Clofarabine for Myelodysplastic Syndrome (MDS) Patients Who Failed Vidaza Treatment (tx)

Myelodysplastic Syndromes Clinical Trial

Official title:

A Pilot Study of IV Clofarabine for Patients With Myelodysplastic Syndrome Who Have Failed 5-azacytidine

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00700011
• Other study ID #: iCLO111
• Status: Terminated
• Phase: Phase 2
• First received: June 17, 2008
• Last updated: March 12, 2013
• Start date: March 2008
• Est. completion date: March 2010

Study information

• Verified date: March 2013
• Source: Texas Oncology Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: March 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Clofarabine
10 mg/m2 x 5 days per 4 to 6 week cycles
• Clofarabine
5 mg/m2 x 5 days per 4 to 6 week cycles

Locations

Country	Name	City	State
United States	Texas Oncology Cancer Center	Amarillo	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Texas Oncology Cancer Center	Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

References & Publications (16)

Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2970-4. — View Citation

Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Gr — View Citation

Faderl S, Gandhi V, O'Brien S, Bonate P, Cortes J, Estey E, Beran M, Wierda W, Garcia-Manero G, Ferrajoli A, Estrov Z, Giles FJ, Du M, Kwari M, Keating M, Plunkett W, Kantarjian H. Results of a phase 1-2 study of clofarabine in combination with cytarabine — View Citation

Faderl S, Verstovsek S, Cortes J, Ravandi F, Beran M, Garcia-Manero G, Ferrajoli A, Estrov Z, O'Brien S, Koller C, Giles FJ, Wierda W, Kwari M, Kantarjian HM. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in — View Citation

Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, Carson DA, Leoni LM. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood. 2000 Nov 15;9 — View Citation

Hellström-Lindberg E. Update on supportive care and new therapies: immunomodulatory drugs, growth factors and epigenetic-acting agents. Hematology Am Soc Hematol Educ Program. 2005:161-6. — View Citation

Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 — View Citation

Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabin — View Citation

Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O'Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase 2 clinical and pharmacologic study of clofarabine in patients with refracto — View Citation

Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, O'Brien S, Ibrahim N, Khuri F, Du M, Rios MB, Jeha S, McLaughlin P, Plunkett W, Keating M. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancer — View Citation

Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood. 2001 Mar 1;97(5):1508-10. — View Citation

Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F. Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, a novel analogue of cladribine in human leukemic cells. Clin — View Citation

Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW, Shortnacy AT, Montgomery JA, Secrist JA 3rd, Bennett LL Jr. Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ri — View Citation

Raj K, John A, Ho A, Chronis C, Khan S, Samuel J, Pomplun S, Thomas NS, Mufti GJ. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia. 2007 Sep;21(9):1937-44. Epub 2007 Jul 5. — View Citation

Reichelova V, Liliemark J, Albertioni F. Liquid chromatographic study of acid stability of 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine and related analogues. J Pharm Biomed Anal. 1995 Apr;13(4-5):711-4. — View Citation

Wang Z, Zhang Y, Ramsahoye B, Bowen D, Lim SH. Sp17 gene expression in myeloma cells is regulated by promoter methylation. Br J Cancer. 2004 Oct 18;91(8):1597-603. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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%.	2-3 months	Yes
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.	2-3 months	No
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).	biweekly for duration of treatment , an average of 3 months	Yes
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.	assessed twice per cycle	Yes

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