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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)

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

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.

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

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

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

Overall Study

Immune System Diseases

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

The starting dose will be 1 mg orally daily x 21 days every 4 weeks +/- 4 days.

Oral Clofarabine

Stefan F. Faderl, M.D.

The goal of this clinical research study is to find the highest tolerable dose of clofarabine when given to patients with CLL. The safety of this drug will also be studied.

The Study Drug:

Clofarabine is designed to interfere with the growth and development of cancer cells.

Screening Tests:

Before you can begin taking the study drug, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

* Your complete medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs (blood pressure, heart rate, temperature, and breathing rate).
* You will also be asked about what drugs you are currently taking.
* You will be asked how well you are able to perform the normal activities of daily living (performance status evaluation).
* Blood (about 2 tablespoons) will be drawn for routine tests.
* You will also have a bone marrow aspirate and/or biopsy. To collect a bone marrow aspirate, an area of the hip is numbed with anesthetic and a small amount of bone marrow and bone is withdrawn through a large needle.
* Women who are able to have children must have a negative blood or urine pregnancy test. The blood would be drawn as part of the routine sample described above.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose level of clofarabine based on when you joined this study. Up to 7 dose levels of clofarabine will be tested. Three (3) to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of clofarabine is found.

The dose of clofarabine may be lowered or delayed to help reduce side effects.

Study Drug Administration:

On Days 1-21 of each 28-day study "cycle", you will take clofarabine by mouth once a day (in the morning) at about the same time everyday.

* You should take clofarabine on an empty stomach.
* You should try to fast (not eat anything or drink anything other than water) from midnight the night before each dose to 1 hour after taking clofarabine.
* Clofarabine should be taken with 4 ounces (1/2 a cup) of water.
* You should not drink coffee and other caffeinated liquids before and for 1 hour after taking the study drug.
* If you vomit more than 15 minutes after you take the drug, you should not replace or make up the drug. If you vomit less then 15 minutes after taking the drug, you should retake the dose. If you vomit again within 15 minutes after retaking the dose, you should not take the drug again that day and make a note of it in the diary.

Study Visits:

* On Day 1 of every cycle, the following tests and procedures will be performed:
* You will have a physical exam, including measurement of your weight and vital signs.
* You will have a performance status evaluation.
* You will be asked if you have experienced any intolerable side effects and how you are feeling.

Once a week of Cycle 1, you will have a physical exam.

Once a week of every cycle, blood (about 1-2 teaspoons) will be drawn for routine tests (blood counts with platelets). Your blood will be drawn more often if the doctor feels it is necessary.

After Cycles 3 and 6, you will have a bone marrow aspiration and/or biopsy to check the status of the disease.

If you go off study before Cycle 3 and the doctor thinks it is necessary, the bone marrow aspiration and/or biopsy may be taken when you go off study.

If you have completed all 6 cycles of the study drug, every 6 months (+/- 2 months), you will have a physical exam and blood (about 1-2 teaspoons) will be drawn to check on the status of the disease and your overall health. The study doctor will tell you any other tests that may be needed.

Length of Study You will be on the study drug for up to 6 cycles (about 6 months). You will be taken off study early if the disease gets worse or you experience any intolerable side effects.

Additional Information:

You will need to stay in Houston for Cycle 1 (28 days). After that, you may return to your home but you will still have to return to Houston before each cycle unless you choose to have check-up visits and blood tests with your local doctor.

This is an investigational study. Clofarabine is FDA approved and commercially available when given by vein to pediatric patients for the treatment of acute lymphoblastic leukemia (ALL) that has come back or not responded to other treatments. The use of clofarabine by mouth is not FDA approved. At this time, oral clofarabine is only being used in research.

Up to 36 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Dose Confirmation Study of Oral Clofarabine for Adult Patients Previously Treated for Myelodysplastic Syndromes (MDS)	NCT00531232	Myelodysplastic... Secondary Acute...	Clofarabine	18 Years -	Sanofi
Oral Clofarabine in Chronic Lymphocytic Leukemia (CLL)	NCT00800566	Leukemia Chronic Lymphoc...	Oral Clofarabin...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for oral clofarabine