|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3396-3403 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.199 Phase I Study of 506U78 Administered on a Consecutive 5-Day Schedule in Children and Adults With Refractory Hematologic MalignanciesFrom the Duke University Medical Center, Durham; GlaxoSmithKline, Research Triangle Park; University of North Carolina, Chapel Hill, NC; Boston University Medical Center, Boston, MA; M.D. Anderson Cancer Center, Houston, TX; and Ohio Northern University, Ada, OH Address reprint requests to Joanne Kurtzberg, MD, Professor of Pediatrics, Box 3350, Duke University Medical Center, Durham, NC 27710; e-mail: kurtz001{at}mc.duke.edu
PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. PATIENTS AND METHODS: Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. RESULTS: The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily x 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. CONCLUSION: Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.
Arabinosyl nucleoside analogs have known efficacy in the treatment of patients with hematologic malignancies. The observation that patients with congenital deficiency of adenosine deaminase or purine nucleoside phosphorylase (PNP) have severe lymphopenia with selective lack of T and or B lymphocytes has provided a rationale to identify selective, and potentially less toxic, nucleoside analogs for use in treatment of lymphoid malignancies.1-4 In 1978, Elion and colleagues synthesized the deoxyguanosine derivative 9-beta-D-arabinosylguanine (araG).5 In 1983, Cohen et al6 demonstrated that araG was resistant to cleavage by PNP as well as toxic to T-lymphoblastoid cells at micromolar concentrations, presumably via conversion to araGTP. AraG competes with deoxyguanosine as a substrate for phosphorylation by deoxycytidine and deoxyguanosine kinases. Efficient accumulation of the analog triphosphate araGTP in cells of the T-lymphoid lineage inhibits DNA synthesis, resulting in cytotoxicity to cells in which it is accumulated.6-9 Subsequent preclinical studies with araG demonstrated selective cytotoxicity for normal and malignant cells of the T-lymphoid lineage10-12; however, the solubility of this agent limited its use in the clinical setting. Nelarabine, the 6-methoxy derivative of araG, which is 10-fold more soluble than araG, was synthesized by Krenitsky et al to address this problem.13,14 Nelarabine is rapidly deaminated by adenosine deaminase in vivo to araG, its active form.14 In preclinical studies, nelarabine did not cause toxicities commonly associated with more traditional cytotoxic chemotherapeutics (ie, myelosuppression, mucositis, nephrotoxicity, and hepatotoxicity). However, neurotoxicity was dose limiting. In 1994, we initiated a limited-center phase I trial of nelarabine in adult and pediatric patients with refractory hematologic malignancies. We now report the results of this trial. Intracellular pharmacokinetics from this trial have been previously reported and demonstrate that intracellular accumulation of araGTP is correlated with cytotoxicity.15,16
Patient Selection Patients were selected based on the following eligibility criteria: age younger than 75 years; histologically or cytogenetically documented diagnosis of a refractory hematologic malignancy in relapse; adequate organ system function as evidenced by serum creatinine  2.0 mg/dL, hepatic transaminases 3x the upper limit of normal, serum bilirubin 3.0 mg/dL, and normal cortical and cerebellar neurologic function; life expectancy of  2 months; no active infection at the time of treatment; adequate nutritional status (> third percentile for weight, normal total serum protein, and albumin/globulin ratio) and adequate performance status (Karnofsky performance status > 30 or Eastern Cooperative Oncology Group performance status of 0 to 3); not receiving any other anticancer agents or enrolled onto any other investigational study during the course of the study; recovery from acute toxicity of all previous chemotherapy; and no history of a seizure disorder or significant neurologic toxicity with prior chemotherapy or radiation therapy. In patients who had experienced relapse after allogeneic or autologous bone marrow transplantation, cardiac and pulmonary function studies were obtained. These patients were required to meet the following criteria: cardiac ejection fraction by echocardiogram or radionuclide scan of greater than 45% for patients 18 years of age and 35% for patients older than 18 years; pulmonary function tests demonstrative forced vital capacity and forced expiratory volume in 1 second of 75% of predicted for age or diffusing capacity of lung for carbon monoxide 60%. All patients (or patient’s legal guardians) were enrolled onto the study after the approval of each institution’s institutional review board and were required to give written informed consent according to institutional and federal guidelines before study enrollment.
