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© 2003 American Society for Clinical Oncology Phase I Clinical and Pharmacology Study of Clofarabine in Patients With Solid and Hematologic Cancers
From the Departments of Leukemia, Experimental Therapeutics, and Breast and Head and Neck, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Hagop M. Kantarjian, MD, Department of Leukemia, Box 428, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: hkantarj{at}mdanderson.org.
Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. Results: The starting dose of clofarabine (15 mg/m2) was myelosuppressive, requiring several dose de-escalations to 2 mg/m2, the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m2, with several escalations to 55 mg/m2. The DLT was reversible hepatotoxicity at 55 mg/m2. The recommended dose for acute leukemia phase II studies was 40 mg/m2. Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m2, the median plasma clofarabine level was 1.5 µmol/L (range, 0.42 to 3.2 µmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m2 for solid tumors, the DLT being myelosuppression; and 40 mg/m2 for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.
THE NUCLEOSIDE analogues are one of the most widely used classes of drugs for the treatment of cancer and have been a rich source of active agents in leukemias and other hematologic cancers. Cytosine nucleoside analogues include cytarabine, the most active drug in acute myeloid leukemia (AML)1; gemcitabine, which has a broad antitumor efficacy in solid cancers and is active against Hodgkin’s disease, lymphomas, and some T-cell malignancies2,3; and hypomethylating agents like 5-azacytidine and decitabine, which are promising in the treatment of myelodysplastic syndrome.4–6 Guanosine analogues include 6-mercaptopurine, 6-thioguanine, and nelarabine (compound 506U, arabinosyl guanine prodrug), which has activity against T-cell acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL).7 Deoxyadenosine nucleoside analogues include fludarabine, cladribine, and deoxycoformycin. All three agents have shown different degrees of activity against lymphoproliferative disorders, including CLL, lymphomas, hairy cell leukemia, and Waldenstrom’s macroglobulinemia.8,9 Fludarabine is most active in CLL and indolent lymphoma. Cladribine is most active in hairy cell leukemia and Waldenstrom’s macroglobulinemia.
Clofarabine (Cl-F-ara-A, 2-chloro-2'-fluoro-deoxy-9-ß-D-arabinofuranosyladenine) was synthesized as a rational extension of the deoxyadenosine analogues experiences. Both fludarabine and cladribine are effective against lymphoproliferative disorders. This led to the synthesis of a series of 2-halo-2' halo-2'-deoxyarabinofuranosyladenine analogues that have activity against P388 tumors in mice. The 2-(F, CI, or Br)-2'-F-ara-A 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 antitumor selectivity) in animals treated with fludarabine.10,11 2-F-adenine is thus thought to contribute to toxicity and results from cleavage of the glycosidic bond by the bacterial purine nucleoside phosphorylase.12 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' deoxyarabinofuranosyladenine analogues (such as clofarabine) are poor substitutes for the enzyme. In addition, similar to fludarabine and cladribine, clofarabine is resistant to deamination by adenosine deaminase (Fig 1
Clofarabine presumably incorporates the most favorable antimetabolic properties of fludarabine and cladribine. Similar to these analogs, clofarabine requires intracellular phosphorylation by deoxycytidine kinase to be metabolized to the triphosphate form necessary for cytotoxic effect. The triphosphate of fludarabine (F-ara-ATP) primarily inhibits DNA polymerases, whereas cladribine triphosphate (CdATP) particularly inhibits ribonucleotide reductase. Clofarabine triphosphate (CI-F-ara-ATP) has the mechanistically favorable properties of both agents with regard to inhibition of DNA polymerases and ribonucleotide reductase.13 Clofarabine has demonstrated cytotoxicity to human cell lines including CEM, K562, Hep2, L1210 leukemia, p388 leukemia, colon 36, and others.14 Animal toxicology studies were conducted at our institution to define the starting dose in human trials. Mouse studies defined a short infusion of 75 mg/kg/d (225 mg/m2/d) for 7 days as the LD10 in rodents and, therefore, 22 mg/m2/d for 7 days as a safe starting dose in man. In dog studies, there was no toxicity with short-infusion clofarabine at 7.5 mg/kg/d for 7 days (equivalent to 150 mg/m2/d in humans). Thus, the suggested starting dose in phase I human trials was 15 mg/m2/d for 5 days (unpublished data). This phase I trial was designed to define the dose-limiting toxicities (DLTs) of clofarabine and to define distinct maximum-tolerated doses (MTDs) for acute leukemia, CLL, and other solid tumors, if myelosuppression were to emerge as the DLT in the latter. Pharmacokinetic studies were planned to determine dose-dependent accumulation of clofarabine in plasma and clofarabine triphosphate in the circulating leukemia cells or peripheral-blood mononuclear cells.
