|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology Phase I Study of an Oral Formulation of ZD9331 Administered Daily for 28 Days
From the Committee on Clinical Pharmacology, Department of Medicine, Cancer Research Center, and Section of Hematology/Oncology, University of Chicago; Committee on Clinical Pharmacology and Cancer Research Center, Chicago, IL; AstraZeneca Pharmaceuticals, Macclesfield, UK, and Wilmington, DE. Address reprint requests to Mark J Ratain, MD, 5841 S Maryland Ave, MC2115, Chicago, IL 60637; email: mratain{at}medicine.bsd.uchicago.edu.
Purpose: To define the maximum-tolerated dose and dose-limiting toxicities (DLTs) of an oral formulation of ZD9331, a novel thymidylate synthase inhibitor that is not a substrate for folylpolyglutamate synthase.
Patients and Methods: Patients had Cancer and Leukemia Group B performance status Results: Fifty-five patients were enrolled at eight dose levels. The DLTs were thrombocytopenia and neutropenia. At 3 mg/d, two of 19 patients developed DLT; one patient had grade 3 thrombocytopenia and grade 4 neutropenia, and the other patient had grade 3 thrombocytopenia only. Anemia was common, with a median hemoglobin nadir of 75% of baseline, before recovery or transfusion. The apparent oral clearance of ZD9931 was 11.6 ± 6.3 mL/min. Dose-limiting myelosuppression was associated with both an increased 24-hour ZD9931 concentration and blood urea nitrogen. Conclusion: The recommended phase II dose on this schedule is 3 mg/d for 4 weeks, followed by a 2-week rest period. ZD9331 seems to have a manageable toxicity profile, although it should be used with caution in patients with renal impairment.
THYMIDYLATE SYNTHASE catalyzes conversion of deoxyuridine monophosphate to thymidylate and is the only de novo source of thymidylate for DNA synthesis.1 The central role of thymidylate synthase in nucleotide synthesis has led to the development of several folate analogs that inhibit thymidylate synthase. CB3717, the first antifolate to specifically target thymidylate synthase, was abandoned because of its unpredictable nephrotoxicity,2 which was thought to be due to its low water solubility.3 Because CB3717 had significant antitumor activity, the Cancer Research Campaign Center for Cancer Therapeutics developed antifolates with improved water solubility. This research led to the development of raltitrexed (Tomudex; ZD1694; AstraZeneca, Macclesfield, UK), which had improved water solubility and decreased nephrotoxicity in animal models.3 Subsequent clinical studies demonstrated activity of ZD1694 in colorectal cancer and led to its approval in Australia, Canada, and Europe for treatment of metastatic colorectal cancer.4 In a later study in the United States, patients with metastatic colorectal cancer were randomly assigned to either fluorouracil and leucovorin or ZD1694; a slight survival advantage was found for fluorouracil and leucovorin.5 On the basis of this study, ZD1694 was not developed further in the United States. ZD1694 required polyglutamation by folylpolyglutamate synthase to effectively inhibit thymidylate synthase.6 In vitro studies have shown that resistance to antifolates can occur by cancer cells decreasing accumulation of polyglutamated antifolates.7,8 In addition, variability in polyglutamation may be a factor in the interpatient variability of antifolate pharmacokinetics. ZD9331 was developed to overcome decreased polyglutamation as a mechanism of resistance to antifolates and have more predictable pharmacokinetics and less interpatient variability than ZD1694. Preclinical studies demonstrated that ZD9331 was active against lymphoid and leukemia cell lines and small-cell lung, gastric, and colorectal cancer xenografts.9 ZD9331 was more active when given by a protracted schedule than an intermittent schedule. In vitro studies using L5178Y TK-/- mouse lymphoma cell lines demonstrated that exposure to 10 µmol/L of ZD9331 for 4 hours inhibited colony formation by 80%, whereas exposure to 0.1 µmol/L of ZD9331 for 24 hours inhibited colony formation by 99.96%. In vivo studies also showed that ZD9331 had superior activity administered on a protracted schedule. Mice were implanted with L5178Y TK -/- cells and treated with ZD9331; nine of 16 mice treated with 100 mg/kg of ZD9331 given by continuous infusion for 7 days were cured, whereas none of the mice treated with 100 mg/kg of ZD9331 given by intraperitoneal injection were cured.10 Preclinical pharmacokinetic studies showed good oral bioavailability: 30% to 60% in rats at 6 mg/m2 and 80% in dogs at 2 mg/m2. These preclinical studies demonstrating increased activity with prolonged exposure to ZD9331 and good oral bioavailability prompted this phase I study of oral ZD9331 with prolonged administration. Because the intravenous formulation of ZD9331 had demonstrated that clearance was independent of body-surface area,11 this oral formulation study used fixed dosing rather than dosing that was based on body-surface area.
