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Clinical Trials |
Departments of Otolaryngology [W. B. A., Q. A. N.] and Medicine [T. H. T., W. L., F. L. M.], Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California 92868; Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 [A. R. K., X. S. W.]; and Surgical [W. B. A.], Pathology [J. J.], and Dental [W. T.] Services, Veterans Affairs Medical Center-Long Beach, Long Beach, California 90822
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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The BBI3 is a soybean-derived serine protease inhibitor with both trypsin and chymotrypsin inhibitory activities (7) . It is also a potential cancer chemopreventive agent with anticarcinogenic activities at concentrations well below those of other potential chemopreventive agents identified in soybeans (8 , 9) . In vivo studies have demonstrated that BBI is able to prevent development of malignancies in a large number of animal model systems (10, 11, 12, 13, 14, 15, 16, 17, 18, 19) . BBIC, which contains active BBI and has the same anticarcinogenic profile as purified BBI (6) has been developed for human trials. BBI and BBIC are nontoxic in several animal species, and the results of pharmacokinetic and toxicity studies for BBIC have been summarized recently (6) . A phase I human chemoprevention trial in patients with oral leukoplakia demonstrated that BBIC had no acute toxicity when ingested p.o. as a troche (20) .
In addition to the clinical response of visible premalignant lesions, phase II chemoprevention trials often rely on modulation of biomarkers to help determine potential effectiveness of the compound, and the identification and development of potential SEBMs is an important goal of phase IIa and IIb trials. We previously studied the levels of PA in cultured cells and tissues treated with ionizing radiation or chemical carcinogens as well as in tissues with higher than normal risks of cancer development (6 , 21, 22, 23, 24, 25) . We observed that exposure of cells to radiation and/or chemical carcinogens often leads to a prolonged elevation of PA (6) . In the hamster cheek pouch, BBI treatment suppressed the carcinogen-induced elevation of PA and inhibited development of malignant tumors (13) . We have also shown that elevated levels of PA are present in patients with oral premalignant lesions, in smokers, and in ex-smokers (24) . Because BBI is a serine-protease inhibitor with both trypsin and chymotrypsin activity (7) , the PA level in premalignant tissues should be a good candidate SEBM for oral cancer chemoprevention trials when BBIC is used as the chemopreventive agent.
Oral leukoplakia is an ideal model for the study of cancer chemoprevention because the lesions are readily accessible to visual examination, diagnostic sampling, and evaluation of response to treatment. In the present study, BBIC was administered daily as an oral troche for 1 month in a single-arm phase IIa trial in patients with oral leukoplakia, and the clinical and histological response, toxicity, oral mucosal cell PA, and serum micronutrient levels were evaluated.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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80); no history of
malignancy other than non-melanoma skin cancer within 5 years; presence
of bidimensionally measurable lesion(s); no prior high-dose vitamin A
(up to 2 multivitamin pills/day allowed), high-dose ß-carotene (no
supplements), or retinoid therapy; willingness to have periodic
photographs to document findings; ability to travel to appointments;
and if female, not pregnant and using an appropriate contraceptive
method. A baseline oral mucosal cell PA >1.5 times normal was also
required for inclusion. Blood and urine were obtained from patients prior to enrollment. Serum was obtained for sequential multichannel AutoAnalyzer-20 (SMA-20; total protein, albumin, uric acid, blood urea nitrogen, creatinine, glucose, sodium, potassium, chloride, CO2, calcium, phosphorous, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, cholesterol, and triglyceride), amylase, lipase, ß-carotene, retinol, vitamin E, and blood for a complete blood cell count. Eligibility requirements included hematocrit >35%, white blood count >4000 cells/mm3 , platelet count >100,000 platelet/mm3 , serum creatinine <1.5 mg/dl, bilirubin <2.0 mg/100 ml, and aspartate aminotransferase or alanine aminotransferase <2.0 times normal. In addition, urinalysis had to show less than 1+ protein, 0–3 casts, or 5 WBCs or RBCs.
Prestudy Evaluation
All participants signed an informed consent approved by the
Institutional Review Boards of the University of California Irvine or
the Long Beach Veterans Affairs Medical Center. Participants had
medical, tobacco, alcohol, drug use, and dietary histories taken. Urine
was obtained for urinalysis. Oral examination was performed, and
clinical lesions were measured, photographed, and recorded on diagrams.
Oral mucosal cell brushings were analyzed for PA. Punch biopsies (3 mm)
were taken from the lesion and from an uninvolved control site after
infiltration with local anesthetic. Counseling and education about the
carcinogenic risks of tobacco and alcohol were discussed, and subjects
were offered referral to counseling and/or cessation programs.