Drug and Other Chemicals Clofarabine for clinical use was initially prepared by Ash Stevens, Inc (Detroit, MI), and formulated for injection by the University of Iowa Pharmaceutical Services (Ames, IA). Subsequently, production of the bulk drug was conducted by Delmar Chemicals (Lasalle, Quebec, Canada). For cellular pharmacokinetics’ high-pressure liquid chromatography standards, clofarabine 5'-triphosphate (Cl-F-ara-ATP) was synthesized by Sierra Biochemicals (Tucson, AZ). All other chemicals were reagent grade.
Study Group
Treatment Plan The phase I study was based on the 3 + 3 design. A minimum of three assessable patients with solid tumors or lymphoma with normal counts (granulocytes > 109/L and platelets > 100 x 109/L) were started at each dose level and observed for at least 2 weeks before starting additional patients at a new dose. Additional patients were entered if the data obtained from previous entries was inadequate because of early death of a patient unrelated to drug toxicity. For dose escalation, dose was increased by 50% until grade 2 toxicity was observed, then it was increased by 35%. If one of three patients experienced grade 3 or 4 toxicity at a dose level, three more patients were treated at that dose level. If grade 3 toxicity was observed in none of three patients or in one of six patients, the dose was escalated to the next level. If three or more patients experienced grade 3 to 4 toxicity, the MTD was exceeded, and three additional patients were treated at the next lower dose (if only three patients were treated previously at this dose). Grade 3 toxicity in two of six patients defined the MTD. Patients who showed no evidence of life-threatening infection or hemorrhage or more than grade 1 toxicity and no residual treatment toxicity at the time of pretreatment after two courses were considered for subsequent courses at the next dose escalation. If toxicity was observed, the patient recovered completely before the next course at the same dose was initiated. Up to three patients with leukemia were allowed to be treated at any dose level at which patients with solid tumors were treated. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, except for defining myelosuppression in patients with acute leukemia. Myelosuppressive toxicity in patients with acute leukemia was defined as marrow with less than 5% cellularity and without evidence of leukemia, lasting for more than 6 weeks from start of therapy. Once the MTD was defined in solid tumors, and if it was myelosuppression, the phase I portion was continued in acute leukemia to define the MTD for acute leukemia, at which level six to 10 patients would be included to define more precisely the toxicity profile and assess preliminary response data.
Patient Evaluation Evaluation during the study included complete blood counts with differential twice a week until remission or in the first two courses at each new level, then evaluation occurred every 1 to 2 weeks as indicated. Liver and renal function were obtained at least weekly until remission or for the first two courses at each new level, then they were obtained every 1 to 4 weeks as indicated. Bone marrow aspiration was performed on days 14 and 21 of therapy and then performed as needed thereafter in patients with acute leukemia. Bone marrow aspiration was performed every 3 months in patients with chronic leukemia. Radiographic studies for tumor measurement were performed every two to three courses, as indicated, to evaluate tumor status.
Response and Toxicity Criteria Toxicity was graded on a scale of 0 to 5 using the National Cancer Institute Common Toxicity Criteria, version 2.0. All patients who received at least one dose of clofarabine were considered assessable for toxicity.
Clinical Pharmacology
Plasma Pharmacology
Cellular Pharmacology
Calculations and Statistical Analyses
Toxicity and MTD Fifty-one patients were treated. Their characteristics are listed in Table 1  . The median age was 48 years (range, 19 to 78 years), and 29 patients (57%) were women. Thirteen patients had metastatic solid tumors, six had CLL or lymphoproliferative disorders, and 32 had acute leukemia.
At the starting dose level of clofarabine 15 mg/m2 daily for 5 days, grade 4 myelosuppression was observed in the first two patients treated (both had CLL). Clofarabine was then reduced by 50% to 7.5 mg/m2. Grade 4 leukopenia and granulocytopenia were observed again in the first two patients treated for metastatic solid tumors (breast and lung). The dose was further reduced to 4 mg/m2. Six patients with metastatic solid tumors and one each with lymphoma, prolymphocytic leukemia, and CLL were treated. Two of the six patients with solid tumors had grade 4 myelosuppression, and two had grade 3 myelosuppression. Grade 4 myelosuppression was observed in all three patients with lymphoproliferative malignancies. An additional patient with ALL was treated at 4 mg/m2 without a response but was not part of the medullary toxicity evaluation. The dose was further reduced to 2 mg/m2, and grade 3 myelosuppression was observed in two of the six patients with solid tumors (n = 5) or follicular lymphoma (n = 1). Nonhematologic toxicity was rare and mild; grade 1 nausea and anorexia were noted in two patients.
