Phase I and Clinical Pharmacology Study of Intravenous Flavone Acetic Acid. (NSC347512)1 .... tration was achieved by evaporation under nitrogen. A standard ...
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Stevens, S. J. Lee, D. A. Lowenthal, I. Haines, T. D. Walsh,. L. Baltzer ..... potential antitumor agents: a selective screening study. Cancer Treat. Rep.,. 62:45-74 ...
Antisense Oligonucleotide ISIS 3521 Administered in Combination with 5-Fluorouracil and Leucovorin in Patients with. Advanced Cancer1. Sridhar Mani,2 ...
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Jul 15, 1995 - Phase I Clinical and Pharmacological Study of Suppression of Human Antimouse. Antibody ... V. V., D. B., H. W., G. H.ÃÂ¡,Laboratory Medicine ÃÂ¡H.F.], and Clinical Immunology and Biological Therapy [J. L M.],. The University of ....
staurosporine family of agents, which have two indole nitrogens linked to a carbohydrate residue. Representatives from both of these subgroups have been the ...
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anemia, and brief transaminasemia. One patient who received antibody alone had an apparent acute immune complex-mediated reaction. Ten of. 11 patients ...
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[CANCER RESEARCH 47, 3303-3308, June 15, 1987]
Phase I and Clinical Pharmacology Study of Trimetrexate Administered Weekly for Three Weeks1 Michael P. Fanucchi,2 T. Declan Walsh, Martin Fleisher, George Lokos, Linda Williams, Cathy Cassidy, Pedro Vidal, Ting-Chao Chou, Donna Niedzwiecki, and Charles W. Young Developmental Chemotherapy Service and Clinical Pharmacology Laboratory, Department of Medicine [M. P. F., T. D. W., G. L., L. W., C. C, C. W. Y.j, Department of Clinical Chemistry [M. F.], Laboratory of Pharmacology [P. K, T-C. C.], and Department of Epidemiology and Biostatistics [D. NJ, Memorial Sloan-Kettering Cancer Center, Cornell University School of Medicine, New York, New York 10021
permitted an analysis of the influence of these factors on the clearance of TMTX. In addition, the effect of TMTX on [6-3H]
Trimetrexate, a new antifolate compound, was administered by 30-min infusions weekly for 3 weeks to 29 patients with solid tumors in a Phase I study. Thrombocytopenia was dose limiting, but highly variable among patients at a given dose level; other toxicity was mild and uncommon. Twenty-three patients participated in pharmacokinetic studies and five patients participated in a study of the effects of trimetrexate on [6-3H|-
deoxyuridine incorporation into DNA from hematopoietic cells was studied in five treated patients.4
deoxyuridine incorporation into hematopoietic cell DNA. The median total body clearance of trimetrexate for each dose level was independent of dose but the total body clearance varied widely among patients at a given dose level. The magnitude of the fall in platelet count in individual patients correlated well with the amount of exposure to trimetrexate, but not with the extent of prior therapy. The amount of [6-3H]deoxyuridine
Patient Selection and Characteristics. Twenty-nine patients with his tologically proven solid tumors refractory to standard therapy and a life expectancy of at least 8 weeks were entered into the study; the patient characteristics are summarized in Table 1. All patients had a Karnofsky performance status of >50%, and 79% of the patients had a performance status of 70% or better. No patient had received chemo therapy or radiation therapy within 4 weeks of this study (6 weeks in the case of nitrosoureas or mitomycin). All patients had the following pretreatment hematological and biochemical parameters: WBC > 400()/niii), platelet count > 150,000/mm, serum total bilirubin and serum creatinine < 1.5 mg/dl. Patients were allowed to receive acet aminophen and narcotics for pain control and benzodiazepines or antihistamines for sleep. The extent of prior therapy was quantified for each patient by calculating a prior therapy score, defined as: prior therapy score = (weeks of chemotherapy x number of drugs given concurrently) + (weeks of radiotherapy x number of sites treated concurrently). The mean prior therapy score for the 29 patients was 66 (range, 0-200). Treatment and Dose Escalation. TMTX, supplied by the Division of Cancer Treatment, National Cancer Institute, was dissolved in 5% dextrose in water and administered by constant infusion over 30 min. One cycle of treatment consisted of a weekly injection of TMTX for 3 weeks followed by a 2-week observation period. The starting dose was 50 mg/m2/week x 3 weeks, which was based on the results of ongoing
incorporation into hematopoietic cell DNA at 72 h after drug administra tion correlated with the total body clearance of trimetrexate. The total body clearance of trimetrexate was reduced in patients with impaired hepatic synthetic function, as judged by low pretreatment serum albumin concentrations. The recommended Phase II starting dose on this schedule is 130 mg/m2 weekly for 3 weeks; patients with hypoalbuminemia should be treated at lower doses.