Patient enrollment began in April 1998, and the study was closed in February 2000. Eligible patients had a solid tumor that was refractory to standard therapies or for which no standard therapy existed; Cancer and Leukemia Group B performance status  2; age  18 years; a life expectancy 12 weeks; a baseline platelet count 100 x 109/L; a total WBC count 3.5 x 109/L or an absolute neutrophil count 2 x 109/L; serum bilirubin concentration 1.25 times the upper limit of normal; ALT and AST 2.5 times the upper limit of normal in the absence of liver metastases and 5 times the upper limit of normal if liver metastases were present; serum creatinine 1.25 times the upper limit of normal; no severe or uncontrolled systemic disease, such as uncompensated respiratory or cardiac conditions; no use of folate-containing vitamin supplements; and no chlorambucil, mitomycin, or nitrosoureas for more than 6 months total duration.
Treatment Plan DLT was defined as grade 4 neutropenia of any duration with fever, grade 4 neutropenia without fever for at least 7 days, or grade 4 thrombocytopenia. Patients stopped treatment if they developed grade 2 neutropenia or thrombocytopenia while still taking ZD9331, and this was considered a DLT. Grade 3 or 4 nonhematologic toxicity that was not ameliorated by symptomatic directed therapy (with the exception of reversible elevations of AST or ALT) was also considered a DLT. Chemistry and hematologic measurements were repeated weekly during the first two cycles and within 3 days of starting the next cycle. Tumor measurements were repeated every two cycles. Patients remained on study until there was evidence of tumor progression, unacceptable toxicity, or until the patient or investigator felt continuing treatment with ZD9331 was not in the patient’s interest. Patients who experienced DLT but who were clinically benefiting from ZD9331 could continue to receive treatment at the investigator’s discretion at a reduced dose. The University of Chicago institutional review board approved the protocol and the consent form. Written informed consent was obtained from all patients.
Pharmacokinetics A noncompartmental approach was used to characterize the pharmacokinetic parameters of ZD9331. The pharmacokinetic software used to analyze the plasma concentrations was WinNonlin (version 2.1; Pharsight Corp, Cary, NC). The area under the concentration-time curve (AUC) was calculated to the 24-hour sampling point (after the first dose) using the linear trapezoidal rule. The terminal half-life was estimated from the terminal part of the log concentration-time curve. The apparent oral clearance (Cl/F) was calculated as dose divided by AUC. Creatinine clearance was estimated using the formula of Cockcroft and Gault.12
Statistics
Demographics A total of 55 patients were enrolled, from April 1998 to February 2000. Patient characteristics are outlined in Table 1  . Patients were assessable for toxicity if they were able to complete cycle 1 of treatment. Forty-five patients were assessable for toxicity. One patient who developed suspected cellulitis during cycle 1 was withdrawn and therefore was not assessable for toxicity. Two patients died while on study, but the deaths were not considered to be related to ZD9331. One patient presented to her local hospital in the third week of treatment with acute shortness of breath; at presentation her WBC count was 9.6 x 109/L, creatinine was 0.5 times the upper limit of normal, and blood urea nitrogen (BUN) was 9 mg/dL. Her respiratory status deteriorated, and she died from a presumed pulmonary embolus. At enrollment, she had a creatinine clearance of 81 mL/min and BUN of 13.5 mg/dL. The other patient had a history of recurrent urinary tract infections and was taking nitrofurantoin to prevent recurrent infections. At enrollment, she had a calculated creatinine clearance of 151 mL/min and a BUN of 9 mg/dL. She developed urosepsis in the fifth week of treatment and presented to her local hospital. She progressed to septic shock and her advance directive precluded inotropic support. She died despite maximal support outside of the intensive care unit. The remaining patients not assessable for toxicity either withdrew consent or developed progressive disease, preventing completion of one cycle.