Patient Treatment
Eligible subjects received BBIC in doses ranging from 200 to 1066
CIU per day (Central Soya Company, Inc., Fort Wayne, IN). Drug was
dispensed as a powder that was reconstituted in Roxane Saliva
Substitute (Roxane Laboratories, Columbus, Ohio) immediately before
use. Patients were instructed to hold the BBIC suspension in the mouth
for 1 min and then swallow. BBIC was administered twice daily for 1
month. Drug administration was planned as a sequential dose escalation
trial. However, because of a complex dosing calculation error
discovered early in the trial, the dosage administration was as
follows: subjects 1–11 received 533 CIU, subjects 12–15 received 1066
CIU, subjects 16–23 received 200 CIU, and subjects 24–32 received 800
CIU.
After completion of 1 month of drug therapy, repeat history and oral examination were performed. The oral cavity lesions were measured, photographed, and recorded on diagrams. Oral mucosal cell brushings, biopsies of lesions and control sites, and serum and urine were again obtained for the same studies performed at enrollment.
Adherence Information and Symptom Monitoring
Patient adherence to the 28-day program was monitored by container
count, self-reported compliance through a personal diary, and patient
interviews. Patients receiving study medication were observed at
initial ingestion for toxic or allergic reactions. Subjects were
contacted by telephone after 2 weeks and underwent a personal interview
at study completion to inquire about side effects, palatability, and
potential toxicity through an open-ended interview process, which
included specific questions about the occurrence of nausea, vomiting,
diarrhea, anorexia, fatigue, oral soreness, epigastric pain, and drug
palatability. Toxicity was monitored using a graded toxicity scale.
Grade 1 (mild) toxicity was followed for symptomatic progression. A
physician was required to evaluate grade 2 toxicity within 48 h to
determine the cause and significance of the toxicity, and drug therapy
was temporarily suspended until a determination was made on whether the
patient would be continued on the trial. Grade 3 toxicity mandated
immediate evaluation by a physician and drug stoppage; the patient was
removed from the study unless a clear alternative explanation for the
symptoms was promptly determined. Palatability was assessed using a
four-point scale: 0 = tastes fine with good medication compliance;
1 = tastes fine with sweetener, good medication
compliance; 2 = tastes bad, with good medication compliance; and
3 = tastes bad, with poor medication compliance.
Assessment of Clinical Response
Clinical response was assessed by recording bidimensional area of
lesions as well as observing changes in color, thickness, and elevation
of the lesions. Multiple lesions were recorded individually, with
lesion areas summed into a total for each subject. Individual lesions
were photographed (35-mm film, 100-mm macro lens and ring flash) during
both the pre- and posttreatment oral examinations. Clinical response
was prospectively defined as follows. Complete clinical response was
defined as complete disappearance of all lesions at completion of
treatment. PR was classified as at least 50% decrease in total lesion
area. No response was classified as between a <50% decrease and 50%
increase in total lesion area. Progression was classified as at least
50% increase in total lesion area, or development of new lesion(s).
For each lesion, the pre- and posttreatment photographs (4 x 6-inch color prints) were mounted on the same page of an album, with relative position determined by a randomization scheme such that, within each dose, the pretreatment photo was in the superior position half the time. The order of pages in the album was randomized such that there was no relationship between dose and page number in the album. Four physicians with experience evaluating oral lesions and who had no contact with the study subjects made independent, comparative judgments of the upper and lower photographs on each page. Independent indications of clinical differences between the two photos in each pair were made. The evaluators selected from seven alternative statements that ranged from "top photo shows a complete response relative to the bottom photo," through "top and bottom photo show the same degree of disease," to "bottom photo shows a complete response relative to the top photo." The statistician later broke the code and transferred the responses to a seven-point Likert scale (26) . Lesions for which photographs were unsuitable or missing were excluded from this analysis. The analysis was based on 204 judgments (55 paired photographs were reviewed by four reviewers). A total of 16 judgments were not included in the analysis because of perceived poor quality of the images by the evaluators.
Histopathological Analysis
Specimens were processed in a standard manner with fixation in
10% neutral buffered formalin. Each biopsy was step-sectioned and
stained with H&E. The biopsies were evaluated for the presence of
hyperkeratosis, parakeratosis, acanthosis, inflammation, dysplasia, and
malignancy. For purposes of this study, dysplasia was defined as
neoplastic epithelium confined within the basement membrane of the
stratified squamous epithelium within which it arose. The degree of
dysplasia was graded using the terminology of low-grade dysplasia,
high-grade dysplasia, and atypia. The criteria for grading dysplasia
were as follows:
Laboratory Procedures
Collection of Oral Mucosal Cells and Serum.
Oral mucosal cell collection was performed atraumatically using
techniques developed in our earlier studies (27)
. Subjects
were instructed not to brush their teeth the morning of oral mucosal
cell collection. After patients rinsed their mouths twice with tap
water, they were instructed to place 
15 ml of sterile PBS in their
mouths and gently brush the entire inside surface of the mouth with a
cytology brush. The cells brushed into the saline solution were
collected into a 50-ml conical tube. The mouth and cytology brush were
rinsed with 30 ml of PBS, the rinse was collected into a 50-ml
centrifuge tube, and the cells were centrifuged at 5000 rpm for 5 min
at 4°C. The supernatant was removed, and the cell pellet was stored
at -70°C until the assays were performed. Approximately 1 to 6
million cells could be easily and comfortably collected in this manner.