INTRODUCTION TMTX3 is a competitive inhibitor of dihydrofolate reducÃ-ase with oncolytic activity against murine and human cell lines and against primary cultures of human tumors (1-4). Unlike the classical antifolates, TMTX enters cells by passive diffusion and does not undergo intracellular polyglutamylation; however, it concentrates in leukemic cells to a greater extent than methotrexate (5). Cells which are resistant to methotrexate due to loss of the ability to transport folates remain sensitive to TMTX; partial sensitivity to TMTX is preserved in those cell lines which overproduce dihydrofolate reducÃ-ase(4, 6, 7). This paper presents a Phase I study of TMTX administered by 30-min infusions weekly for 3 weeks to 29 patients with solid tumors. This schedule of administration was evaluated because of the efficacy of methotrexate when given by a weekly schedule and because of the suggestion that TMTX was more efficacious in in vivo murine systems when administered inter mittently (4). Twenty-three of the patients participated in a clinical pharmacology study; in these patients the observed toxicity was correlated with the 24-h plasma concentration of TMTX and with selected pharmacokinetic parameters. The inclusion of patients with varying hepatic and renal function Received 10/3/86; revised 3/11/87; accepted 3/17/87. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported in part by National Cancer Institute Contract NO1-CM-57732, Grants CA-08S62 and CA-08748. and a Fellowship Grant from the J. M. Foundation (T. D. W.). 1 To whom requests for reprints should be addressed, at Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, NY 10021. 3 The abbreviations used are: TMTX, trimetrexate glucuronate (6-|[(3,4,5trimethoxyphenyl)amino]methyl)-5-methyl-2,4-quinazolinediamineglucuronate); HPLC, high-pressure liquid chromatography; 1)1II K, dihydrofolate reducÃ-ase; SGOT, serum glutamic oxaloacetic transaminase.
MATERIALS AND METHODS
single dose Phase I studies (8,9). The proposed dose escalation schedule utilized the following modified Fibonacci sequence: 100, 160, 240, and 300 mg/m2/week x 3 weeks. History and physical examination were obtained weekly and a com plete blood count and biochemical screening profile were obtained twice weekly. Standard toxicity criteria were used (10). Tumor response was assessed every 5 weeks by physical examination and/or X-ray exami nation. Standard response criteria were used (10). Escalation to a higher dose level was allowed in individual patients who had stable disease and no toxicity at a given dose level. Responding patients and stable patients with Grade 1 or 2 toxicity were retreated at the same dose level. Pharmacokinetic Studies. The elimination of the initial dose of TMTX was studied in 23 patients. Heparinized blood samples were obtained pretreatment, at end of infusion, and 2.4, 4, 10, 15, 20, 30, 45, 60, 90, 120 min, and 3,4, 6, 8, 12, 24, 32,48, 56, 72, 80, 96 h after the infusion. Urine was collected in 4-h aliquots for the first 24 h, then in 12-h aliquots through 96 h. Blood samples were collected on ice, spun down, and the plasma was stored at -70Â°C. Urine volumes were recorded and aliquots stored at -70Â°C. Analytical Methodology. TMTX was extracted from samples of urine and plasma by elution from bonded phase extraction columns as de scribed in (11), except that the internal standard was 6-|[(3,4,5-trime4 A preliminary report has appeared (Fanucchi, M., Fleisher, M., Vidal, P., Williams, L., Bauer, T., Cassidy, C., Chou, T-C., and Young, C. Phase I and pharmacologie study of trimetrexate. Proc. Am. Assoc. Cancer Res., 26: 179, 1985).