Because the DLT was myelosuppression in solid tumors, the MTD was defined at 2 mg/m2 daily for 5 days. Since there were only 13 patients with solid tumors, an additional study is needed to define more precisely the MTD of clofarabine in this group of patients. The phase I study was continued in acute leukemia starting at 7.5 mg/m2 because no prolonged myelosuppression had been observed; one additional patient with ALL was treated at 4 mg/m2 before that decision was made. The dose levels were then escalated to 11.25, 15, 22.5, 30, 40, and 55 mg/m2. At the clofarabine dose of 55 mg/m2 daily for 5 days, grade 3 hepatic toxicity was observed in two of four patients treated. Therefore, we expanded the number of patients at the lower dose schedule of 40 mg/m2 daily for 5 days. Of the first three patients treated, none had grade 3 hepatic toxicity; with the addition of three more patients, one patient had grade 3 and one patient had grade 2 hepatic toxicity. This was judged to be a reasonable dose schedule to be recommended for the phase II studies, and accrual was expanded to include eight additional patients to define more precisely the efficacy and toxicity profiles. The toxicities are listed in Table 2
Response In the first portion of the phase I study in patients with solid and hematologic cancers other than acute leukemia, responses were seen in two patients with lymphocytic leukemia. A 50% decrease in the size of palpable adenopathy was observed in one patient with CLL and a 75% decrease in peripheral lymphocytosis was seen in a second patient with CLL, both of whom had received clofarabine at 15 mg/m2 daily for 5 days. The disease in both patients had been refractory to multiple therapies including fludarabine. The first patient who had attained a partial response based on a more than 50% reduction in palpable adenopathy received a second course of clofarabine at a 50% dose reduction because of grade 4 neutropenia and thrombocytopenia. He developed Pseudomonas aeruginosa pneumonia and died of respiratory failure (confirmed by autopsy) before marrow recovery on day 20 of the second course. Stable disease lasting for 9 months was noted in one patient with metastatic breast cancer receiving clofarabine at the 7.5 mg/m2 level, with subsequent doses given at 4 mg/m2, then 2 mg/m2, and then 1.5 mg/m2 for a total of six courses. No objective responses were observed in patients treated for solid cancers.
Responses in patients in the phase I acute leukemia trial are listed in Tables 3
At the clofarabine dose level of 22.5 mg/m2 daily for 5 days, one patient with a third recurrence of CML-BP reverted back to a second chronic phase. He was then maintained with imatinib mesylate (STI571) and remained in remission for 6 months. On relapse, he was treated with vincristine, steroids, and hydroxyurea and died 13 months later.
At the clofarabine dose of 40 mg/m2 daily for 5 days, two patients achieved CR. One patient had ALL in third relapse. He achieved CR, did not receive maintenance therapy, and relapsed after 3 months. Another patient with AML had failed induction therapy with cyclophosphamide, cytarabine, and topotecan, achieved a CR with gemtuzumab ozogamicin 9 mg/m2 on day 1 and 15, and relapsed 4 months later. She achieved CR after the first cycle of clofarabine at a dose of 40 mg/m2 daily for 5 days, received two additional cycles at 30 mg/m2 daily for five days, and remained in CR for 8 months. At the dose of 55 mg/m2 daily for 5 days, one patient with AML in first salvage achieved marrow CR with low platelet counts (hematologic improvement). Table 3
Plasma Pharmacology
Cellular Pharmacology Levels of clofarabine triphosphate were analyzed at the end of clofarabine infusion in the PBMC or in the circulating leukemia blasts of 40 patients. As shown in Fig 3 , there was a wide variation regarding intracellular concentration of clofarabine triphosphate, which was more apparent at higher doses ( 30 mg/m2). There seemed to be a dose-dependent accumulation of triphosphate in the blood cells of these patients. At the MTD, the median clofarabine triphosphate level was 19 µmol/L (range, 3 to 52 µmol/L). Comparison of clofarabine triphosphate in PBMC versus leukemia cells was not feasible in this study because of the low number of patients with solid tumors that were successfully analyzed for cellular pharmacology.