Study Drug Administration
Patients were stratified at enrollment into the following groups: adult patients with leukemia, pediatric patients (age Nelarabine was supplied by GlaxoWellcome in vials that contained 200 mg of drug as a lyophilized powder. The lyophilized powder was reconstituted with a minimum volume of 25 mL of 0.45% normal saline and diluted to a final concentration of 8 mg/mL. The drug was administered as a 1-hour intravenous infusion daily for 5 consecutive days.
Treatment Plan
Nelarabine was administered in the inpatient or outpatient setting. Antiemetics, antibiotics, blood and platelet transfusions, and other supportive care measures (including granulocyte colony-stimulating factors) were used as clinically indicated. All patients were treated with allopurinol 10 mg/kg/d (maximum daily dose, 300 mg) during the day before and for at least 5 days after maximal blast lysis. Patients with massive leukemic leukocytosis also received prophylactic hydration with bicarbonate to maintain a urine pH The physical examination was repeated at each outpatient visit during treatment. The CBC with differential was obtained every other day during drug administration, then weekly until peripheral counts normalized, the patient was due for another course of drug, or obvious disease progression occurred. The chemistry panel and coagulation studies were repeated on days 1 and 5 of drug administration, then weekly thereafter. All laboratory studies were repeated before each additional course of nelarabine. Any abnormal studies present after the final dose of nelarabine were repeated on a weekly basis until normalization. The chest x-ray was repeated before each subsequent course of nelarabine or weekly (if clinically indicated). In patients with a positive baseline study, the bone marrow aspirate/biopsy was repeated between days 21 and 28, unless the patient had obvious disease progression as evidenced by circulating blasts in the peripheral blood or increased bulky disease in patients with lymphoma. The lumbar puncture was repeated between days 21 and 28 if CNS disease was present on study entry or if the patient developed clinical evidence of neurotoxicity. Magnetic resonance imaging, computed tomography, lumbar punctures, and electroencephalogram studies were performed in patients who experienced signs or symptoms of neurotoxicity after treatment with nelarabine. Toxicities were evaluated at each clinic visit and were graded according to the Pediatric Oncology Group Toxicity Criteria (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening).
Response Criteria
Blood Sampling for Determination of Plasma Nelarabine, araG, and Intracellular araGTP Concentrations Blood samples for pharmacokinetic measures were collected and processed as previously described.15,16 In patients with more than 10,000/mL circulating blasts at the M.D. Anderson Cancer Center, blood samples were obtained for determination of intracellular concentrations of araGTP.15
Patient Characteristics Table 2 details the characteristics of the 93 patients enrolled onto the study. Fifty-nine patients were adults and 34 patients were children. Of the patients enrolled, 66% had T-cell malignancies, 22% had B-cell malignancies, and 13% had myeloid or other hematologic malignancies. All patients were assessable for nonhematologic toxicity, whereas only patients without disease involvement in the bone marrow were considered assessable for hematologic toxicity (n = 16).
The majority of patients enrolled onto the study had experienced treatment failure with at least two prior therapies for their disease, with a median number of three prior regimens (range, one to 11 regimens; Table 3). Twenty-seven patients had previously received a bone marrow transplant, with three patients having received two or more prior allogeneic transplants. A total of 39 patients had received prior radiation therapy of some type (20 patients received total-body irradiation and 14 patients received cranial or craniospinal irradiation), and 45 patients had received intrathecal chemotherapy as prophylaxis or treatment of the CNS.
Dosing History Seven dose levels between 5 and 75 mg/kg/d for 5 days were explored in this study (Table 4). A total of 198 cycles of nelarabine were administered to 93 patients. The median number of cycles per patient was one (range, one to 16 cycles). Eight patients were dose reduced from either 10, 20, and 40 mg/kg/d to the next lower dose level on subsequent treatment cycles because of neurotoxicity, whereas the dose was escalated for four patients in an attempt to maximize efficacy on subsequent cycles. Drug was initially dosed on a milligram per kilogram basis at dose levels ranging between 5 and 75 mg/kg/d. No grade 3 or 4 toxicity was reported during the first course of therapy in any pediatric patient treated at dose levels 60 mg/kg/d or any adult patient treated at less than 30 mg/kg/d.