Dose Escalation A total of 128 cycles were administered, and the median number of cycles completed by each patient was two (range, one to seven cycles). The treatment duration was escalated to 28 days (at a dose of 0.5 mg/d) without the occurrence of DLT. The dose of ZD9331 was then escalated from 0.5 to 5 mg/d. No DLTs occurred until the 5 mg/d dose level, at which two patients developed DLTs. At the prior dose level of 3 mg/d, no significant drug-related toxicity was observed, which led us to examine 4 mg/d. The three initial patients evaluated at 4 mg/d experienced more severe toxicity than patients treated at 5 mg/d. A preliminary analysis suggested that patients who experienced DLT at the 4 and 5 mg/d dose levels had decreased drug clearance and that this was correlated with an elevated BUN. Seven additional patients were enrolled at the 4-mg level to test this hypothesis; three patients had a high BUN, 20 mg/dL (4.0H), and four patients had a low BUN, less than 20 mg/dL (4.0L). An additional 16 patients were subsequently enrolled at the recommended phase II dose of 3 mg/d to better define the toxicity and pharmacodynamics at this dosage level.
Hematologic Toxicity
Anemia was a common toxicity at doses 3 mg/d (Fig 1), but was not dose-limiting. This was managed with erythropoietin and RBC transfusions. Midway through the study, one patient developed anemia associated with a low haptoglobin, elevated bilirubin and lactate dehydrogenase (LDH), and a negative Coombs test. After this index case, all subsequent patients had haptoglobin levels measured along with routine biochemistry. At the 3-mg dose level, five of 16 patients had anemia with undetectable haptoglobin levels. As Fig 2 demonstrates, the decrease in hemoglobin was gradual over several weeks. There was no significant difference in nadir hemoglobin, bilirubin, or LDH between patients with or without low haptoglobin levels.
Nonhematologic Toxicity The most frequent toxicities encountered at the 3-mg dose level are listed in Table 3 . The most common toxicity was fatigue, which occurred in almost all patients. Nausea was a frequent side effect but was not dose-limiting. Four patients developed an erythematous maculopapular rash, which preceded the development of myelosuppression. Six patients developed elevated AST and ALT while receiving therapy, but the ALT and AST levels returned to baseline during the rest period and did not exceed grade 2 toxicity.
Tumor Response Patients were evaluated after the first two cycles and every two cycles thereafter. There were no objective minor or major responses observed, but 14 patients had prolonged stabilization of disease. The median duration of stable disease was 12 weeks (range, 12 to 48 weeks). At the 3-mg dose level, five of 19 patients achieved stable disease, including two patients who had prolonged stable disease (36 and 48 weeks). The majority of patients with stable disease had colorectal cancer (n = 10), but two patients with ovarian cancer also had disease stabilization.
Pharmacokinetics
As the dose of ZD9331 increased from 3 to 5 mg (a 67% increase in dose), the mean AUC increased from 2,839 to 3,431 ng/mL • h (a 21% increase), and the mean peak concentrations were 206 ng/mL and 298 ng/mL, respectively (a 45% increase).
The Cl/F, AUC, Cmax, and Cmin for each dose level are listed in Table 4
Pharmacodynamics
Demographic characteristics, pharmacokinetic parameters, and organ function were examined for possible relationships with thrombocytopenia and anemia. In the univariate analysis, significant predictors of log platelet nadir were RBC folate, dose, Cmin, half-life, AUC, clearance, bilirubin, BUN, and log Cmin (Table 5
In univariate analysis, significant predictors of log hemoglobin nadir were baseline hemoglobin, dose, Cmin, bilirubin, albumin, creatinine clearance, and log Cmin. Serum folate, Cmax clearance, AUC, performance status, BUN, and BUN/creatinine ratio did not reach statistical significance. In multivariate analysis, significant predictors of log nadir hemoglobin were log baseline hemoglobin, albumin, and log Cmin (r2 = 0.61; P < .001).
