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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.]
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ABSTRACT |
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 Top ABSTRACT IntroductionPatients and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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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.
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Patients and Methods |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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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) .
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Results |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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summarizes the
patient characteristics for each dose level.
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Cp as a Surrogate Measure of Copper Status
Fig. 1
shows the response of Cp as a
function of time on TM therapy, expressed as the ratio of Cp at time
t to baseline Cp level for each patient enrolled at the 90,
105, and 120 mg/day dose levels. Increasing the in-between meals dose
from 10 mg three times daily to 15 or 20 mg three times daily had no
significant effect on the rate of decrease of the Cp level, reaching a
level of 50% baseline at a mean of 30 days (median = 28 days).
The response of Cp to TM therapy as a function of time exhibited only
minor fluctuations; when TM was discontinued, a rapid rise in Cp was
observed within 48 h.
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Dose Adjustments to Maintain Target Cp
TM doses were adjusted to maintain a Cp target level of 20% of
baseline and to prevent absolute Cp values < 5 mg/dl. Due to the
routine 7-day turn-around for the Cp test at our laboratory, these dose
changes were made approximately 7–10 days after the blood for the Cp
measurement was taken. After achieving the target Cp, the in-between
meals dose was typically decreased by 20 mg. Further decreases of
15–30 mg were necessary during long-term therapy. A patient with
metastatic chondrosarcoma secondary to radiation treatment for breast
cancer on long-term therapy has stable disease after 12 months of
copper deficiency, with stable quality of life. One biopsy-proven
metastatic nodule on her third digit is easily measurable and has been
stable. Other sites of suspected disease in the chest also remain
stable. Interestingly, this patient has required only a minor
adjustment to her TM dose from the initial loading dose level to
maintain the target Cp throughout this relatively long period. Fig. 2, A and B
,
illustrates the Cp response to dose adjustments required for two more
representative patients over approximately 100 days of therapy. Thus
far, the patient in Fig. 2A
has required only decreases in
dose 60 days apart. Most patients have required both an increase and a
decrease in dose during long-term therapy. For example, as shown in
Fig. 2B
, the TM dose was increased after day 100 to respond
to an increase in Cp outside the target range. Overall, there was
considerable individual variability in the dose adjustments required.
In conclusion, the Cp response to TM therapy evaluated weekly is not
brittle or subject to wide fluctuations.
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summarizes the clinical course of the
18 patients.
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The remaining six patients experienced stable disease (five of six patients) or progression of disease at one site, with stable disease elsewhere (one of six patients). Two patients who have stable disease by standard criteria also experienced complete disappearance of some lung lesions and a decrease in the size of other lung lesions during observation periods at target Cp of 120 and 49 days. The five patients on long-term (>90 days) maintenance therapy with stable disease have been copper deficient for 120–413 days at the time of this analysis.
Radiological Evaluation.
Serial evaluations of tumor masses by conventional imaging with CAT
scan or magnetic resonance imaging revealed that the radiographic
appearance of certain masses changed significantly over time. In
particular, areas of presumed central necrosis (corresponding to lower
attenuation of the X-ray signal) were observed in a variety of tumor
types, most notably renal cell cancer, angiosarcoma, and breast cancer.
Seeking to evaluate the blood flow to the tumors as a function of time
during copper deficiency on long-term TM therapy, lesions accessible to
ultrasound were imaged with color flow three-dimensional ultrasound at
the onset of copper deficiency and at 2–4-month intervals thereafter.
A representative example of the comparison between conventional CAT
scan images and blood flow-sensitive three-dimensional ultrasound is
depicted in Fig. 3
. Here, a rib
metastasis from renal cell carcinoma is depicted when the patient
reached target copper deficiency (Fig. 3, A and C)
and 8 weeks later (Fig. 3, B and D)
by these two complementary imaging modalities. Fig. 3, A and B
, shows stable size of this lesion by CAT scan over time,
although a more distinct region of probable central necrosis is
observed in Fig. 3B
. In comparison, the color pixel density
shown in Fig. 3, C and D
, is the fraction of
image voxels within the margins of the mass filled with color flow
signals. There has been a 4.4-fold decrease in blood flow to this mass
over a period of approximately 8 weeks. In addition to the mass
depicted in Fig. 3
, this patient had extensive disease in the chest,
pelvis, and femurs.
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.
Two patients with extensive angiosarcoma of the face and scalp achieved
stable disease on TM. In one patient with severe chronic bleeding from
an ocular lesion that threatened the orbit, IFN-
2 was added to TM to
attempt to enhance tumor response. Given the suggestion that, based on
studies of progressing hemangiomas, the use of low-dose IFN may be
efficacious for the treatment of hemangioma (41)
, IFN-
was administered to both of these patients at a dose of 500,000 units
s.c. twice a day. Radiotherapy was also given to these two patients
while on TM to attempt to control actively bleeding (but not
progressing) lesions. Both patients had disease stabilization for >60
days, with one of these patients remaining with stable disease for over
5 months before discontinuation of therapy due to patient choice. No
exacerbation of toxicity was observed by the addition of any of these
treatment modalities to TM.