Dose-limiting neurotoxicity was encountered in the only patient (a 6-year old child) treated at 75 mg/kg, resulting in closure of this dose stratum. Grade 3 neurotoxicity was observed in a total of three children, one each treated at 20 and 60 mg/kg/d and one treated at 1.2 g/m2/d (approximately 30 to 40 mg/kg/d). Reversible neurotoxicity consisting of somnolence, confusion, malaise, and ataxia was experienced by approximately 40% of adults receiving 40 mg/kg/dose/d. Irreversible peripheral neuropathy was seen in one patient at this dose level. Because patients with malignancies of the T-lymphoid lineage demonstrated significant responses at all dose levels, the study remained open after the initial safety data were obtained to allow additional patients access to nelarabine therapy. To refine dosing accuracy in these patients, a prospective analysis of the additional cohort of adult and pediatric patients treated at the 30 to 60 mg/kg/d levels led to the projection that a dose of 1.2 g/m2/d (approximately 30 to 40 mg/kg/d) might be explored in phase II studies. For this reason, this dose was administered to an additional 20 patients (eight children and 12 adults) to score toxicity at this dose level.
Neurotoxicity
Retrospective review of the data revealed the development of cumulative neurotoxicity in the form of hypoesthesias, paresthesias, or peripheral neuropathies in a total of 11 patients, all treated at the higher dose levels (1.2 g/m2; 30 and 60 mg/kg). These symptoms were graded as severe in three of the 11 patients and remained unresolved in four patients at the time of final data analysis. Eight of these 11 patients had received prior vincristine, which may have predisposed them to the development of this toxicity. However, there were 70 additional patients who had also received prior vincristine therapy who did not develop cumulative peripheral neurotoxicities. No patient on this study was treated with vincristine within 1 month of study entry. The single patient treated at the 75 mg/kg/d dose was a child with T-cell acute lymphoblastic leukemia in refractory relapse who experienced severe and irreversible neurotoxicity. Beginning approximately 12 days after the initiation of nelarabine therapy, after rapidly clearing peripheral blasts, this child developed seizures, myoclonic jerks, ascending paralysis, and coma over the next 2 weeks. A battery of tests revealed abnormal findings only on the electroencephalogram, which demonstrated diffuse slowing, and the electromyelogram, which demonstrated decreased conduction velocity of the peroneal nerves. This patient required support with mechanical ventilation for 2 weeks and subsequently recovered ability to ventilate without assistance, but the patient never regained full consciousness. This patient achieved a complete remission, which was sustained for approximately 6 weeks. He ultimately died of progressive leukemia 3 months after starting nelarabine therapy. At the time of death, he had not recovered from the majority of neurotoxicity experienced. A similar, but less severe, syndrome was observed in six other study patients treated at varying dose levels (0.8 to 2.25 g/m2/d dose). Three of these patients completely recovered from this toxicity, whereas the other three had persistence of clinical problems at the time of death. There was no common clinical feature in the histories of the patients experiencing severe neurotoxicity. There was also no apparent relationship between the maximum concentration and areas under the curve of nelarabine or araG and maximum level of neurologic toxicity.
Nonhematologic Toxicity
Hematologic Toxicity
Clinical Responses Three of 10 patients with B- or T-lineage chronic lymphocytic leukemia experienced partial remissions, and one patient with prolymphocytic leukemia experienced hematologic improvement after treatment with nelarabine. An additional patient coded as a partial response because of lack of examination of the bone marrow at the designated evaluation time was removed from the study and remained in a documented CR 1 year after study entry without any intervening therapy (Table 7).
Eighteen patients (19%) enrolled onto the study were considered nonassessable for response for the following reasons: hypocellular bone marrow at evaluation (n = 1), incomplete bone marrow/tumor evaluation at maximal clinical response (n = 7), death before 21 days (n = 9), and removal from study secondary to adverse events before 21 days (n = 1). None of the deaths reported before day 21 were attributable to study drug administration.
