
38 participants
Where
6 sitesUnited States
Study dates
7 May 2007to 12 May 2011
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Had a pathologically confirmed secondary Acute Myeloid Leukemia ([sAML]; following a history of MDS) or MDS with an intermediate-1 (with marrow blasts greater than or equal to [>=] 5%) or intermediate-2 or high risk score as assessed by the International Prognostic Scoring System at study entry. Participants with refractory anemia with excess blasts in transformation recognized by the French-American-British system, and chronic myelomonocytic leukemia were allowed into the study. Pathologic confirmation was the responsibility of the site investigator.
  • Had previously treated MDS defined as follows: a) Participants must had at least one, but no more than two, prior treatment regimens [a.) treatment regimen was defined as any drug or drug combination administered for treatment of MDS with the intent of inducing at least hematologic improvement (consistent with International Working Group criteria); Inadequate treatment, due to drug intolerance or other factors, was considered a prior treatment regimen. Hematopoietic growth factors, hydroxyurea, anti-thymocyte globulin, or supportive care measures (e.g., blood transfusions, immunosuppressive agents, antibiotics) were not considered treatment regimens for the purpose of study entry.] b.) One of the treatment regimens had to be either 5-azacytidine or decitabine. If 5-azacytidine or decitabine was given as a treatment regimen more than once, it was considered as 2 different treatment regimens. c.) Participants could not be refractory (i.e., progression of disease, or no evidence of response, while on the treatment) to more than one prior treatment regimen (to be considered refractory to decitabine or 5-azacitidine, participants must have received >= 4 cycles).
  • Had documentation of prior transfusion requirements for the preceding 8 weeks (8 weeks prior to first dose of study drug).
  • Had Eastern Cooperative Oncology Group performance status 0-2.
  • Was able to comply with study procedures and follow-up examinations.
  • Had adequate renal and hepatic functions as indicated by predefined laboratory values: a.) Total bilirubin less than or equal to (<=) 1.5 * institutional Upper Limit of Normal (ULN) except for unconjugated hyperbilirubinemia secondary to treatment for MDS or Gilbert's syndrome; and b.) Aspartate aminotransferase and Alanine aminotransferase <= 2.5*ULN; and c.) Serum creatinine <= 1.0 milligrams per deciliter, then the estimated glomerular filtration rate (GFR) had to be greater than (>) 30 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation.
  • Was non-fertile or agreed to use birth control during the study through the end of last treatment visit and at least 90 days after.

Who cannot join

  • Had an adjustment of dose and/or schedule of erythropoietin, granulocyte colony stimulating factor or other growth factors within 8 weeks prior to the first dose of oral clofarabine.
  • Had any prior therapy for treatment of sAML. Hydroxyurea must not have been received within 24 hours prior to first dose of study drug.
  • Had any other chemotherapy or any investigational therapy within four weeks of first dose of study drug.
  • Had any prior pelvic radiotherapy.
  • Had a prior hematopoietic stem cell transplant for MDS.
  • Had not recovered to <= Grade 2 from any drug-related non-hematologic toxicity prior to first dose of the study drug.
Show all 15Show fewer
  • Had an uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
  • Had a psychiatric disorder that would interfere with consent, study participation, or follow-up.
  • Had any other severe concurrent disease, or had a history of serious organ dysfunction or disease involving the heart, kidney, or liver, in particular: a.) New York Heart Association classification stage II, III, or IV congestive heart failure; b.) Coronary artery disease or arteriosclerotic cardiovascular disease (angina, myocardial infraction) within 3 months of first dose of study drug; c.) Any other primary cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
  • Had any other severe concurrent disease, or had a history of serious organ dysfunction or disease involving the heart had any prior treatment with Clofarabine.
  • Had a diagnosis of another malignancy, unless the participants had been disease-free for at least 3 years following the completion of curative intent therapy with the following exceptions: a.) Participants with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease -free duration, were eligible for this study if definitive treatment for the condition had been completed. b.) Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen values were also eligible for this study if hormonal therapy had been initiated or a radical prostatectomy had been performed.
  • Had prior positive test for the Human Immunodeficiency Virus.
  • Had currently active gastrointestinal disease, or prior surgery that might affect the ability of the participants to absorb oral Clofarabine.
  • Participating in other concurrent investigational protocols that were not restricted to data and/or sample collection for participants demographic and/or sample collection for participants demographic and/or disease purposes.
  • Had prior treatment with a known nephrotoxic drug within 2 weeks of the first dose of study drug, unless the participants had a calculated GFR >30 at 2 time points no <7 days apart during the 2-week period prior to the first dose of study drug.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • The University of Chicago