AUC (during the first 24 hours), Cmin, creatinine clearance, and BUN were examined as predictors for dose-limiting myelosuppression (Table 6
The recommended phase II dose for ZD9331 is 3 mg/d for 4 weeks followed by a 2-week rest period. Some patients were able to tolerate ZD9331 doses of 4 and 5 mg/d without toxicity. Because preliminary pharmacokinetic analysis suggested that elevated BUN predisposed patients to develop ZD9331 toxicity, we therefore re-examined the 4 mg/d dose level, enrolling patients on the basis of BUN levels. However, even in the group with low BUN, we could not safely administer ZD9331 at 4 mg/d and could not recommend 4 mg/d as the initial phase II dose. Given that only two of 19 patients at 3 mg/d had DLT, patients who tolerate ZD9331 3 mg/d might be considered for escalation to a dose of 4 mg/d. The DLT of ZD9331 on this oral schedule was neutropenia and thrombocytopenia; this contrasts with other studies in which cutaneous toxicity and myelosuppression were found to be the DLTs.11,14 In the study by de Jonge et al,14 dose-limiting cutaneous toxicity occurred at 10 mg twice a day given for 5 days. In the study by Goh et al,11 dose-limiting skin toxicity occurred at 12 mg/m2 and 25 mg/d given daily for 5 days. In this study, the daily administration of ZD9331 was more prolonged at 4 weeks, and the highest daily dose administered was 5 mg/d. The total dose of ZD9331 administered per cycle in the three studies was not substantially different (100 v 125 v 84 mg/cycle). ZD9331 was administered four times more rapidly in the two schedules associated with skin toxicity than in this study. This indicates that skin toxicities may be related to peak concentrations and the rate at which thymidylate synthase was inhibited. Anemia was a common toxicity at or above the 3-mg dose level, but was not dose-limiting and was easily managed with erythropoietin and RBC transfusions. Midway through the study, one patient developed anemia associated with a low haptoglobin level. The decrease in hemoglobin was gradual over several weeks, which is more likely secondary to decreased production than hemolysis. Three studies have implicated methotrexate (in combination with other agents) with elevations of LDH or anemia associated with a low haptoglobin level. Klimo and Connors15 first reported elevation of LDH levels in the majority of patients treated with a regimen consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin. The patients with elevated LDH were in complete or partial remission and had no elevations in other hepatic enzymes. In another study of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin, McAdam et al16 noted an increase in LDH during treatment that returned to baseline before the next cycle. In a study of cyclophosphamide, doxorubicin, methotrexate, bleomycin, vincristine, etoposide, ifosfamide, and prednisolone, Maruyama et al17 observed an elevation of LDH isoenzymes 1 and 2. In addition, six patients had undetectable haptoglobin levels. We speculate that anemia with elevation of LDH and suppressed haptoglobin may be an unappreciated side effect of the antifolate class of chemotherapeutic agents as a result of ineffective erythropoiesis.
Given orally, ZD9331 showed a less than dose-proportional increase of AUC at doses The dominant role of reabsorption in the renal handling of ZD9331 may explain the relationship between Cmin and BUN of ZD9331 and the poor correlation between Cmin and calculated creatinine clearance; the latter is an estimation of the amount of blood that is filtered at the glomerulus and enters the proximal tubule. Creatinine clearance is a useful surrogate for predicting the clearance of drugs that are predominantly filtered, such as carboplatin, but may not be well correlated with the ability of the proximal tubule to reabsorb solutes and electrolytes. BUN is a better surrogate for tubular function because urea is reabsorbed. The parallels between urea reabsorption and ZD9331 reabsorption may be the basis for the apparent relationship between Cmin and BUN. Thus ZD9331, like other renally excreted drugs, should be used with caution in patients with renal insufficiency or in combination with drugs that affect proximal tubular reabsorption. Plasma 2'-deoxyuridine (dUrd) is the substrate of thymidylate synthase that is elevated when thymidylate synthase is inhibited. Jackman et al18 and Mitchell et al19 have shown that plasma levels of dUrd are correlated with the degree of thymidylate synthase inhibition. We had planned to measure dUrd levels in this study as a measure of thymidylate synthase inhibition; unfortunately, plasma interference prevented analysis of dUrd in samples obtained. In this study, we observed disease stabilization of colorectal and ovarian cancers at a dose of 3 mg/d given for 28 days followed by a 2-week rest period. The results from this study indicate that phase II studies of ZD9331 are warranted in metastatic colorectal and ovarian cancer.