Pharmacokinetic Studies
In this report we have demonstrated that nelarabine, a novel purine nucleoside analog, exhibits significant antitumor efficacy at doses that do not produce intolerable toxicity in patients with refractory malignancies of the T-cell lineage. The dose-limiting toxicity is neurologic in both adult and pediatric patients. Significant myelosuppression was not observed in the smaller patient population assessable for hematologic toxicity. Nelarabine has a favorable profile for incorporation into multiagent myelosuppressive chemotherapy regimens. Use in combination with other neurotoxic drugs (eg, vincristine) will require further study. Many nucleoside analogs commonly used in front-line therapy of patients with hematologic malignancies cause dose-limiting and often cumulative myelosuppression. In the present study, we found that nelarabine does not exert dose-limiting hematologic effects. This is particularly significant given that the patients enrolled onto this study were heavily pretreated. In addition to myelosuppression, many other nucleoside analogs are also immunosuppressive. The acute and chronic effects of nelarabine on the immune system, if any, have not yet been characterized. In the present study, no opportunistic infections were observed in nelarabine-treated patients on therapy. Longer-term follow-up will be required to definitively determine whether this drug causes immunosuppression. The neurotoxicities associated with nelarabine are similar to those observed with other purine analogs.18 To date, the mechanism of purine analog-induced neurotoxicity remains unknown. In the case of fludarabine and pentostatin, higher than recommended doses have resulted in life-threatening and fatal central neurologic adverse events that were often delayed in onset for weeks or months after drug discontinuation. Dose reduction significantly abrogated these neurologic events. As with other purine analogs, we hypothesize that the risk of nelarabine-induced neurotoxicity (all grades) could be potentially associated with multiple factors, including advanced age, prior high-dose cytarabine therapy, prior intrathecal therapy, prior CNS irradiation, prior vincristine therapy or vincristine-associated peripheral neuropathy, and history of leukemic cells in the cerebral spinal fluid. However, we did not observe increased neurotoxicity in patients with these characteristics. Gandhi et al15 have shown that patients achieving a response to therapy with nelarabine accumulated significantly higher peak araGTP levels compared with nonresponders. This relationship was also seen in a pilot study using a combination of nelarabine and fludarabine.19 In this study, clinical responses were seen in fludarabine-refractory diseases and in one case of B-cell chronic lymphocytic leukemia. Rodriguez et al20 have proposed different doses and dosing schedules that may augment the accumulation of araGTP in target T and B cells. Several factors have been identified that are responsible for the T-cell–selective cytotoxicity of araG, including the pharmacokinetics of araGTP accumulation, initiation of S-phase–specific cell death, binding to apoptotic complexes, and transcriptional and translational upregulation of the soluble Fas ligand, which may account for S-phase–independent cell death.21 In conclusion, nelarabine is an effective prodrug of araG that is clearly active in T-lymphoid lineage diseases at all dose levels tested. Efficacy was best correlated with intracellular pharmacokinetics.15,16 A specific maximum-tolerated dose was not identified, but given that efficacy was observed at all dose levels tested, a dose range (30 to 40 mg/kg) was recommended for initial phase II trials. A phase II trial in pediatric patients with refractory T-cell malignancies has shown substantial single-agent activity with an objective response rate of more than 50% in patients with T-cell leukemia in first bone marrow relapse at 650 mg/m2 daily for 5 days.22 Dosing in this trial was started at 1.2 mg/m2; there were two dose de-escalations as a result of toxicity. A phase II study in adult patients with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma has shown a response rate of 32% at a dose of 1.5 g/m2 on an alternate-day (days 1, 3, and 5) schedule.23 This dose and schedule was chosen for the adult study based on experience with this regimen at M.D. Anderson Cancer Center.19 Additional larger scale clinical trials will be necessary to refine dose and schedule, particularly if nelarabine is incorporated into multiagent chemotherapy regimens.
The authors indicated no potential conflicts of interest.
We dedicate this article to the memory of Gertrude "Trudy" Elion, whose love of science and compassion for people continue to inspire.
