|
Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Clinical Trials References presented on Clinical Trials Search is not intended to be a substitute for proven healthcare advice, trips or professional assistance by using a real medical. We aren't mDs. Always confer with your physician about Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) conditions. Clinical Trials Search.org is a website devoted to listing clinical research studies in human subjects. Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Clinical research trials and Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) medical trials take place in hundreds of localities across the U.S.. A clinical trial or clinical study is a research project with human volunteer subjects. Clinical drug trials and pharmaceutical clinical trials usually evaluate the effectualness of new does drugs. The purpose of the studies / projects is to solve specific human health questions. Clinical trials are a popular way for physicians, government agencies, and private sector companies to discover treatments for all sorts of conditions, such as Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL). Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Clinical Trials and other clinical trials permit volunteers to access healthcare treatment choices before they are available to the general public. Some times the subjects recieve professional assistance for without cost, and every now and again they are compensated for their time. Sometimes there is a cost for a Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) clinical trial. Subjects often receive the most expert healthcare possible for their Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) condition. Risks are a reality, nevertheless, and could include additional or frequent dr. calls, healthcare dangers (perhaps life-jeopardising), and/or the treatment being ineffective. Trials are federally governed with stern guidelines to protect clinical trials subjects.
|
|
|
|
|
|
|
Home > "S" Clinical Trials Conditions > Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)  Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
For Condition: Chronic Lymphocytic Leukemia
Status: Recruiting
Sponsor(s): M.D. Anderson Cancer Center , ILEX Oncology
Synopsis: The goal of this clinical research study is to find the highest safe dose of clofarabine that can be given on a weekly schedule for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). The effectiveness of this treatment will also be studied.
Details: Cure rates that are currently achievable in patients with relapsed or refractory hematological malignancies are dismal. Therefore, new agents need to be identified and tested in clinical trials that can be incorporated into effective regimens to improve the prognosis of these patients. This study is directed at patients with relapsed and refractory chronic lymphocytic leukemia (CLL). Once patients fail front-line therapy, their therapeutic options are limited. This population of patients typically has a response rate of 10% to 20% when relapsed or refractory to established frontline therapies. Nucleoside analogs are among the most active antileukemic agents available. Clofarabine was synthesized as a rational extension of the experience with other deoxyadenosine analogs in particular fludarabine and cladribine. Both fludarabine and 2-CDA are effective against lymphoproliferative disorders. This led to the synthesis of a series of 2-halo-2’ halo-2’ deoxyarabinofuranosyl adenine analogues that have activity against P388 tumors in mice. The 2-(F, Cl, or Br)-2’-F-araA analogues (but not the 2’-Cl or 2’-Br analogues) were found to be potent inhibitors of cell growth. These analogues were synthesized because of the noted antitumor activity of 2-halodeoxyadenosine analogues, and the appearance of 2-F-adenine (a toxic compound with no anti-tumor selectivity) in animals treated with F-ara-A. 2-F-adenine is thus thought to contribute only to toxicity, and results from cleavage of the glycosidic bond by purine nucleoside phosphorylase. Substitution of a fluorine at C-2’ of an inosine derivative, while retaining the arabino configuration, makes these derivatives highly resistant to bacterial purine nucleoside phosphorylase. Therefore 2-halo-2'halo-2’-deoxyarabinofuranosyl adenine analogues (such as Clofarabine) are poor substitutes for the enzyme; furthermore, any cleavages of Clofarabine that does occur will produce 2-Cl-adenine, which is much less toxic than 2-F-adenine. To become active, clofarabine needs to be converted intracellularly to the triphosphate form. Phosphorylation of clofarabine is substantially more efficient than that of other nucleosides such as fludarabine and so is intracellular retention of the active triphosphate form of clofarabine. Mechanisms of action include inhibition of DNA synthesis, inhibition of DNA polymerases, and potent inhibition of ribonucleotide reductase (RNR) resulting in depletion of normal nucleotides and increased DNA uptake of the nucleoside analog. We had previously conducted all the animal toxicology studies at M.D. Anderson Cancer Center (mice, dogs) because of the lack of interest in Clofarabine by the Drug Industry (expired patent protection, small drug market). We then conducted the phase I studies in a broad range of solid and hematologic cancer. Animal studies suggested a starting dose of 15mg/m2 IV over 1 hour daily x 5 days every 3 to 4 weeks. The phase I study of clofarabine included 52 patients (13 metastatic solid tumor patients and 38 patients with hematologic malignancies including 6 patients with CLL and other lymphoproliferative disorders). The starting dose of 15mg/m2/d daily for 5 days was severely myelotoxic for solid tumor and CLL patients requiring dose de-escalations to 7.5, 4, and 2 mg/m2 IV daily x 5 days. The maximum tolerated dose (MTD) in solid tumors was 2 mg/m2 IV over 1 hour daily x 5 every month, and the dose-limiting toxicity (DLT) was myelosuppression. In CLL, the MTD was 4 mg/m2 daily x 5 every month, the DLT being thrombocytopenia. Reductions in lymphocytosis occurred in 2 (> 25%) and 4 (>50%) of CLL patients. Reductions in the size of lymphadenopathy to > 25% were observed in 1 and to > 50% in 3 patients with CLL. The dose was then re-escalated to 7.5, 11.5, 15, 22.5, 30, 40 and 55 mg/m2 IV daily x 5 days in acute leukemias. Thirty-one patients with AML (16), ALL (12), or CML-BP (3) were treated. DLT was grade 3-4 hepatotoxicity occurring in 2/4 patients at 55 mg/m2, and 4/12 patients at 40 mg/m2. The latter dose schedule was expanded and suggested for future phase II studies. 2/31 evaluable patients (6%) achieved CR, and 3 patients had marrow CR (blasts < 5%). Decreased marrow blasts to < 10% during therapy was noted in 9/31 evaluable patients. The activity of clofarabine has further been established in phase II trials in patients with acute leukemias and chronic myeloid leukemia (CML) in blast phase. Sixty-two patients with relapsed/refractory AML/MDS, ALL, and CML blast phase were treated. Twenty patients (32%) achieved CR, 1 had a PR, and 9 (15%) achieved CR but without platelet recovery (CRp) for an overall response rate of 48%. The response rate was highest in patients with AML (OR 55%, CR42%), especially in patients with long (> 12 months) first remission durations. In a subsequent phase I/II study, clofarabine was combined with ara-C in a very similar patient population. Of 29 patients with AML and high-risk MDS, 7 (24%) achieved CR and 5 (17%) CRp for an overall response rate of 41%. The treatment was well tolerated. Only one early death occurred due to cytopenia and sepsis. Pharmacokinetic studies showed dose-dependent increases of plasma clofarabine levels and intracellular levels of clofarabine triphosphate. Studies in patients with acute leukemias further demonstrated a correlation of the level of intracellular clofarabine triphosphate levels and response. When using a daily x 5 days i.v. bolus schedule, the recommended dose of clofarabine in these studies has been 40 mg/m2/day. Using the same schedule in a phase I study including patients with CLL and solid tumors, the MTD was only 4 mg/m2/day and 2 mg/m2/day, respectively, with myelosuppression as the dose limiting toxicity. Recent evidence from solid tumor studies, however, shows that doses of up to 52 mg/m2 of clofarabine can be tolerated without undue toxicities when given weekly x 3 every 4 weeks (ILEX Oncology, personal communication, January 6 2004). We hypothesize that weekly administration of clofarabine to patients with CLL will lead to increased accumulation of clofarabine triphosphate in CLL cells and at the same time give hematopoietic stem cells sufficient time to recover to prevent myelosuppression. We therefore propose a dose finding study of a weekly schedule of administration of clofarabine for patients with CLL. Objectives: 1. To determine the maximum tolerated dose (MTD) of clofarabine administered i.v. once weekly for 3 weeks every 4 weeks. 2. To determine the toxicity profile of clofarabine when administered in this fashion. 3. To investigate the plasma clofarabine and cellular clofarabine triphosphate pharmacology profile when administered in this fashion.
Eligibility:
Study Type: Interventional, Treatment, Non-Randomized, Open Label, Historical Control, Single Group Assignment, Safety/Efficacy Study
Minimum Age/Maximum Age: /
Genders: Both
Protocol Entry Criteria: Inclusion: - Patients with chronic lymphocytic leukemia (CLL), CLL/PLL (as defined by FAB), and PLL (B- and T-cell phenotypes) who have relapsed from or are refractory to at least one fludarabine-based regimen. - Absolute neutrophil count (ANC) >= 1 x 109/L and platelet count >= 50 x 109/L. - Adequate liver function (total bilirubin <= 2.5mg/dL, SGPT <= 4 x ULN) and renal function (serum creatinine <= 2.5mg/dL). - ECOG performance status <= 2. Exclusion: - Patients with NYHA grade 3 heart disease as assessed by history and/or physical examination. - Pregnancy.
Total Enrollment: 36
Location and Contact Information:
M.D. Anderson Cancer Center *Recruiting*
Houston, Texas, 77030
United States
Recruiting Stefan Faderl 713-745-4613
Additional Information:
Study ID Numbers: 2004-0134;
Study Start Date: May 2004
Record last reviewed: May 2004
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00081887
Other Chronic Lymphocytic Leukemia Studies:
1. Dose-Escalating and Safety Study of CP-461 in Patients with Chronic Lymphocytic Leukemia
2. Immunosuppressive Preparation Followed by Blood Cell Transplant for the Treatment of Blood Cancers in Older Adults
3. Campath-1H Plus Rituximab for CD52- and CD20- Positive Refractory or Relapsed Chronic Lymphoid Disorders
4. Combination Chemotherapy and Rituximab in Treating Patients With Chronic Lymphocytic Leukemia or Lymphocytic Lymphoma
5. Bortezomib and Fludarabine in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia
Related Studies:
Other Chronic Lymphocytic Leukemia Clinical Trials
Other Texas Clinical Trials
Other Houston Clinical Trials
Study of Weekly Clofarabine for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
|
|
|
|
|
|
|
|