Clofarabine, a deoxyadenosine nucleoside analog designed to incorporate the better antimetabolic properties of fludarabine and cladribine, has shown encouraging activity in both lymphoproliferative disorders and acute leukemias. The starting dose of clofarabine, 15 mg/m2 intravenous daily for 5 days, was far above the MTD for solid tumors, which was ultimately defined as 2 mg/m2 intravenous daily for 5 days; the DLT was myelosuppression. Surprisingly, the MTD for acute leukemia was 40 mg/m2 daily for 5 days, 20-fold higher than the MTD of solid tumors. This is one of the highest margins between the MTD of solid tumors and acute leukemia, the usual difference being often two- to seven-fold for other agents. The DLT in acute leukemia was hepatotoxicity, which had been observed with other bi-halogenated nucleoside analogues. Two of five patients treated for refractory lymphoproliferative disorders showed some response. Importantly, objective responses were observed in five patients with refractory acute leukemia, including AML, ALL, and CML-BP, at tolerable doses (which was not the case, for example, with either fludarabine or cladribine as single agents for adult acute leukemia). This indicates a potential role for clofarabine in the spectrum of acute leukemia, which could not be defined for other deoxyadenosine analogues as single agents, except for the experience with cladribine in pediatric AML. On the basis of this information and the success of cladribine in pediatric AML, we are currently testing the efficacy of clofarabine in pediatric leukemia. Animal toxicology studies of clofarabine suggested a starting clofarabine dose of 15 mg/m2 daily for 5 days, which was six to seven times higher than the MTD defined in our study. This is similar to the fludarabine experience in which 0.1 of the LD10 in mice overestimated the tolerable starting dose in humans. The tendency for preclinical animal toxicology studies to overestimate tolerable starting doses of new agents in man is particularly rare. In a review of phase I studies, fludarabine was the only one of 57 drugs in which the ratio between the human MTD and 0.1 of the mouse LD10 was less than 1. The median ratio of the MTD/LD10 was 20 for the other agents.18
Overestimating the safe starting dose of fludarabine for phase I trials in man through animal toxicology is now known to be a result of different pharmacokinetic profiles for the drug in dogs versus humans.19,20 A higher volume of distribution indicated greater tissue binding of fludarabine in humans than in dogs. In humans, fludarabine is not metabolized to 2-fluoro-ara-hypoxanthine as it is in dogs, resulting in less renal excretion. WBCs of dogs contain lower levels of deoxycytidine kinase compared with humans, which allows for less phosphorylation of fludarabine to the active triphosphate form and, therefore, possibly less cytotoxicity.20 At the higher doses needed to attain responses in acute leukemia, fludarabine demonstrated an unfavorable therapeutic index. At fludarabine doses of Clofarabine, as discussed, seems to demonstrate encouraging activity in acute leukemia at dose schedules not associated with significant extramedullary toxicities. Responses were obtained with patients with heavily pretreated refractory acute leukemia including AML, ALL, and CML-BP. Plasma pharmacokinetic studies demonstrated a dose-dependent peak level of clofarabine. Similar to fludarabine and cladribine, the first step in the activation of clofarabine to the triphosphate is conducted by deoxycytidine kinase. Compared with these analogs, clofarabine is a preferred substrate for phosphorylation; the Km values of deoxycytidine kinase for fludarabine, cladribine, and clofarabine are 100 to 1,600, 5 to 80, and 10 to 20 µmol/L, respectively.22–25 Hence, the clofarabine levels achieved in plasma should be effective for efficient conversion to monophosphate by the enzyme and accumulation of triphosphate. In fact, cellular triphosphate accumulation indicated dose-dependency, although there was substantial heterogeneity among individuals at each dose. This may be a result of differences among patients with regard to phosphorylation of clofarabine, variation in the rate of conversion of clofarabine mono- and diphosphates to di- and triphosphates, respectively, and rates of cellular elimination of the triphosphate. The intracellular concentration of triphosphate in leukemia blasts in patients infused with doses between 2 and 55 mg/m2 ranged between less than 1 µmol/L and 50 µmol/L, which seemed to be dose-proportional. Evaluation of triphosphate accumulation with respect to total daily dose gave an identical relationship (r = 0.60). In a currently active phase II trial of relapsed acute leukemia, we are relating the triphosphate concentrations with the total daily dose to more rigorously assess whether the body-surface area modifies the relationship and whether this is associated with toxicity. On the basis of the data from these 40 patients, there does not seem to be a diagnosis-dependent accumulation of the triphosphate. Additional cellular pharmacokinetic studies of clofarabine triphosphate, such as retention in blasts and total accumulation during the five-dose course, are needed. This information should be related to the pharmacodynamic actions of clofarabine treatment on deoxynucleotide pools and DNA synthesis in leukemic blasts to evaluate its prognostic value in predicting responsiveness to clofarabine therapy. This knowledge may also guide the design of optimal dose schedules for clofarabine in combination regimens In summary, clofarabine has shown activity in lymphoproliferative disorders and in acute leukemia. The MTD in solid tumors was 2 mg/m2 daily for 5 days, and the DLT was myelosuppression. The MTD in acute leukemia was 40 mg/m2 daily for 5 days, and the DLT was hepatotoxicity. Phase II studies are currently ongoing at the respectively defined dose schedules in lymphoproliferative disorders and in acute leukemia to define more precisely the drug efficacy profile. Cellular pharmacokinetics studies are also planned on the basis of the individual heterogeneity in the phase I study and potential association with antileukemic activity.
We thank ILEX Oncology, Inc, for supporting analyses of clofarabine in plasma samples.
Supported in part by grants CA32839, CA57629, and CA81534 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD, grant FD-R-001972 from the Food and Drug Administration, and Bioenvision, Inc.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 mg %) and renal functions (creatinine 