second dose level (100 mg/m2). This led to a reduction in dosage level to 75 mg/m2 for the next cohort of patients;
sion (WBC, 900/mm3; platelet count, 11,000/mm3) 7 days after a single dose of 75/mg/m2 of TMTX. Despite platelet transfu
subsequent dose levels were escalated by 20% increments. Myelosuppression was observed at all dose levels and was dose limiting. The time required for marrow recovery was approximately 1 week. Thrombocytopenia occurred in excess of neutropenia, but considerable variability was observed in the severity of myelosuppression among patients at a given dose level. Twelve patients were unable to complete the initial cycle of treatments as scheduled due to Grade 2 or higher hematological toxicity. However, five of six patients at 90 mg/m2, all the patients at 110 mg/m2, and five of the seven patients at 130 mg/m2 completed the treatments as scheduled. Eight patients
sions, she experienced a sudden massive gastrointestinal hem orrhage with hypotension and cardiac arrest; there was no prior history of gastrointestinal disease. This patient participated in the pharmacokinetic study and in the [6-3H]-deoxyuridine in corporation study and is listed as patient 9 in Tables 4 and 5. The second patient was a 49-year old woman with pulmonary and pleural metastasis from cutaneous angiosarcoma and a prior therapy score of 55. She had sudden onset of respiratory distress after two doses of TMTX at 100 mg/m2 due to a large
Â°The 0-24-h urine collection contained 55-75% of the recovered TMTX; the 72-96-h urine collection contained <4% of the recovered TMTX. * 24-h concentration of TMTX. ' Incomplete collection. * ND, Not determined. ' Median for each dose level. ^Harmonic mean for each dose level. 3305
patients with adenocarcinoma of the breast and in one patient with adenocarcinoma of the lung. The last patient also had a marked improvement in his chronic generalized psoriasis while receiving TMTX. Elimination of TMTX. The concentrations of TMTX in plasma obtained over 96 h after a dose of 50 mg/m2 to patient 3 (Table 4), measured by HPLC and by DHFR inhibition, and after a dose of 130 mg/m2 to patient 22 (Table 4), measured by HPLC, are summarized in Fig. 1. TMTX declined 2 logs in concentration over 48 h and was no longer detectable by HPLC beyond 72 h. The concentrations measured by DHFR inhibition were substantially higher than the concentrations measured by the specific HPLC assay, particularly at the latter time points. The elimination data, as determined by HPLC, were best fit by a triexponential equation (JV = 3) with the sum of squares interactions weighted by 1/(concentration)2; the pharmacoki-
netic parameters are summarized in Table 4. There was consid erable variation in the elimination of TMTX among patients at a given dose level, as shown by a comparison of the observed 24-h plasma concentration, AUCo-^o and Cl,b. The median Cl,b for each dose level was independent of TMTX dose (r, = 0.11, P = 0.630). TMTX was eliminated from the plasma primarily by nonrenal clearance; the ( '/, of unchanged drug accounted for a mean of 33% of the Cltt. Chromatograms of urine revealed the presence of two unidentified early eluting peaks (Fig. 2); fractions obtained from each peak strongly inhibited DHFR. The binding of TMTX at concentrations of 0.1, 1.0, and 10 Mg/ml to plasma proteins of a normal volunteer was >98%. Correlation between Clinical and Pharmacokinetic Parameters. There was no correlation between the prior therapy score and the percent change in platelet count (r, = â€”0.23,P = 0.20) or
Fig. 2. Partial chromatogram of 12-16 h urine collection from patient 18 (Table 4) given 90 mg/m2 of TMTX. HPLC conditions as discussed in -Materials and Methods." The peaks at retention times of 11.5 and 12.5 min were not present in the pretreatment urine sample; the fractions of eluant containing the two peaks strongly inhibited DHFR. The retention time of TMTX was 45.0 min (not shown).
ifV \MSX ^
0xXXXX 20 PER
Fig. 3. 24-h plasma concentration TMTX in Mg/ml (y-axis) verms percent change in platelet count, as defined in "Materials and Methods" (jr-axis).
50mg/m' HPLC SOmg/m1 DHFR 130mg/m* HPLC
I I 2 4
Hours Fig. 1. Clearance of TMTX from the plasma after a dose of 50 mg/m2 to patient 3 (Table 4) and after a dose of 130 mg/m2 to patient 22 (Table 4).
the percent change in WBC count (r, = 0.17, P = 0.28). The percent change in platelet count was strongly correlated with the observed 24-h plasma concentration of TMTX (r, = 0.66, P = 0.0007; Fig. 3) and with AUCoâ€”(r, = 0.68, P = 0.0005). There was a strong negative correlation between percent change in platelet count and the Cl,b (r, = -0.70, P = 0.0003; Fig. 4). A correlation between percent change in WBC and 24-h plasma concentration of TMTX was suggested (r, = 0.51, P = 0.01); however, there was no correlation between percent change in WBC and Cl,b. The terminal phase f./,could not be correlated with the percent change in platelet count or the percent change in WBC. The Cla, was strongly correlated with pretreatment serum albumin concentration (rs = 0.66, P = 0.0005; Fig. 5) but not with pretreatment SCOT or creatinine clearance. A negative
all 5 patients at 24 h after drug administration, compared to pretreatment levels (Table 5; P = 0.0008). There was a trend towards continued inhibition at 72 h after drug administration (P = 0.06), but the amount of incorporation varied among the five patients. There was a strong linear correlation between the amount of incorporation at 72 h and the ("/â€ž, for each patient (r2 = 0.938, P < 0.005).
