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

NCT00700011 | Terminated Phase 2 Results DMC

• 1 other identifier: iCLO111
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Myelodysplastic Syndromes

Keywords

Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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

Secondary Outcomes (1)

• Number of Participants With DNA Hypomethylation During the Study

  assessed twice per cycle

Study Arms (2)

10 mg/m2 group

ACTIVE COMPARATOR

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.

Drug: Clofarabine

5 mg/m2 group

ACTIVE COMPARATOR

Patients were treated with Clofarabine 5 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.

Drug: Clofarabine

Interventions

Clofarabine DRUG

10 mg/m2 x 5 days per 4 to 6 week cycles

Also known as: Clolar

10 mg/m2 group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Texas Oncology Cancer Center: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (1)

Texas Oncology Cancer Center

Amarillo, Texas, 79106, United States

Location

Related Publications (16)

• Hellstrom-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. doi: 10.1182/asheducation-2005.1.161.

  PMID: 16304375 RESULT

• 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. doi: 10.1182/blood.v97.5.1508.

  PMID: 11222401 RESULT

• 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. doi: 10.1038/sj.bjc.6602160.

  PMID: 15381930 RESULT

• 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 refractory or relapsed acute leukemia. Blood. 2003 Oct 1;102(7):2379-86. doi: 10.1182/blood-2003-03-0925. Epub 2003 Jun 5.

  PMID: 12791647 RESULT

• 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. doi: 10.1016/0731-7085(95)01325-f. No abstract available.

  PMID: 9696594 RESULT

• 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. doi: 10.1073/pnas.89.7.2970.

  PMID: 1348362 RESULT

• Lotfi K, Mansson 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 Cancer Res. 1999 Sep;5(9):2438-44.

  PMID: 10499616 RESULT

• 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 ribonucleotide reductase and DNA polymerases by its 5'-triphosphate. Cancer Res. 1991 May 1;51(9):2386-94.

  PMID: 1707752 RESULT

• 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;96(10):3537-43.

  PMID: 11071652 RESULT

• 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 cancers. J Clin Oncol. 2003 Mar 15;21(6):1167-73. doi: 10.1200/JCO.2003.04.031.

  PMID: 12637486 RESULT

• 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 (ara-C) in relapsed and refractory acute leukemias. Blood. 2005 Feb 1;105(3):940-7. doi: 10.1182/blood-2004-05-1933. Epub 2004 Oct 14.

  PMID: 15486072 RESULT

• 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 patients 50 years of age or older. Blood. 2006 Jul 1;108(1):45-51. doi: 10.1182/blood-2005-08-3294. Epub 2006 Jan 10.

  PMID: 16403905 RESULT

• 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 clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. doi: 10.1200/JCO.2005.03.8554.

  PMID: 16622268 RESULT

• 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. doi: 10.1182/blood-2003-06-2122. Epub 2003 Oct 9.

  PMID: 14551141 RESULT

• 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 Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.

  PMID: 16609072 RESULT

• 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. doi: 10.1038/sj.leu.2404796. Epub 2007 Jul 5.

  PMID: 17611569 RESULT

Related Links

• Texas Oncology
• Texas Oncology - Amarillo

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Clofarabine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides

Results Point of Contact

• Title: Dr. Seah Lim
• Organization: Texas Oncology - Amarillo

seah.lim@usoncology.com

806-358-8654

Study Officials

• Seah Lim, MD

  Texas Oncology Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2008
• First Posted: June 18, 2008
• Study Start: March 1, 2008
• Primary Completion: March 1, 2010
• Study Completion: March 1, 2010
• Last Updated: March 15, 2013
• Results First Posted: January 9, 2013

Record last verified: 2013-03

Locations

US (1)