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Trial record 12 of 448 for:    "Juvenile myelomonocytic leukemia"

Low-dose Oral Clofarabine for the Treatment of IPSS INT-1, INT-2 or HIGH Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

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ClinicalTrials.gov Identifier: NCT00708721
Recruitment Status : Terminated (Data analysis revealed sufficient data for safety and efficacy)
First Posted : July 2, 2008
Results First Posted : June 1, 2017
Last Update Posted : June 1, 2017
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
University of Utah

Brief Summary:

Study and Dose Rationale The safety profile of clofarabine appears acceptable within the target populations studied to date in the clinical studies summarized in Section 2.3. clofarabine has demonstrated anti-cancer activity through inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms. The effect of clofarabine on DNA methylation has not been determined. Numerous responses have been observed after treatment with clofarabine in heavily pre-treated relapsed/refractory patients with ALL or AML.

Recently 2 small studies were conducted at the M.D. Anderson Cancer Center looking at the use of clofarabine in the treatment of MDS.31 The first study randomized patients in a Bayesian fashion to 15 vs. 30 mg/m2 given IV daily for 5 days every 4 to 8 weeks. In the 15 mg/m2 arm 3 of 7 patients had a complete remission according to the International Working Group (IWG)32 criteria for response. In the 30 mg/m2 arm, 2 of 6 patients had a complete remission while 1 patient had hematologic improvement according to IWG criteria. In the second study, patients were treated with oral clofarabine at a dose of 40 mg/m2 daily for 5 days every 4 to 8 weeks. Two of 7 patients had hematologic improvement according to IWG criteria. The main toxicities in both trials were prolonged myelosuppression and liver function abnormalities.

Preclinical animal models have shown increased clofarabine activity against multiple different tumors with repetitive daily dosing for prolonged periods of time.33 The use of an oral therapy is advantageous for the treatment of a chronic malignancy such as MDS. Furthermore, based on the pre-clinical data mentioned above daily repetitive dosing over a protracted period may provide increased efficacy. Since most MDS patients are elderly and may not tolerate aggressive therapy, a schedule of administration of low dose oral clofarabine over a protracted period may provide the advantage of increased efficacy without severe toxicity. The safety of a protracted daily dosage of oral clofarabine in humans has not been determined. The dosing scheme for this study will therefore include a dose escalating phase I component followed by a phase II component. The starting dose will be 5 mg (fixed dose) orally daily for 10 days. This dose will be escalated in cohorts of 3 patients as tolerated up to a maximal dose of 15 mg (fixed dose) orally for 10 consecutive days. Note that at the latter dose a patient will receive a total of 150 mg of clofarabine per cycle, which far lower than the MD Anderson study of oral clofarabine in MDS whereby patients received 200 mg/m2 per cycle.

OBJECTIVES:

Study Overview The purpose of this study is to determine the efficacy and toxicity of Clofarabine administered orally at a low daily dose for the treatment of myelodysplastic syndromes.


Condition or disease Intervention/treatment Phase
Cancer Chronic Myelomonocytic Leukemia Drug: Clofarabine Phase 1 Phase 2

Detailed Description:

Primary Objectives

  1. Phase I: To determine the MTD within the planned dose range for this patient population and assess the toxicity of oral clofarabine
  2. Phase II: To estimate the overall response rate (complete, partial and hematologic improvement by modified IWG criteria) in response to low dose daily oral clofarabine in patients with high risk myelodysplastic syndrome or chronic myelomonocytic leukemia (dysplastic type).

Secondary Objectives

  1. To evaluate the toxicity of low dose daily oral clofarabine in this patient population.
  2. To determine the time to progression to acute myeloid leukemia (AML) of MDS patients treated with low dose daily oral clofarabine.
  3. To determine the duration of response, overall survival (OS) and progression free survival (PFS) of MDS patients treated with low dose daily oral clofarabine.
  4. To determine the effect of low dose daily oral clofarabine on global methylation in patients with MDS.
  5. To determine the effect of low dose daily oral clofarabine on miRNA and mRNA expression patterns in patients with MDS.

Treatment Patients will take Clofarabine by mouth once daily for 10 days followed by 18 days of no Clofarabine. This 28 day period of time is called one treatment cycle. After they complete three cycles of treatment they will have bone marrow and blood tests done to find out if their MDS or CMML is responding to the treatment. If these tests show the MDS or CMML is responding to treatment they will continue taking the same dose of Clofarabine for 3 more cycles. If the tests show that the MDS or CMML is not responding to treatment the dose of Clofarabine will be increased and they will continue on the same schedule (10 days on, 18 days off) for 3 more cycles.

After 6 cycles patients will again have bone marrow and blood tests done to find out if the MDS or CMML is responding to the treatment. If the tests show that the MDS or CMML is not responding to treatment the dose of Clofarabine will be increased again and they will continue on the same schedule (10 days on, 18 days off) for 6 more cycles.

5-3-11 Update: The phase I portion of the study has now been closed to accrual. The Phase II portion of the trial will enroll up to 20 patients. Patients will be evaluated on a weekly basis for toxicity. At the completion of cycle 3 and within 1 week of starting cycle 4, patients will receive a bone marrow aspirate and biopsy in addition to a complete blood count in order to evaluate for response according to IWG criteria. Patients who have evidence of a response to therapy or stable disease will be continued on the same dose and schedule of oral clofarabine. Bone marrow evaluation for response will be obtained at the completion of 6 and then 12 cycles. If the patient continues treatment after cycle 12 a bone marrow evaluation will be done at the discretion of the investigator. Treatment will continue at the same dose and schedule indefinitely until either disease progression, the development of unacceptable toxicity or the patient decides to go off study.