    Chicago, Illinois, 60637

  • Cleveland Clinic

    Cleveland, Ohio, 44195

  • Baylor University Medical Center Blood Marrow Transplantation Research

    Dallas, Texas, 75246

  • University of Texas MD Anderson Cancer Center

    Houston, Texas, 77030

  • Weill Medical College of Cornell University

    New York, New York, 10065

  • Wake Forest University Baptist Medical Center

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

Official title: A Phase IIa Open-label, Dose Confirmation Study of Oral Clofarabine in Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)

There was no well accepted standard of care for participants who failed or were intolerant to any of the currently approved therapies for myelodysplastic syndromes (MDS). In this study, participants were initially assigned to receive 55 or 35 milligrams (mg) of oral clofarabine daily for 5 days. After safety review of the first participants enrolled, the dose was reduced to 25 milligrams per day (mg/day) for up to 8 cycles as long as the participants continued to benefit and in the absence of progressive disease.

Being tested
Clofarabine
Keywords
Previously treated MDS, oral clofarabine, Intermediate-1, Intermediate-2 and High Risk MDS, secondary AML (with history of MDS)
Medical subject headings
Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ClofarabineDrug

    Also called Clolar

    Pharmaceutical form: Tablet,

    Route of administration: Oral

Study groups in NCT00531232
Study groupRoleWhat they receive
Clofarabine 55 mg/dayExperimentalParticipants received Clofarabine 55 mg/day orally for 5 consecutive days of each 28-day treatment cycle until disease progression or death, whichever comes first (maximum study duration: up to 4 years).
Receives: Drug: Clofarabine
Clofarabine 35 mg/dayExperimentalParticipants received Clofarabine 35 mg/day orally for 5 consecutive days of each 28-day treatment cycle until disease progression or death, whichever comes first (maximum study duration: up to 4 years).
Receives: Drug: Clofarabine
Clofarabine 25 mg/dayExperimentalParticipants received Clofarabine 25 mg/day orally for 5 consecutive days of each 28-day treatment cycle until disease progression or death, whichever comes first (maximum study duration: up to 4 years).
Receives: Drug: Clofarabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With Overall Response

    Overall Response: complete remission(CR) or marrow CR or partial remission (PR), or hematologic improvement (HI) in participants with myelodysplastic syndromes (MDS);CR or CR with incomplete count recovery(CRi),or PR in participants with secondary acute myeloid leukemia (sAML). Per International Working Group (IWG) criteria, CR:<= 5% myeloblasts in bone marrow; persistent dysplasia had to be noted; peripheral blood showing hemoglobin (Hgb)>=11g/dL, platelets >=100*10^9/L,neutrophils >=1*10^9/L, blasts 0%. Marrow CR:<=5%myeloblasts in bone marrow and decreased by >=50% over pretreatment; any HI response in peripheral blood. CRi: meeting all criteria for CR except for residual thrombocytopenia (platelet <100*10^9/L) or neutropenia (ANC <1.0*10^9/L). PR: all CR criteria if abnormal before treatment except that marrow blasts should have decreased by >=50% over pretreatment but still >5%. HI: meeting any of the erythroid, platelet, or neutrophil improvement categories for at least 8 weeks.