Supported in part by AstraZeneca and grant no. CA 14599 from the National Cancer Institute, National Institutes of Health. Michael B. Sawyer was the Gordon E. Richards Fellow of the Canadian Cancer Society.
1. Hillman RS: Hematopoietic agents: Growth factors, minerals and vitamins, in Hardman JG, Limbird LE, Molinoff PB, et al (eds): Goodman and Gilman’s Pharmacological Basis of Therapeutics (ed 9). New York, NY, McGraw-Hill, 1996, pp 1311–1340 2. Vest S, Bork E, Hansen HH: A phase I evaluation of N10-propargyl-5,8-dideazafolic acid. Eur J Cancer Clin Oncol 24:201–204, 1988[CrossRef][Medline] 3. Jodrell DI, Newell DR, Morgan SE, et al: The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice. Br J Cancer 64:833–838, 1991[Medline]
4. Clarke SJ, Hanwell J, de Boer M, et al: Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors. J Clin Oncol 14:1495–1503, 1996 5. Blackledge G: New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed (Tomudex). Br J Cancer 77:29–37, 1998 (suppl) 6. Jackman AL, Boyle FT, Harrap KR: Tomudex (ZD1694): From concept to care, a programme in rational drug discovery. Invest New Drugs 14:305–316, 1996[CrossRef][Medline]
7. Pizzorno G, Mini E, Coronnello M, et al: Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug. Cancer Res 48:2149–2155, 1988
8. Rhee MS, Wang Y, Nair MG, et al: Acquisition of resistance to antifolates caused by enhanced gamma-glutamyl hydrolase activity. Cancer Res 53:2227–2230, 1993 (suppl) 9. Jackman AL, Kimbell R, Brown M, et al: The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase inhibitor. Adv Exp Med Biol 370:185–188, 1994[Medline] 10. Jackman AL, Kimbell R, Aherne GW, et al: Cellular pharmacology and in vivo activity of a new anticancer agent, ZD9331: A water-soluble, nonpolyglutamatable, quinazoline-based inhibitor of thymidylate synthase. Clin Cancer Res 3:911–921, 1997[Abstract]
11. Goh BC, Ratain MJ, Bertucci D, et al: Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations. J Clin Oncol 19:1476–1484, 2001 12. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41, 1976[Medline] 13. Mick R, Ratain MJ: Statistical approaches to pharmacodynamic modeling: Motivations, methods, and misperceptions. Cancer Chemother Pharmacol 33:1–9, 1993[CrossRef][Medline]
14. de Jonge MJ, Punt CJ, Sparreboom A, et al: Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors. J Clin Oncol 20:1923–1931, 2002 15. Klimo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 102:596–602, 1985[Medline] 16. McAdam B, Smith T, Love WC, et al: Lactate dehydrogenase levels during MACOP-B chemotherapy for non-Hodgkin’s lymphoma. Med Oncol Tumor Pharmacother 10:95–101, 1993[Medline] 17. Maruyama F, Ezaki K, Okamoto M, et al: Increased blood cell destruction during vigorous regeneration of bone marrow after intensive chemotherapy for non-Hodgkin lymphoma. Eur J Cancer 29A:1499, 1993[Medline] 18. Jackman AL, Mitchell F, Lynn S, et al: Plasma 2-'deoxyuridine (dUrd) as a surrogate market of thymidylate synthase (TS) inhibition in patients treated with ZD9331. Proc Am Soc Clin Oncol 18:171a, 1999 (abstr 654) 19. Mitchell F, Lynn S, Jackman AL: Modified high-performance liquid chromatography assay for the measurement of 2'-deoxyuridine in human plasma and its application to pharmacodynamic studies of antimetabolite drugs. J Chromatogr B Biomed Sci Appl 744:351–358, 2000[CrossRef][Medline] Submitted January 30, 2002; accepted February 13, 2003. This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
