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

Study Overview
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Brief Summary
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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.

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

Conditions
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Myelodysplastic Syndromes, Secondary Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Clofarabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clofarabine 55 mg/day<br>Participants 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). | Drug: Clofarabine<br>* Pharmaceutical form: Tablet, Route of administration: Oral<br>* Other names: Clolar;|
| Experimental: Clofarabine 35 mg/day<br>Participants 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). | Drug: Clofarabine<br>* Pharmaceutical form: Tablet, Route of administration: Oral<br>* Other names: Clolar;|
| Experimental: Clofarabine 25 mg/day<br>Participants 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). | Drug: Clofarabine<br>* Pharmaceutical form: Tablet, Route of administration: Oral<br>* Other names: Clolar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years) | 
| 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. | From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years) | 
| 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. | From date of randomization until disease recurrence or death, whichever occurred first (maximum study duration: up to 4 years) | 
| 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. | From date of first dose of study drug until date of death due to any cause (maximum study duration: up to 4 years) | 
| 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. | Cycle 1 (28 days) | 
| 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]). | From Baseline up to 45 days post last dose of study drug (maximum study duration: up to 4 years) | 
| 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. | From Baseline up to 45 days post last dose of study drug (maximum duration: up to 4 years) | 
| Number of Participants Who Reported Death Within 30 Days of First Dose |  | Within 30 days of first dose administered on Day 1 of Cycle 1 | 
| 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. | Cycle 1 (28 days) | 
| Pharmacokinetics (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Clofarabine | Cmax was defined as maximum observed plasma concentration of study drug. | Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1 | 
| 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). | Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1 | 
| 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. | Pre-dose and at 1, 3, and 5 hours Post-dose on Day 1 of Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Previously treated MDS, oral clofarabine, Intermediate-1, Intermediate-2 and High Risk MDS, secondary AML (with history of MDS)