Clinical trial NCT00531232: A Dose Confirmation Study of Oral Clofarabine for Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)
Official title: A Phase IIa Open-label, Dose Confirmation Study of Oral Clofarabine in Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Secondary Acute Myeloid Leukemia (AML)
Keywords: Previously treated MDS
oral clofarabine
Intermediate-1, Intermediate-2 and High Risk MDS
secondary AML (with history of MDS)
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2007-09-18
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. 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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.
* 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.

Primary outcomes:
measure: Percentage of Participants With Overall Response
timeFrame: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)
Secondary outcomes:
measure: Duration of Response (DoR)
timeFrame: 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)
measure: Number of Participants Who Achieved Hematologic Improvement (HI)
timeFrame: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)
measure: Percentage of Participants Achieving Overall Remission (OR)
timeFrame: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)
measure: Time to Acute Myeloid Leukemia (AML) Transformation
timeFrame: From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years)
measure: Overall Survival (OS)
timeFrame: From date of first dose of study drug until date of death due to any cause (maximum study duration: up to 4 years)
measure: Maximum Tolerated Dose (MTD) of Oral Clofarabine
timeFrame: Cycle 1 (28 days)
measure: Number of Participants With Febrile Neutropenia
timeFrame: From Baseline up to 45 days post last dose of study drug (maximum study duration: up to 4 years)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From Baseline up to 45 days post last dose of study drug (maximum duration: up to 4 years)
measure: Number of Participants Who Reported Death Within 30 Days of First Dose
timeFrame: Within 30 days of first dose administered on Day 1 of Cycle 1
measure: Number of Participants With Unacceptable Drug-related Toxicities During Cycle 1
timeFrame: Cycle 1 (28 days)
measure: Pharmacokinetics (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Clofarabine
timeFrame: Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1
measure: PK Parameter: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Clofarabine
timeFrame: Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1
measure: PK Parameter: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Plasma Concentration (AUC0-last) of Clofarabine
timeFrame: Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1
Other outcomes:
Locations:
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dallas
country: United States
facility: Baylor University Medical Center Blood Marrow Transplantation Research
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References: