Myelodysplastic Syndromes
Conditions
Keywords
Myelodysplastic Syndromes
Brief summary
The investigators hypothesize that, in addition to its apoptotic effect, clofarabine induces DNA hypomethylation. If the investigators' hypothesis is correct, findings from the present proposal will not only contribute to information relating to the mechanisms of action of clofarabine but also provide the opportunity for combined epigenetic targeting of MDS using clofarabine with either another hypomethylating agent or a histone deacetylase inhibitor. Clofarabine has demonstrated anti-cancer activity through inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms. Numerous responses have been observed after treatment with clofarabine in heavily pre-treated relapsed/refractory patients with ALL, AML and high risk MDS. In the present proposal, the investigators will study the clinical and laboratory effects of 2 different dosages of clofarabine in patients who have failed the hypomethylating agent, 5-azacytidine. This study will recruit patients who have received at least six cycles of 5-azacytidine without response or whose disease has progressed or relapsed while on 5-azacytidine. The first cohort of patients will receive clofarabine 10 mg/m2/day for five days and the second cohort of patients 5 mg/m2/day for five days, both every four to six weeks. The investigators will determine the frequency of response to the two dosages of nucleoside analog in this group of patients. Measurement of responses will include improvement in the peripheral blood count, reduction in the blood and platelet transfusion need and eradication of cytogenetically abnormal clones. Successful completion of this study will define the position of clofarabine in MDS in the era of epigenetic targeting.
Detailed description
Study Overview This study will recruit patients who have received at least six cycles of 5-azacytidine without response or whose disease has progressed or relapsed while on 5-azacytidine. The first cohort of patients will receive clofarabine 10 mg/m2/day for five days and the second cohort of patients 5 mg/m2/day for five days, both every four to six weeks. The investigators will determine the frequency of response to the two dosages of nucleoside analog in this group of patients. Measurement of responses will include improvement in the peripheral blood count, reduction in the blood and platelet transfusion need and eradication of cytogenetically abnormal clones. * Primary Objectives 1. To determine the frequency and duration of peripheral blood responses to IV clofarabine in MDS patients who have failed 5-azacytidine 2. To determine the frequency and duration of bone marrow responses to IV clofarabine, including CR + PR * Secondary Objectives To determine whether clofarabine exhibits a DNA hypomethylating property
Interventions
DRUGClofarabine
10 mg/m2 x 5 days per 4 to 6 week cycles
Sponsors
Genzyme, a Sanofi Company
Texas Oncology Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with MDS of any risk group who have, just immediately prior to being entered into this study, already received at least six cycles of 5-azacytidine and have failed, either due to no response or to disease relapse despite being still on 5-azacytidine, or patients whose MDS has progressed while on 5-azacytidine, irrespective of the number of cycles the patient has received. We have specifically chosen to be very stringent about our patient population in order to address our question of whether clofarabine can be used to salvage patients who have failed 5-azacytidine with only a small patient population, i.e. 10 patients in each cohort. * ECOG Performance status of 0 - 2 * Recombinant erythropoietin is allowed, if the patients are already receiving erythropoietin. G-CSF can be given during the neutropenic stage following therapy since this would not affect evaluation of response because the response will be made based on CBC and bone marrow changes upon recovery from clofarabine. * Patients must have been at least four weeks after the last course of 5-azacytidine * Age over 18 years * Have adequate renal and hepatic functions as indicated by the following laboratory values: * Serum creatinine 1.0 mg/dL; if serum creatinine 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black) * Serum bilirubin ≤1.5 mg/dL × upper limit of normal (ULN) * Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 × ULN * Alkaline phosphatase 2.5 × ULN * Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide signed informed consent. * Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment. * Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
Exclusion criteria
* Nursing or pregnant women * Prior clofarabine therapy * Life expectancy of less than 3 months due to other intercurrent illness. * Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. * Use of investigational agents within 30 days or any anticancer therapy within 4 weeks before study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicities from any previous therapy. * Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment. * Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). * Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Peripheral Blood Count and Reduction in Number of Transfusions | 2-3 months | Hematologic improvement will be an increased Hemoglobin of 1.5 g/dL or a reduction in the need for PRBC transfusions by at least 4 units over an 8 week period, at least 100% increase and an ANC of \>0.5 x 10\^9/L and an absolut platelet count increase of \>30 x 10\^9/L for patients who start at \> 20 x 10\^9/L, or increase from \<20 x 10\^9/L to \>20 x 10\^9/L and by at least 100%. |
| Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | 2-3 months | The International Working Group response criteria was used. Complete remission is defined as \<5 % marrow blasts without evidence of dysplasia and normalization of the peripheral blood counts, including hemoglobin \>11 g/dL, neutrophil count of \>1 x 10\^9/L. and platelet count of \>100 x 10\^9/L. Patients must also be transfusion-independent and not require any recombinant erythropoietin. Partial remission (PR) is defined as: satisfying complete remission criteria if abnormal before treatment, except that blasts are reduced by 50% or more compared to pretreatment levels, but still \>5 %. Stable disease is defined as: failure to achieve at least a PR but without evidence of disease progression for at least 8 weeks.Progression of disease is defined as: disease progression with worsening cytopenias. Best response of these patients is used in the determination for this outcome below. |
| To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | biweekly for duration of treatment , an average of 3 months | Assess for adverse events in all the patients receiving the Clofarabine at the dose schedules described in the protocol (CTCAE 3.0 used). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With DNA Hypomethylation During the Study | assessed twice per cycle | Since we previously observed decreases in DNA methylation in tumor cells after in vitro treatment with Clofarabine, we compared the long interspersednuclear element-1 methylation of genomic DNA obtained from CD3-depletedperipheral blood mononuclear cells between day 1 and day 5 of each cycle of Clofarabine. |
Countries
United States
Participant flow
Recruitment details
The recruitment period started 3/24/08 (date of consent of the first patient), to 4/8/10 which was the date IRB lists as date of study closure. All patients were consented and treated at our clinic, Texas Oncology - Amarillo. Eight patients were treated to the 10 mg/m2 arm and two patients to the 5 mg/m2 arm. Study closed due to poor recruitment.
Pre-assignment details
There were no screen fails due to pre-screening thoroughly. The plan was to sign eight patients to the 10 mg/m2 arm and then eight to the 5 mg/m2 arm, but recuitment was difficult and decision was made to close study in early 2010, so only two patients were assigned to 5 mg/m2 arm.
Participants by arm
| Arm | Count |
|---|---|
| 10 mg/m2 Group Patients were treated with Clofarabine 10 mg/m2 daily x 5 days per cycle. Cycles were intended on being every 28 days but this was flexible due to the bone marrow neding to recover from each cycle before strting the next one. Neulasta was given on day 5 of each cycle. Patients were treated until disease progression, or intolerable toxicities. | 8 |
| 5 mg/m2 Group Patients were treated with Clofarabine 10 mg/m2 daily x 5 days per cycle. Cycles were intended on being every 28 days but this was flexible due to the bone marrow neding to recover from each cycle before strting the next one. Neulasta was given on day 5 of each cycle. Patients were treated until disease progression, or intolerable toxicities. | 2 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
Baseline characteristics
| Characteristic | 5 mg/m2 Group | 10 mg/m2 Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 8 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 77.5 years STANDARD_DEVIATION 0.707 | 73.38 years STANDARD_DEVIATION 4.10357 | 74.2 years STANDARD_DEVIATION 4.022 |
| Region of Enrollment United States | 2 participants | 8 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 2 / 2 |
| serious Total, serious adverse events | 6 / 8 | 2 / 2 |
Outcome results
Primary
Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine
The International Working Group response criteria was used. Complete remission is defined as \<5 % marrow blasts without evidence of dysplasia and normalization of the peripheral blood counts, including hemoglobin \>11 g/dL, neutrophil count of \>1 x 10\^9/L. and platelet count of \>100 x 10\^9/L. Patients must also be transfusion-independent and not require any recombinant erythropoietin. Partial remission (PR) is defined as: satisfying complete remission criteria if abnormal before treatment, except that blasts are reduced by 50% or more compared to pretreatment levels, but still \>5 %. Stable disease is defined as: failure to achieve at least a PR but without evidence of disease progression for at least 8 weeks.Progression of disease is defined as: disease progression with worsening cytopenias. Best response of these patients is used in the determination for this outcome below.
Time frame: 2-3 months
Population: All patients considered except one on the 5 mg/m2 arm who we didn't have enough time to assess response as he died within 2 weeks after receiving cycle 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | complete remission | 1 participants |
| 10 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | partial remission | 1 participants |
| 10 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | stable disease | 4 participants |
| 10 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | progressive disease | 2 participants |
| 5 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | progressive disease | 0 participants |
| 5 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | complete remission | 0 participants |
| 5 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | stable disease | 1 participants |
| 5 mg/m2 Group | Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine | partial remission | 0 participants |
Primary
Improvement in Peripheral Blood Count and Reduction in Number of Transfusions
Hematologic improvement will be an increased Hemoglobin of 1.5 g/dL or a reduction in the need for PRBC transfusions by at least 4 units over an 8 week period, at least 100% increase and an ANC of \>0.5 x 10\^9/L and an absolut platelet count increase of \>30 x 10\^9/L for patients who start at \> 20 x 10\^9/L, or increase from \<20 x 10\^9/L to \>20 x 10\^9/L and by at least 100%.
Time frame: 2-3 months
Population: All patients considered for analysis except for one on the 5 mg/m2 arm who died within 2 weeks after cycle one making this unassessable for that patient.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg/m2 Group | Improvement in Peripheral Blood Count and Reduction in Number of Transfusions | 3 participants |
| 5 mg/m2 Group | Improvement in Peripheral Blood Count and Reduction in Number of Transfusions | 1 participants |
Primary
To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above)
Assess for adverse events in all the patients receiving the Clofarabine at the dose schedules described in the protocol (CTCAE 3.0 used).
Time frame: biweekly for duration of treatment , an average of 3 months
Population: All participants considered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Vomiting | 2 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | ALT elevation | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Hyperbilirubinemia | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | AST elevation | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Mucositis | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Dyspnea | 0 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Dehydration | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Dizziness | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Nausea | 2 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Headache | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Rash | 1 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Pulmonary edema | 0 participants |
| 10 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Fatigue | 4 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Pulmonary edema | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Fatigue | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Mucositis | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Vomiting | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Nausea | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Hyperbilirubinemia | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Dehydration | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Rash | 0 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | ALT elevation | 0 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | AST elevation | 0 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Dyspnea | 1 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Dizziness | 0 participants |
| 5 mg/m2 Group | To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above) | Headache | 0 participants |
Secondary
Number of Participants With DNA Hypomethylation During the Study
Since we previously observed decreases in DNA methylation in tumor cells after in vitro treatment with Clofarabine, we compared the long interspersednuclear element-1 methylation of genomic DNA obtained from CD3-depletedperipheral blood mononuclear cells between day 1 and day 5 of each cycle of Clofarabine.
Time frame: assessed twice per cycle
Population: All participants were considered except one patient on 5 mg/m2 arm who died within 2 weeks after cycle 1, so this was unassessable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg/m2 Group | Number of Participants With DNA Hypomethylation During the Study | 2 participants |
| 5 mg/m2 Group | Number of Participants With DNA Hypomethylation During the Study | 0 participants |