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Clofarabine

Antimetabolites

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).

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).

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).

Pharmaceutical form: Tablet,

Route of administration: Oral

Medical Monitor

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.

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

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

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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.

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.

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.

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.

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.

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.

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.

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 \[L\]).

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.

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.

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

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

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

Genzyme, a Sanofi Company

Reported AEs and deaths were TEAEs that developed, worsened, or became serious during the treatment period (from signature of the informed consent form up to 45 days post last dose of study drug). Analysis was performed on FAS.

Clofarabine 25 mg/Day

Clofarabine 35 mg/Day

Clofarabine 55 mg/Day

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Analysis was performed on full analysis set (FAS) that included all participants who had received at least 1 dose of oral Clofarabine, regardless of participant's compliance with protocol procedures after enrollment.

Trial Transparency Team

Analysis was performed on modified Full Analysis Set (mFAS) that included participants assigned to all doses who had received at least 1 dose of clofarabine, excluding participants treated at 55 mg. Data for this outcome measure (OM) was not planned to be collected and analyzed for Clofarabine 55 mg/day arm.

Percentage of Participants With Overall Response

Analysis was performed on subset of participants who had response. Data for this OM was not planned to be collected and analyzed for Clofarabine 55 mg/day arm.

Duration of Response (DoR)

Analysis was performed on mFAS. Data for this OM was not planned to be collected and analyzed for Clofarabine 55 mg/day arm.

Number of Participants Who Achieved Hematologic Improvement (HI)

Percentage of Participants Achieving Overall Remission (OR)

Time to Acute Myeloid Leukemia (AML) Transformation

Overall Survival (OS)

Analysis was performed on all participants who received study drug.

Maximum Tolerated Dose (MTD) of Oral Clofarabine

Number of Participants With Febrile Neutropenia

Any TEAE

Any treatment emergent SAE

Any TEAE leading to discontinuation

Any TEAE leading to death

Deaths within 45 days of last dose

Grade 4 Toxicities

Grade 5 Toxicities

Participants received Clofarabine 25 mg/day orally for 5 consecutive days of each 28-day treatment until disease progression or death, whichever comes first (maximum study duration: up to 4 years).

Number of Participants With Adverse Events (AEs)

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

Any unacceptable drug-related toxicities

Drug-related prolonged myelosuppression

Grade 4 drug-related non-haematologic toxicity

Grade 3 drug-related recurrent or persistent non-haematologic toxicity

Drug-related toxicity precluding completion of at least 4 daily doses

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

Analysis was performed on PK population that included all participants who had received at least 1 dose of oral Clofarabine and had at least 1 sample available for PK analysis.

Spots Global Cancer Trial Database for A Dose Confirmation Study of Oral Clofarabine for Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)

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