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Discussion |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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summarizes the stages of copper
deficiency in humans and their clinical characteristics. This
information was derived from studies of patients with Wilson’s
disease, from occasional patients with chemical and clinical copper
deficiency, and from copper-deficient small rodents. Note that as Cp is
reduced below 5 mg/dl, it becomes an insensitive marker of the degree
of copper deficiency. However, based on observations in humans with
normal copper metabolism from this trial, we find that Cp is a
sensitive and valid marker of copper status for levels above 5 mg/dl.
This key finding allows the targeting of the antiangiogenic window of
copper deficiency that appears to be required to slow or arrest tumor
growth.
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As a result of this study, it is apparent that with our present TM dose regimens, there is considerable lag between the initiation of TM therapy and the reduction of copper levels in tumors to a likely antiangiogenic level. Further retarding the ability to reach antiangiogenic levels of copper deficiency is the likelihood that most tumors sequester copper (42, 43, 44, 45) . Thus, it is reasonable to hypothesize that additional time may be required to deplete the tumor microenvironment to an effectively low level of copper, which is defined as a level low enough to inhibit angiogenesis. It is difficult to estimate this time accurately from our study. Thus, patients with very rapidly progressive large tumors may be relatively poor candidates for this approach to antiangiogenesis therapy as a single modality.
Another level of complexity is added by the fact that in bulky disease,
initially effective antiangiogenesis may cause brisk tumor necrosis, as
was documented in the mass shown in Fig. 3
. Tumor lysis may result in
the release of additional copper from the dying cells. In the case of
the patient whose mass is shown in Fig. 3
, a transient rise in Cp was
observed at approximately the same time as the ultrasound suggested
that the large tumor mass might be undergoing central necrosis due to a
significant decrease in blood flow. For these reasons, we conclude that
a period of 60–90 days of Cp at the target level of 20% of baseline
is a reasonable starting point for evaluation of response to anticopper
therapy in future trials in patients with measurable disease. In the
two patients who exhibited partial regression of lung lesions, tumor
control may have begun earlier. It is also interesting to note that in
both of these patients, the lung parenchymal metastases were the sites
of tumor regression. It is possible that mild clinical copper
deficiency impairs superoxide dismutase function (46)
so
that under conditions of high oxidant stress, such as those present in
the lung, the metastatic foci are more susceptible to oxidative damage.
Despite individual differences, the use of three-dimensional ultrasound to determine the total blood flow to a given mass demonstrates that maintenance of mild copper reduction to 20% of baseline induced for at least 8 weeks appears sufficient to alter tumor blood flow. Due to the relative insensitivity of CAT to the blood flow or metabolic status of the lesions, parallel imaging modalities, as demonstrated here for three-dimensional ultrasound, will be required to assess functional response in addition to tumor size.
In light of the data presented above, we advance the preliminary conclusion that the size of solid tumors of a variety of types may be stabilized or decreased by TM, given sufficient time in a state of mild clinical copper deficiency represented by a decrease in Cp to or below 20% of baseline, as defined by this study. Among the patients maintained at the target Cp level for more than 90 days, a significant proportion of cases (five of six) were stabilized, with no detriment to their quality of life. However, in this population of patients with advanced disease, only 39% of those treated were able to be maintained at the target Cp for this duration.
The pattern and speed of progression observed in these patients have also provided useful preliminary information. One patient achieved stable disease at all sites but one and has chosen to remain on TM therapy due to disease stabilization at the more life-threatening sites of disease (bowel and paratracheal lymph nodes; the site of progression in this patient with melanoma is a large adrenal metastasis. This and other observations in this trial suggest that whereas copper deficiency may be generally inhibitory of angiogenesis, heterogeneity of tumor type and the specific location of metastases may modulate the response to this therapeutic modality. The small number of patients in this study and the design of this study preclude more detailed conclusions regarding efficacy at specific metastatic sites. Because it appears that lesions progress at a much faster rate on copper repletion than while on TM therapy, future trials may formally incorporate the use of adjunct modalities, either systemically or loco-regionally, to address the specific sites of progression while allowing the patients to remain in a copper-deficient state.
We report preliminary observations of combination therapies of TM with
radiotherapy, trastuzumab, and IFN- without apparent exacerbation of
toxicity of the added modality. Taken as a whole, the safety and
preliminary efficacy data derived from this trial support the conduct
of additional studies designed to test the specific efficacy of TM
alone or in combination for the treatment of early metastatic disease,
minimal disease, and in adjuvant high-risk clinical settings,
including chemoprevention.
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FOOTNOTES |
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1 Supported by NIH Grants RO3-CA-77122 (to
S. D. M.), P30-CA46592 (to M. W.), and MO1-RR00042 (to the General
Clinical Research Center); the Tracy Starr Award from the Cleveland
Foundation (to S. D. M.); a grant from the Tempting Tables
Organization (to S. D. M.); and donors to the University of Michigan
Comprehensive Cancer Center. 
2 To whom requests for reprints should be
addressed, at University of Michigan Comprehensive Cancer Center, 7217
CCGC, 1500 East Medical Center Drive, Ann Arbor, MI
48109-0948.
3 The abbreviations used are: TM,
tetrathiomolybdate; Cp, ceruloplasmin; Hct, hematocrit; GI,
gastrointestinal; CAT, computer-assisted tomography.
Received 7/19/99; revised 11/ 1/99; accepted 11/ 9/99.
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