Follow-up For this protocol, all patients, including those who discontinue protocol therapy early, will be followed for response until progression and for survival for 5 years from the date of registration. All patients must also be followed through completion of all protocol therapy.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Low-dose Oral Clofarabine for the Treatment of IPSS INT-1, INT-2 or HIGH Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia (Dysplastic Type) Patients Who Have Failed Hypomethylating Therapy
Study Start Date : March 2008
Actual Primary Completion Date : November 2014
Actual Study Completion Date : November 2014


Arm Intervention/treatment
Experimental: All patients
All participants enrolled.
Drug: Clofarabine
Clofarabine is a rationally designed, second generation purine nucleoside analogue. Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate the best qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA) both of which are currently approved by various regulatory authorities for treatment of hematologic malignancies.
Other Name: Clofarabine (2-chloro-9-[2-deoxy-2-fluoro-D-arabinofuranosyl]adenine; Cl-F-ara A; CAFdA




Primary Outcome Measures :
  1. Number of Participants Who Experienced a Dose-Limiting Toxicity [ Time Frame: 28 days after the first admistration of oral clofarabine ]
    Dose-limiting toxicity was defined as any nonhematologic toxicity grade 3 or greater except for alopecia or nausea (which may be of grade 4 severity), or any grade 4 hematologic toxicity lasting more than 28 days after the last day of therapy.

  2. The Overall Response Rate in Response to Low Dose Daily Oral Clofarabine in Patients With High Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (Dysplastic Type). [ Time Frame: 4 weeks ]
    Response rate was measured as complete, partial and hematologic improvement by modified IWG criteria. For complete remission the following must be present for four weeks in a bone marrow aspirate and biopsy: <5% myeloblasts, normal maturation of all cell lines, persisted dysplasia. Peripheral blood counts need to be hemoglobin >11 g/dL, neutrophils >1000/mm3, platelets>100000/mm3, blasts 0%. Partial remission requires all criteria for complete remission except blasts decreased by >50% over pretreatment. Stable disease is defined as failure to achieve at least partial remission, but no evidence of progression for > 8 weeks. Failure is defined as death during tre3atment or disease progression characterized by worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment.


Secondary Outcome Measures :
  1. Time to Progression to Acute Myeloid Leukemia (AML) [ Time Frame: approximately 4 years ]
    Longest documented duration of time until progression to AML.

  2. Response of MDS Patients Treated With Low Dose Daily Oral Clofarabine. [ Time Frame: approximately 4 years ]
    Stable disease is defined as failure to achieve at least PR, but no evidence of progression for > 8 weeks.

  3. The Effect of Low Dose Daily Oral Clofarabine on Global Methylation in Patients With MDS. [ Time Frame: through end of treatment ]
    Potential genomic changes following low dose daily oral clofarabine administration will be assessed.

  4. The Effect of Low Dose Daily Oral Clofarabine on miRNA and mRNA Expression Patterns in Patients With MDS [ Time Frame: through end of treatment ]
    Assessment of potential change in miRNA and mRNA genetic expression patterns in patients following administration of low dose daily clofarabine.

  5. Number of Participants With Adverse Events [ Time Frame: To 30 days after end of treatment or until full resolution. ]
    NCI CTCAE version 3.0 will be used to assess adverse events. The number of participants experiencing adverse events and the number of adverse events per patient will be documented through the course of study.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A bone marrow biopsy confirmed diagnosis of MDS or CMML (dysplastic subtype) according to WHO criteria within 2 weeks of registration.

  1. Patients must have an International Prognostic Scoring System (IPSS), see Appendix D, score of INT-1 or higher at study entry.35 Patients with an IPSS score of INT-1 with the 5q- deletion should have failed Lenalidomide therapy and should have more than 5% blasts in the bone marrow or a platelet count < 50,000/mm3 or an absolute neutrophil count < 500/mm3 or be requiring therapy (e.g. being transfusion dependent). Patients with CMML must have a WBC < 12,000/mm3 documented within 4 weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken).
  2. Patients with MDS should have failed or relapsed after treatment with one regimen of hypomethylating agents (5-Azacytidine or Decitabine) but no more than 2 prior therapies including only 1 hypomethylating agent... Patients with CMML (dysplastic subtype) may be enrolled even if they have not received any prior therapy.
  3. Untreated patients who are ineligible for or unwilling to undergo hypomethylating agent therapy can be enrolled
  4. Age ≥ 18 years.
  5. Patients must have and ECOG performance status of 0 - 2.
  6. Provide signed written informed consent.
  7. 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 30 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
  8. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.
  9. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.
  10. 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:

  1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
  2. Pre-treatment with more than 2 previous regimens.
  3. Use of investigational agents within 30 days or any anticancer therapy within 30 days before study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicities from any previous therapy.
  4. 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.
  5. 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).
  6. Pregnant or lactating patients.
  7. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00708721


Locations
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
University of Utah
Genzyme, a Sanofi Company
Investigators
Principal Investigator: Paul J Shami, MD Huntsman Cancer Institute

Responsible Party: University of Utah
ClinicalTrials.gov Identifier: NCT00708721     History of Changes
Other Study ID Numbers: HCI26135
First Posted: July 2, 2008    Key Record Dates
Results First Posted: June 1, 2017
Last Update Posted: June 1, 2017
Last Verified: May 2017

Keywords provided by University of Utah:
hypomethylating therapy
CML
myelodysplastic syndromes

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Clofarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents