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发表于 2008-11-1 00:59:03
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来自： 美国
Treatment of Metastatic Cancer with Tetrathiomolybdate: Phase I Study
Treatment of Metastatic Cancer with Tetrathiomolybdate, an Anticopper, Antiangiogenic Agent: Phase I Study
George J. Brewer, Robert D. Dick, Damanjit K. Grover, Virginia LeClaire, Michael Tseng, Max Wicha, Kenneth Pienta, Bruce G. Redman, Thierry Jahan, Vernon K. Sondak, Myla Strawderman, Gerald LeCarpentier and Sofia D. Merajver2
Departments of Human Genetics [G. J. B., R. D. D.], Internal Medicine [G. J. B., V. L., M. T., M. W., K. P., B. G. R., S. D. M.], Surgery [K. P., V. K. S.], and Radiology [G. L.], Clinical Research Center [D. K. G.], and Comprehensive Cancer Center [V. L., M. T., M. W., K. P., B. G. R., V. K. S., M. S., S. D. M.], University of Michigan Health System, Ann Arbor, Michigan 48109, and Department of Internal Medicine, University of California at San Francisco, San Francisco, California 94115 [T. J.]
Introduction
Patients and Methods
Results
Discussion
REFERENCES
Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15–20% of baseline. The level III dose of TM (120 mg/day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.
The concept of antiangiogenic treatment for solid tumors, which was pioneered by Folkman (1, 2, 3) , has a firm rationale and shows efficacy in animal tumor models (4, 5, 6, 7, 8, 9, 10, 11, 12) . Compounds that interfere with critical steps in the angiogenesis cascade are reaching the clinic (13) . The steps required for successful tumor angiogenesis at the primary and metastatic sites are diverse, and they depend on an imbalance between angiogenesis activators (14, 15) such as vascular endothelial growth factor and basic fibroblast growth factor and inhibitors such as thrombospondin 1 (16, 17, 18, 19, 20) , angiostatin (21, 22, 23) , and endostatin (10) . The relative importance of the different angiogenesis-modulating molecules in different tissues may determine the relative potency of antiangiogenic compounds to elicit a response at both the primary and metastatic sites. Therefore, it would be very desirable to develop an antiangiogenic strategy that would affect multiple activators of angiogenesis in order for it to be generally applicable to human tumors. Because copper is a required cofactor for the function of many key mediators of angiogenesis, such as basic fibroblast growth factor (24, 25, 26, 27) , vascular endothelial growth factor, and angiogenin (28) , we have developed an antiangiogenic strategy for the treatment of cancer based on the modulation of total body copper status. The underlying hypothesis of this work is that a window of copper deficiency exists in which angiogenesis is impaired, but other copper-dependent cellular processes are not affected enough to cause clinical toxicity.
It has been amply demonstrated that copper is required for angiogenesis (29, 30, 31) , and several years ago, some promising animal tumor model studies were carried out using an anticopper approach (32, 33) . The chelator penicillamine and a low-copper diet were used to lower copper levels in rats and rabbits with implanted intracerebral tumors. However, although they showed reduced tumor size, the animals treated with the low-copper regimen did not show improved survival over untreated controls.
For the past 20 years, we have developed new anticopper therapies for Wilson's disease, an autosomal recessive disease of copper transport that results in abnormal copper accumulation and toxicity. One of the drugs currently being used, TM,3 shows unique and desirable properties of fast action, copper specificity, and low toxicity (34, 35, 36) , as well as a unique mechanism of action. TM forms a stable tripartite complex with copper and protein. If given with food, it complexes food copper with food protein and prevents absorption of copper from the GI tract. There is endogenous secretion of copper in saliva and gastric secretions associated with food intake, and this copper is also complexed by TM when it is taken with meals, thereby preventing copper reabsorption. Thus, patients are placed in a negative copper balance immediately when TM is given with food. If TM is given between meals, it is absorbed into the blood stream, where it complexes either free or loosely bound copper with serum albumin. This TM-bound copper fraction is no longer available for cellular uptake, has no known biological activity, and is slowly cleared in bile and urine.
The underlying hypothesis of an anticopper, antiangiogenic approach to cancer therapy is that the level of copper required for angiogenesis is higher than that required for essential copper-dependent cellular functions, such as heme synthesis, cytochrome function, and incorporation of copper into enzymes and other proteins. Because of the unique and favorable characteristics of TM as an anticopper agent compared with other anticopper drugs, we evaluated it in animal tumor models for toxicity and efficacy as an anticopper, antiangiogenic therapy. These studies showed efficacy in impairing the development of de novo mammary tumors in Her2-neu transgenic mice (12) , and TM showed no clinically overt toxicity as copper levels were decreased to 10% of baseline. Here we report the first human trial of an anticopper approach to antiangiogenesis therapy based on the use of TM in patients with metastatic cancer. This Phase I trial of TM yielded information on dose, dose response, evaluation of copper status in patients, and toxicity (37) . Although the study was not designed to definitively answer efficacy questions, we report preliminary observations on efficacy and novel approaches to following disease status in trials of antiangiogenic compounds.
Patients.
Eighteen adults with metastatic solid tumors exhibiting measurable disease, life expectancy of 3 or more months, and at least 60% Karnofsky performance status were enrolled. We excluded patients with effusions or bone marrow involvement as the only manifestations of disease and those who had severe intercurrent illness requiring intensive management or were transfusion dependent. Patients had to have recovered from previous toxicities and had to meet the following requirements for laboratory parameters: (a) WBC 3,000/mm3; (b) absolute neutrophil count 1,200/mm3; (c) Hct 27%; (d) hemoglobin 8.0 g/dl; (e) platelet count 80,000/mm3; (f) bilirubin 2.0 mg/dl; (g) aspartate aminotransferase and alanine aminotransferase 4 times the upper limit of institutional norm; (h) serum creatinine < 1.8 mg/dl or calculated creatinine clearance 55 ml/min; (i) calcium < 11.0; (j) albumin 2.5 g/dl; (k) prothrombin time 13 s; and (l) partial thromboplastin time 35 s. Other requirements were demonstrable progression of disease in the previous 3 months after standard treatments such as surgery, chemotherapy, radiotherapy, and/or immunotherapy or progressive disease after declining conventional treatment modalities.
Treatment Schema: Doses and Escalation.
Three dose regimens were evaluated. All dose levels consisted of 20 mg of TM given three times daily with meals plus an escalating (levels I, II, and III) in-between meals dose given three times daily for a total of six doses/day. Loading dose levels I, II, and III provided TM at 10, 15, and 20 mg, three times daily between meals, respectively, in addition to the three doses of 20 mg each given with meals at all dose levels.
Baseline Cp was taken as the nearest Cp measurement to day 1 of treatment (including day 1) because blood was drawn before TM treatment from all patients. The target Cp reduction was defined as 20% of baseline Cp. Due to Cp assay variability of approximately 2% at this institution, a change of Cp to 22% of baseline was considered as achieving the desired reduction of copper. In addition, if the absolute Cp was less than 5 mg/dl, then the patient was considered as having reached the target Cp. No patient reached the 5 mg/dl target without also being at least 78% reduced from baseline. After reaching the target copper-deficient state, TM doses were individually tailored to maintain Cp within a target window of 70–90% reduction from baseline.
Six patients were to be enrolled at each dose level. After four patients were enrolled at level I, if one patient experienced dose-limiting toxicity (defined as Hct < 80% of baseline), two more patients were enrolled at level I. If no dose-limiting toxicity was observed, patients were enrolled at the next dose level. Treatment was allowed to continue beyond induction of target copper deficiency if the patients experienced a partial or complete clinical response or achieved clinical stable disease by the following definitions. Complete response is the disappearance of all clinical and laboratory signs and symptoms of active disease; partial response is a 50% or greater reduction in the size of measurable lesions defined by the sum of the products of the longest perpendicular diameters of the lesions, with no new lesions or lesions increasing in size. Minor response is a 25–49% reduction in the sum of the products of the longest perpendicular diameters of one or more measurable lesions, no increase in size of any lesions, and no new lesions; stable disease is any change in tumor measurements not represented by the criteria for response or progressive disease; progressive disease is an increase of 25% or more in the sum of the products of the longest perpendicular diameters of any measurable indicator lesions compared with the smallest previous measurement or appearance of a new lesion. Because copper deficiency is not a cytotoxic treatment modality, the patients who provide information about the efficacy of TM for long-term therapy in this population of patients with advanced cancer are primarily those who remained within the target Cp window of 20 ± 10% of baseline for over 90 days without disease progression.
