Phase I Trial and Pharmacokinetic Study of High-Dose Clofarabine And
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Leukemia (2011) 25, 599–605 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu ORIGINAL ARTICLE Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia SS Farag1,2, LL Wood1,2, JE Schwartz1,2, S Srivastava1,2, RP Nelson Jr1,2, MJ Robertson1,2, R Abonour1,2, A Secrest2, E Cox2, J Baute2, C Sullivan2, K Kane2 and DR Jones3 1Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; 2Blood and Bone Marrow Transplantation Program, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA and 3Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA We conducted a phase I trial to determine the maximum Although cyclophosphamide adds significant immunosuppres- tolerated dose (MTD) of clofarabine with high-dose busulfan sion,9 its dose-limiting cardiac toxicity and risks of hemorrhagic followed by allogeneic stem cell transplantation (SCT) in cystitis and hepatic sinusoidal obstruction syndrome remain patients with high-risk and refractory acute leukemia. Patients 6–8,10,11 received intravenous busulfan 0.8 mg/kg every 6 h on days À6 problematic. to À3 and clofarabine 30–60 mg/m2 per day on days À6toÀ2. Recently, the substitution of fludarabine for cyclophospha- Graft-versus-host disease prophylaxis included sirolimus plus mide in combination with targeted oral or intravenous busulfan tacrolimus (days À2to þ 180). A total of 15 patients, median has suggested that disease control equivalent to the BuCy2 age 48 (30–58) years, with acute leukemia that was relapsed and regimen can be achieved with reduced toxicity.12,13 Although refractory (n ¼ 8), primary refractory (n ¼ 6), or in CR2 (n ¼ 1), fludarabine has significant immunosuppression to prevent graft were treated at four clofarabine dose levels: 30 (n ¼ 3), 40 14 (n ¼ 3), 50 (n ¼ 3) and 60 mg/m2 per day (n ¼ 6) with busulfan. All rejection, fludarabine has only modest anti-leukemic activity. engrafted, and the MTD was not reached. Grades 3–4 non- Clofarabine (2-chloro-2-fluoro-deoxy-9-D-arabinofuranosyla- hematological toxicities included vomiting (n ¼ 3), mucositis denine) is a second generation purine nucleoside analogue (n ¼ 9), hand-foot syndrome (n ¼ 1), acute renal failure (n ¼ 1) designed to maintain the favorable qualities of fludarabine and reversible elevation of aspartate aminotransferase/alanine without dose-limiting neurotoxicity.15 In particular, single agent aminotransferase (n ¼ 10). The 1-year event-free survival was clofarabine is active in heavily pre-treated, relapsed and/or 53% (95% confidence interval: 33–86%), and the 1-year overall refractory patients with acute lymphoblastic leukemia and acute survival was 60% (95% confidence interval: 40–91%). Given the 16–18 good tolerability and promising results, we recommend clofar- myeloid leukemia, including older patients with high-risk 19,20 abine 60 mg/m2 per day  5 days as a phase II dose in features. In addition, in vitro studies have shown synergistic combination with busulfan (12.8 mg per kg total dose) for activity between clofarabine and alkylating agents.21 We, further study as a myeloablative regimen for allogeneic SCT for therefore, hypothesize that the substitution of clofarabine for high-risk acute leukemia. fludarabine, in combination with high-dose busulfan may be a Leukemia (2011) 25, 599–605; doi:10.1038/leu.2010.319; published online 21 January 2011 well-tolerated preparative regimen with improved anti-leukemic Keywords: allogeneic hematopoietic cell transplantation; activity for patients undergoing allogeneic HSCT. As an initial clofarabine; busulfan; acute leukemia step, we conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose busulfan and allogeneic HSCT in patients with high-risk and refractory acute leukemia (ClinicalTrials.gov Identifier: NCT00477542). Introduction Allogeneic stem cell transplantation (SCT) remains an important Patients and methods curative option for many patients with acute leukemia.1,2 Although reduced-intensity regimens appear to be better Patient and donor eligibility tolerated and allow older patients the opportunity for transplan- Patients were eligible if they had acute myeloid leukemia or tation, recent evidence indicates that dose-intensity is important acute lymphoblastic leukemia that was primary refractory, for disease control in spite of a graft-versus-leukemia effect, 4 3,4 relapsed and refractory ( 5% bone marrow blasts or extra- particularly in patients at high-risk of relapse. The combina- medullary disease), or who were in second or subsequent tion of cyclophosphamide with busulfan (BuCy2) is a commonly complete remission (CR). Patients also had to be 18–60 years used regimen for allogeneic HSCT in patients with acute X 5 6–8 old, have a Karnofsky performance status 70%, a left leukemia, although it is associated with significant toxicity. ventricular ejection fraction 445%, DLCO 450%, creatinine clearance 460 ml/min/1.73 m2, and serum bilirubin, aspartate Correspondence: Dr SS Farag, Division of Hematology and Oncology, aminotransferase and alanine aminotransferase (ALT) levels Department of Internal Medicine, Indiana University School of o2  upper limits of normal. Patients were excluded if Medicine, Walther Hall-R3, C414, 980 West Walnut Street, Indianapolis, they had a previous HSCT, central nervous system leukemia, IN 46202, USA. E-mail: [email protected] or if they were seropositive for HIV. Donors were eligible Received 30 August 2010; revised 25 October 2010; accepted if they were related and matched at 5 or 6 of the 6 3 December 2010; published online 21 January 2011 human leukocyte antigen-matched loci (human leukocyte High-dose clofarabine/busulfan in acute leukemia SS Farag et al. 600 antigen-A, -B and -DRB1), or unrelated and 10 of 10 antigen- relapse, or death from any cause; otherwise patients were matched (human leukocyte antigen-A, -B, -C, -DRB1 and censored on the date of last follow-up. Overall survival (OS) was -DQB1) by high-resolution typing. The study was approved by measured from the date of transplantation until death from any the Institutional Review Board of Indiana University. All patients cause, censoring for patients alive on date of last follow-up. and donors gave informed consent. The study was conducted in accordance with the Declaration of Helsinki. Pharmacologic assays and pharmacokinetic analysis Plasma clofarabine samples were obtained on day À6 before infusion, at the end of infusion, and at 2, 3, 4, 5, 6 and 24 h after Study design and treatment plan the start of dosing. In addition, samples were also collected Busulfan was administered at 0.8 mg/kg (lower of actual or ideal immediately before infusion, at the end of infusion and at 6 and body weight) intravenously over 2 h every 6 h on day À7toÀ4 24 h after subsequent doses on days À5toÀ2. Clofarabine was (16 doses), and the dose not adjusted according to pharmaco- extracted from plasma and quantified by high pressure liquid kinetic monitoring. Clofarabine was administered as a daily 1-h chromatography-tandem mass spectrometry (MS/MS) as intravenous infusion for 5 days on days À6toÀ2, with the dose previously described.26 escalated in four successive cohorts: 30, 40, 50 and 60 mg/kg For busulfan, blood was sampled in association with the first per day. On days À6toÀ4, when both drugs were administered and ninth infusion, and in each case collected immediately on the same day, clofarabine was infused 1–2 h before busulfan. before infusion, at the end of infusion, and at 135 and 150 min, Corticosteroids were not used before clofarabine infusion for and at 3, 4, 5 and 6 h after the start of infusion. Busulfan plasma prophylaxis of hand-foot syndrome. Bone marrow or PBSC were levels were assayed using gas chromatography–mass spectro- infused on day 0, and growth factors were not administered. metry, with a dynamic concentration range of 25–4500 ng/ml Sirolimus and tacrolimus were administered for graft-versus-host and coefficient of variation of o8%.27 disease (GvHD) prophylaxis, starting day À3 until day þ 100 to Concentration-time data were analyzed by a non-compart- maintain a serum level of 5–10 ng/ml for both drugs, followed by mental approach using WinNonlin v4.1 (Pharsight, Mountain tapering through day þ 180. All patients received fluconazole, View, CA, USA). The area under the plasma concentration acyclovir and ciprofloxacin prophylaxis. Preemptive treatment curve (AUC) was calculated for busulfan following the first with valganciclovir was instituted if cytomegalovirus activation (AUC ) and ninth (AUC ) doses. The following was detected on plasma monitoring in the first 100 days after 1st dose 9th dose pharmacokinetic parameters were calculated for clofarabine: transplantation. No specific therapy was used for prevention of maximum plasma concentration (C ), terminal elimination sinusoidal obstruction syndrome. max constant (k ), terminal half-life (t ) and AUC from time zero to A standard 3 þ 3 trial design was followed. Three patients el 1/2 the last concentration for each day of infusion, with the average were enrolled on the first clofarabine dose level. If one of the AUC of all doses of clofarabine also calculated (AUC ). three patients experienced dose limiting toxicity (DLT; defined av In addition, the area under the plasma concentration curve below) at a given dose level, three more patients were treated at extrapolated to infinity (AUC -N) was estimated from plasma that dose level. If no DLT was observed in any of the three 0 levels obtained following the first dose (day À6) and the patients or in one of the six patients, the dose was escalated to systemic clearance was calculated from the dose and AUC -N. the next level. If two or more patients experienced DLT, the 0 MTD was exceeded, and three additional patients were to be treated at the next lower dose.