The dose-limiting toxicity of TMTX given on a weekly x3 schedule is myelosuppression, with thrombocytopenia in excess of neutropenia. The magnitude of the drop in platelet count 90 70 was highly variable among patients at a given dose level and 30 PER CENT CHANGE IN PLATELET COUNT correlated well with the amount of exposure to TMTX but not Fig. 4. Total body clearance of TMTX in ml/min/m! (>>-axis)versus percent with the extent of prior therapy. Variability in the C/r*value of change in platelet count, as defined in "Materials and Methods" (jr-axis). TMTX was correlated with pretreatment serum albumin. TMTX was eliminated from the plasma primarily by nonrenal clearance. The mechanism for the nonrenal clearance is biotransformation and elimination in the liver. We and others have detected the presence of two metabolites in plasma and urine (19). Tong et al. have provided evidence that the first metabolite is formed by demethylation at the 4-position of the phenoxymethyl ring and the second by conjugation with glucuronic acid at this site (19). These investigators have also shown that both metabolites were secreted in bile, together with small amounts of the parent drug, by perfused rat liver prepa rations (20). We and others have found that both metabolites are capable of inhibiting DHFR (19) but the cytotoxic activity X of these compounds is unknown. X There can be wide variability among patients in the clearance rates for drugs which are predominantly eliminated by the liver (21). Hepatic blood flow, binding to plasma proteins and the PRETREATMENT SERUM ALBUMIN (am/dl) intrinsic ability of the liver to clear a drug from the blood (in Fig. 5. Total body clearance of TMTX in ml/min/m2 ty-axis) versus pretreatthe absence of flow limitations) are primary determinants of ment serum albumin in g/dl (jr-axis). hepatic clearance (21). Thus, hepatic clearance can be affected by the age, sex, and race of the patients, and by the presence of Table 5 Effect of TMTX on (6-3H]deoxyuridine incorporation into primary hepatic disease or systemic illnesses. Patients with liver hematopoietic cell DNA dysfunction may have reduced clearance compared with normal incorporated subjects, but there is often considerable overlap (22). However, pmol(10-2)/MgDNA2.660.071.342.730.020.622.300.040.180.990.030.021.090.030.17C/Â» Patient" Time1 (ml/min/m2)41.126.417.817.014.4 there is now evidence that when hepatic synthetic functions are Pretreatment24 markedly diminished, as judged by serum albumin <3.0-3.5 g/ h72h3 dl, drug clearance by the liver can be markedly impaired (23). The incorporation of [6-3H]deoxyuridine into DNA provides Pretreatment24h72h7 10
a measure of the intracellular activity of thymidylate synthetase which is the rate-limiting enzyme in the conversion of deoxyuridine monophosphate into thymidine triphosphate and its subsequent incorporation into DNA. The results in this study must be interpreted in light of the fact that TMTX-induced changes in deoxyuridine monophosphate pools will result in dilution of the isotope (4). Nevertheless, the inhibition of [63H]deoxyuridine incorporation provides relative information on
Pretreatment24h72h9 Pretreatment24h72h1 2
" Patient number used in Table 4.
correlation between the terminal phase tv, and albumin concen tration was suggested (rs = -0.49, P = 0.02); there was no correlation between the terminal phase tv,and SCOT or creatinine clearance. The 24-h concentration of TMTX did not correlate with pretreatment albumin, SCOT, or creatinine clearance. Incorporation of |6-'H|Deoxyuridine into Hematopoietic Cell DNA. The incorporation of [6-3H]deoxyuridine into hemato poietic cell DNA was inhibited to nearly undetectable levels in
the degree of depletion of tetrahydrofolate cofactors in hema topoietic cells by TMTX and on the time course with which TMTX exerts its effects. The marked suppression of [6-3H] deoxyuridine incorporation at 24 h after drug administration is consistent with rapid diffusion of TMTX from the plasma into cells and its known potent inhibition of DHFR (4), whereas the variability observed at 72 h reflected the ability of individual patients to eliminate the drug. Based on the observed toxicity, we recommend a Phase II starting dose for TMTX of 130 mg/m2/week for 3 weeks. However, patients with a low serum albumin will have a reduced
clearance and are more likely to have thrombocytopenia; patients should be initially treated at lower doses.
these 10. 11.
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STUDY OF TRIMETREXATE
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Phase I and Clinical Pharmacology Study of Trimetrexate Administered Weekly for Three Weeks Michael P. Fanucchi, T. Declan Walsh, Martin Fleisher, et al. Cancer Res 1987;47:3303-3308.
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