Monitoring of Copper Status.
A method was required to monitor copper status easily and reliably, so that the TM dose could be adjusted appropriately during this trial. With TM administration, serum copper is not a useful measure of total body copper because the TM-copper-albumin complex is not rapidly cleared, and the total serum copper (including the fraction bound to the TM-protein complex) actually increases during TM therapy (34, 35, 36) . The serum Cp level obtained weekly was used as a surrogate measure of total body copper status. Cp was measured by the oxidase method; the Cp measurements were made by nethelometry (differential light scattering from a colored or turbid case solution with respect to a control solution) using an automated system and reagents available commercially (Beckman Instruments, Inc., Fullerton, CA). The serum Cp level is controlled by Cp synthesis by the liver, which, in turn, is determined by copper availability to the liver (38) . Thus, as total body copper is reduced, the serum Cp level is proportionately reduced. The serum Cp level is in the range of 20–35 and 30–65 mg/dl for normal controls and cancer patients, respectively. Our objective was to reduce Cp to 20% of baseline and to maintain this level, within a window spanned by 20 ± 10% of baseline Cp, with typical Cp values in the range of 7–12 mg/dl. Because there appears to be no untoward clinical effects from this degree of copper reduction, we have termed this level of copper deficiency "chemical copper deficiency." The first indication of true clinical copper deficiency is a reduction in blood cell counts, primarily anemia, because copper is required for heme synthesis as well as cellular proliferation (36) . Thus, the copper deficiency objective of this trial was to reduce the Cp to 20% of baseline without decreasing the patient's Hct or WBC to below 80% of baseline value at entry.
Toxicity, Follow-Up, and Disease Evaluation.
Complete blood counts, liver and renal function tests, urinalyses, and Cp level were performed weekly for 16 weeks and then performed biweekly at the clinical laboratories of the University of Michigan Health System or at other affiliated certified laboratories. Physical examinations and evaluations of toxicity were carried out every 2 weeks for 8 weeks and then performed every 4 weeks for the duration of therapy. Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria. Extent of disease was evaluated at entry, at the point of achievement of copper deficiency (defined as Cp 20% of baseline), and every 10–12 weeks thereafter. CAT or magnetic resonance imaging was used as appropriate for conventional measurement of disease at all known sites and for evaluation of any potential new sites of disease. Angiogenesis-sensitive ultrasound with three-dimensional Doppler analyses was used in select cases as an adjunct to conventional imaging to evaluate blood flow to the tumors at different time points.
TM Preparation and Storage.
TM was purchased in bulk lots suitable for human administration (Aldrich Chemical Company, Milwaukee, WI). Because TM is slowly degraded when exposed to air (oxygen replaces the sulfur in the molecule, rendering it inactive; Refs. 34, 35, 36 ), it was stored in 100-g lots under argon. At the time a prescription was written, the appropriate dose of TM was placed in gelatin capsules by research pharmacists at the University of Michigan Health System. Previously, we had shown that TM dispensed in such capsules retained at least 90% of its potency for 8 weeks (34) . Thus, TM was dispensed to each patient in 8-week installments throughout the trial.
Measurement of Blood Flow.
Blood flow was measured by ultrasound in select patients with accessible lesions at the time they became copper deficient and at variable intervals of 8–16 weeks thereafter. Three-dimensional scanning was performed on a GE Logiq 700 ultrasound system, with the 739 L, 7.5 MHz linear array scanhead. The scanning and vascularity quantification techniques were as described previously by the authors (39 , 40) .
Patient Characteristics
Eighteen eligible patients (10 males and 8 females) with 11 different types of metastatic cancer who had progressed through or (in one case) declined other treatment options were enrolled in the trial in the order in which they were referred. Six, five, and seven patients were enrolled at the 90, 105, and 120 mg/day drug levels, respectively, following the protocol dose escalation schema. One patient originally assigned to the 105 mg/day level was removed early to pursue cytotoxic chemotherapy, due to rapid progression of disease. This same patient was later retreated at the 120 mg/day level for a longer duration; thus, he is counted only at the 120 mg/day level for the analyses. The average age was 59 years; the average baseline Cp was 47.8 mg/dl, which is elevated with respect to the normal level, reflecting the patients' disease status. Table 1 summarizes the patient characteristics for each dose level.
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