    Measured: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)

Secondary outcomes (13)

  1. Duration of Response (DoR)

    DoR: time (in months) from 1st documentation of response to date of 1st documentation of disease relapse, progression or death due to any cause, whichever occured first. Response defined as CR, marrow CR, or PR (MDS participants) and CR/CRi (sAML participants). Per IWG criteria, relapse defined as: return to pretreatment bone marrow blast %; decrease of >=50% from maximum remission levels; reduction in Hgb by >=1.5g/dL.CR:<= 5%myeloblasts in bone marrow; persistent dysplasia; peripheral blood showing Hgb>=11g/dL. Marrow CR:<=5%myeloblasts (bone marrow) and decreased by >=50% over pretreatment; any HI response in peripheral blood. CRi:meeting all criteria for CR except for residual thrombocytopenia/neutropenia. PR: all CR criteria if abnormal before treatment except that marrow blasts should have decreased by >=50%. Progression: at least 50% decrease from maximum remission/response in granulocytes/platelets; reduction in Hgb by >=2g/dL; transfusion dependence. Analyzed by Kaplan-Meier.

    Measured: From first documentation of response to date of documentation of disease relapse, progression or death due to any cause, whichever occurs first (maximum study duration: up to 4 years)

  2. Number of Participants Who Achieved Hematologic Improvement (HI)

    Per IWG criteria, HI was defined as meeting any of the erythroid, platelet,and/or neutrophil independence categories for at least 8 consecutive weeks. Erythroid response (pre-treatment,<11 grams per deciliter [g/dL]) was defined as Hgb increased by >=1.5 g/dL;relevant reduction of units of red blood cell (RBC) transfusion by an absolute number of at least 4 RBC transfusion/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks; only RBC transfusions given for Hgb of <=9.0 g/dL pre-treatment counted in the RBC transfusion response evaluation. Platelet response(pretreatment, <100*109/L) was defined as absolute increase of >=30*109/L for participants starting with >20*109/L platelets, increase from <20*109/L to >20*109/L and by at least 100%. Neutrophil response (pre-treatment, <1.0*109/L) was defined by at least 100% increase and an absolute increase >0.5*109/L. Number of participants who achieved HI for MDS participants only was reported in outcome measure.

    Measured: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)

  3. Percentage of Participants Achieving Overall Remission (OR)

    OR was defined as a best response of CR, marrow CR, or PR in participants with MDS or a best response of CR or CRi in participants with sAML. As per IWG criteria, CR was defined as the following: bone marrow <=5% myeloblasts with normal maturation of all cell lines; persistent dysplasia had to be noted; peripheral blood showing hemoglobin >=11 g/dL, platelets >=100*10^9/L, neutrophils >=1*10^9/L, blasts 0%. Marrow CR was defined as: bone marrow <=5% myeloblasts and decreased by >=50% over pretreatment; any HI response in peripheral blood had to be noted. CRi was defined as meeting all criteria for CR except for residual thrombocytopenia (platelet count <100*10^9/L) or neutropenia (ANC <1.0*10^9/L). PR was defined as all CR criteria if abnormal before treatment except that marrow blasts should have decreased by >=50% over pre-treatment but still >5%. HI was defined as meeting any of the erythroid, platelet, or neutrophil improvement categories for at least 8 weeks.

    Measured: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)

  4. Time to Acute Myeloid Leukemia (AML) Transformation

    Time to AML transformation was defined as time (in months) from date of the first dose of oral Clofarabine to the date of AML transformation, (i.e., the earliest date when participants experienced bone marrow or peripheral blasts >30%). The analysis was performed by Kaplan-Meier method.

    Measured: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)

  5. Overall Survival (OS)

    OS defined as date of the first dose of oral Clofarabine until date of death due to any cause. If death was not observed, the participant was censored at the earliest of the last date the participant was known to be alive or the study cut-off date. The analysis was performed by Kaplan-Meier method.