Supported by grants Nos. CA32839 and CA57629 from the National Cancer Institute. Presented in part in Kisor et al18 and Gandhi et al.17 Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Giblett ER, Ammann AJ, Wara DW, et al: Nucleoside phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet 1 : 1010 -1013, 1975[Medline]
2. Carson DA, Kaye J, Seegmiller JE: Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: Possible role of nucleoside kinase(s). Proc Natl Acad Sci U S A 74
: 5677
-5681, 1977
3. Carson DA, Kaye J, Matsumoto S, et al: Biochemical basis for the enhanced toxicity of deoxyribonucleosides toward malignant human T cell lines. Proc Natl Acad Sci U S A 76
: 2430
-2433, 1979
4. Mitchell BS, Mejias E, Daddona PE, et al: Purinogenic immunodeficiency diseases: Selective toxicity of deoxyribonucleosides for T cells. Proc Natl Acad Sci U S A 75
: 5011
-5014, 1978 5. Reist EJ, Goodman L: Synthtesis of 9-beta-D-arabinofuranosylguanine. Biochemistry 3 : 15 , 1964
6. Cohen A, Lee JW, Gelfand EW: Selective toxicity of deoxyguanosine and arabinosyl guanine for T-leukemic cells. Blood 61
: 660
-666, 1983 7. Scharenberg JG, Spappen LJ, Rijkers GT, et al: Mechanisms of deoxyguanosine toxicity for human T and B lymphocytes. Adv Exp Med Biol 195B : 191 -199, 1986
8. Shewach DS, Daddona PE, Ashcraft E, et al: Metabolism and selective cytotoxicity of 9-beta-D-arabinofuranosylguanine in human lymphoblasts. Cancer Res 45
: 1008
-1014, 1985
9. Verhoef V, Fridland A: Metabolic basis of arabinonucleoside selectivity for human leukemic T- and B- lymphoblasts. Cancer Res 45
: 3646
-3650, 1985 10. Hebert ME, Greenberg M, Chaffee S, et al: Pharmacologic purging of malignant human T cells from human bone marrow using 9-beta-D-arabinofuranosylguanine. Transplantation 52 : 634 -640, 1991[Medline] 11. Kurtzberg J: Guanine arabinoside as a bone marrow purging agent. Ann NY Acad Sci 685 : 225 -236, 1993[Medline] 12. Gravatt LC, Chaffee S, Hebert ME, et al: Efficacy and toxicity of 9-beta-D-arabinofuranosylguanine (araG) as an agent to purge malignant T-cells from murine bone marrow: Application to an in vivo T-leukemia model. Leukemia 7 : 1261 -1267, 1993[Medline] 13. Krenitsky TA, Koszalka GW, Tuttle JV, et al: An enzymatic synthesis of purine-D-arabinonucleosides. Carbohydrate Res 97 : 139 -146, 1981[CrossRef]
14. Lambe CU, Averett DR, Paff MT, et al: 2-amino-6-methoxypurine arabinoside: An agent for T-cell malignancies. Cancer Res 55
: 3352
-3356, 1995 15. Gandhi V, Plunkett W, Rodriguez CO, et al: Compound GW506U78 in refractory hematologic malignancies - relationship between cellular pharmacokinetics and clinical response. J Clin Oncol 16 : 3607 -3615, 1998[Abstract]
16. Kisor DF, Plunkett W, Kurtzberg J, et al: The pharmacokinetics of 506U78 and 9-Beta-D-Arabinofuranosyl Guanine in pediatric and adult patients during a phase I study of 506U78 for the treatment of refractory hematological malignancies. J Clin Oncol 18
: 995
-1003, 2000
17. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-Sponsored Working Group Guidelines for Chronic Lymphocytic Leukemia: Revised guidelines for diagnosis and treatment. Blood 87
: 4990
-4997, 1996
18. Cheson BD, Vena DA, Foss FM, et al: Neurotoxicity of purine analogs: A review. J Clin Oncol 12
: 2216
-2228, 1994
19. Gandhi V, Plunkett W, Weller S, et al: Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics and pharmacodynamics in leukemia cells. J Clin Oncol 19
: 2142
-2152, 2001 20. Rodriguez CO Jr, Legha JK, Estey E, et al: Pharmacological and biochemical strategies to increase the accumulation of arabinofuranosylguanine triphosphate in primary human leukemic cells. Clin Cancer Res 3 : 2107 -2113, 1997[Abstract]
21. Rodriguez CO Jr, Stellrecht CM, Gandhi V: Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood 102
: 1842
-1848, 2003 22. DeAngelo DJ, Yu D, Dodge RK, et al: A phase II study of 2-amino-9-beta-D-arabinosyl-6-methoxy-9H-purine (506U78) in patients with relapsed or refractory T-lineage acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): CALGB Study 19801. Blood 100 : 198a , 2002 (abstr 743) 23. Berg SL, Blaney SM, Bernstein M, et al: Activity of compound 506U78 in patients with refractory T-cell malignancies: A POG/CCG Intergroup Phase 2 study. Blood 102 : 226a , 2003 (abstr 792) Submitted March 29, 2004; accepted January 27, 2005.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