    Measured: From date of first dose of study drug until date of death due to any cause (maximum study duration: up to 4 years)

  6. Maximum Tolerated Dose (MTD) of Oral Clofarabine

    The MTD was the highest dose level of Clofarabine that caused less than (<) 2 participants to experience unacceptable drug-related toxicities after receiving 1 or more of the initial 5 daily doses of Clofarabine. Unacceptable drug-related toxicities included: drug-related prolonged myelosuppression, which was defined as hypocellular bone marrow with <5 percent (%) cellularity at 6 weeks after starting treatment, which required a 1-dose level reduction for subsequent cycles; Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 drug-related non-hematologic toxicity; CTCAE Grade 3 drug-related non-hematologic toxicity that either recovered to Baseline grade but was recurrent to Grade 3 upon re-treatment during the first cycle or did not recover to Grade 1 or Baseline within 3 weeks when the drug was held or dose reduced; drug-related non-hematologic toxicity that resulted in non-completion of at least 4 daily doses of oral Clofarabine at the original assigned dose level.

    Measured: Cycle 1 (28 days)

  7. Number of Participants With Febrile Neutropenia

    Febrile neutropenia was defined as fever (e.g., greater than or equal to (>=) 38.5 Celsius (°C) on a single occasion, or greater than (>) 38°C on 2 occasions within 12 hours) in the setting of neutropenia (defined as Absolute Neutrophil Count <1.0*10^9/liter [L]).

    Measured: From Baseline up to 45 days post last dose of study drug (maximum study duration: up to 4 years)

  8. Number of Participants With Adverse Events (AEs)

    Adverse Event (AE): any undesirable physical, psychological/behavioral effect experienced by participant during their participation in clinical study, with study drug usage, whether or not product related.Treatment Emergent AEs (TEAEs): AEs that developed, worsened, or became serious during treatment period (from signature of informed consent form up to 45 days post last dose). Serious AE (SAE):any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, medically important event. Per National Cancer Institute (NCI)-CTCAE v3.0 severity for each AE were graded as: Grade 1=Mild AE; Grade 2=Moderate AE; Grade 3=Severe AE, Grade 4=Life-threatening/disabling AE and Grade 5=Death related to AE. Participants with TEAEs, SAEs, death, discontinuations, Grade 4 and 5 toxicities were reported.

    Measured: From Baseline up to 45 days post last dose of study drug (maximum duration: up to 4 years)

  9. Number of Participants Who Reported Death Within 30 Days of First Dose

    Measured: Within 30 days of first dose administered on Day 1 of Cycle 1

  10. Number of Participants With Unacceptable Drug-related Toxicities During Cycle 1

    Unacceptable drug-related toxicities included: drug-related prolonged myelosuppression, which was defined as hypocellular bone marrow with <5% cellularity at 6 weeks after starting treatment, which required a 1-dose level reduction for subsequent cycles; CTCAE Grade 4 drug-related non-hematologic toxicity; CTCAE Grade 3 drug-related non-hematologic toxicity that either recovered to Baseline grade but was recurrent to Grade 3 upon re-treatment during the first cycle or did not recover to Grade 1 or Baseline within 3 weeks when the drug was held or dose reduced; drug-related non-hematologic toxicity that resulted in non-completion of at least 4 daily doses of oral clofarabine at the original assigned dose level. Participants with unacceptable drug-related toxicities during Cycle 1 only was reported in the outcome measure.

    Measured: Cycle 1 (28 days)

  11. Pharmacokinetics (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Clofarabine

    Cmax was defined as maximum observed plasma concentration of study drug.

    Measured: Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1

  12. PK Parameter: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Clofarabine

    Tmax was defined as the time to reach Cmax (maximum observed plasma concentration).

    Measured: Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1

  13. PK Parameter: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Plasma Concentration (AUC0-last) of Clofarabine

    AUC0-last was defined as area under the concentration-time curve from time 0 to time of last measurable plasma concentration.

    Measured: Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Sep 2007 (estimated)
  2. Study start7 May 2007
  3. Primary completion12 May 2011
  4. Study completion12 May 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
38 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00531232
Sponsor's protocol ID
CLOMDS02507
Status last verified
Mar 2022
First submitted
14 Sep 2007
Last updated
24 Mar 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Clofarabine in people with Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia (AML), run by Genzyme, a Sanofi Company at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Overall Response (time frame: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00531232.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2022.

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