Collected blood samples were allowed to clot and centrifuged at 1500
rpm for 10 min to separate the blood clot from the serum. The serum
samples were saved and stored at -70°C before analysis.
Oral Mucosal Cell PA Measurements.
Oral mucosal cell PA was determined as described previously
(28)
. PA was measured by the Boc-Val-Pro-Arg-MCA substrate
hydrolysis method, and the results were expressed as number of
µM of substrate hydrolyzed per hour per µg of sample
protein (µM/h/µg).
Micronutrient Analysis.
Approximately 4 ml of fasting blood per subject was collected by
venipuncture into a foil-wrapped, green-top (heparinized) Vacutainer
and immediately placed on ice. The blood was centrifuged at 1200 x g for 10 min at 4°C, and the plasma was transferred
into two microcentrifuge tubes (Intermountain Scientific Corp.,
Bountiful, UT), at 1 ml/tube, and stored at -70°C. The samples were
shipped to The Arizona Cancer Center periodically for micronutrient
(carotenoids, retinoids, and tocopherols) analysis using previously
published methods (29
, 30)
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Statistical Methods |
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Bivariate relationships were summarized by the Pearson correlation coefficient, and trend lines were fitted by the least-squares criterion (32) . Judgments of photographs were analyzed by one-way (BBIC dose), nonparametric ANOVA using the Kruskal-Wallis test (33) . Ordinary, simultaneous multiple regression was used to estimate the residual association of BBIC and total lesion area, adjusting for pretreatment PA (32) .
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RESULTS |
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Clinical response (PR + CR) was demonstrated in 10 of 32 subjects
(31%; 95% confidence interval, 18–49%). There were two CRs and
eight PRs. Progression, defined as a >50% increase in total lesion
area or appearance of new lesions, was found in two subjects (outliers,
described below). The clinical results are tabulated in Table 1
. Blinded judgments of lesion photographs by four physicians showed a
dose-dependent (P < 0.01) increase in mean clinical
response scores after BBIC treatment (Table 2)
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. The mean pretreatment total lesion area was of 615
mm2 (range, 40–5270 mm2)
and decreased to 438 mm2 (range, 0–5030
mm2) after BBIC treatment. This represents a
24.2% decrease in total lesion area across all doses administered
(sign rank = -142; P < 0.004). For the 75
individual lesions in the data set, 44 (58.7%) showed an arithmetic
decrease in size, 11 (14.7%) remained arithmetically the same, and 20
(26.7%) showed an arithmetic increase in size. The null hypothesis (no
change in lesion size after BBIC treatment) was rejected by the
sign-rank test (sign rank = -142; P < 0.004).
The relative percentage of change in total lesion area for each subject
versus dose of BBIC is shown in Fig. 2
, with a best-fitting (least-squares) trend line superimposed on the
data. An increased dose of BBIC was associated with a decrease in
lesion area (P < 0.08; Pearson two-tailed
r = -0.32). Two outliers in the 800-CIU dose group who
registered increased total lesion areas after drug treatment greatly
influenced these data. One of the two patients had a very subtle lesion
observed at completion of treatment that had not been identified as
abnormal at initial examination. The other patient developed a new
lesion at the site of the prior control biopsy of normal-appearing
mucosa, which accounted for the entire increase in total lesion area
observed in this patient. Exclusion of both outliers produced a
stronger correlation (P < 0.001; Pearson two-tailed
r = -0.60).
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;r = -0.44; P < 0.02;
n = 30). A possible relationship between initial PA and
relative change in total lesion area after BBIC treatment was
determined (Fig. 4
;r = 0.28; P < 0.12; n = 31), but this did not reach statistical significance. There was no
evident relationship between pre- and posttreatment mucosal cell PA
levels (Fig. 5
; sign rank = 34.5; P < 0.49; n =
30). The distribution of pretreatment PA values among subjects
receiving different doses of BBIC was comparable between dosing groups
(P < 0.27; n = 31; ANOVA, data not
shown).
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Symptom Monitoring, Side Effects, and Compliance.
No acute toxic or allergic reactions were documented. Grade 1 nausea,
diarrhea, and oral soreness were recorded in one patient each at 2
weeks. After 4 weeks of BBIC treatment, grade 1 nausea was observed in
two subjects, and grade 1 diarrhea, oral soreness, and epigastric pain
were each observed in one patient. No grade 2 or higher side effects
were observed in any subject during the study.
At 2 weeks, 24 of 32 patients rated the palatability as grade 0, 2 as grade 1, 6 as grade 2, and 0 as grade 3. At 4 weeks, palatability decreased. Only 14 of 32 patients rated palatability as grade 0, 4 rated palatability as grade 1, 14 as grade 2, and 0 as grade 3. Despite the high percentage of patients describing poor palatability, compliance in this trial was very high. Overall doses, the average number of bottles not returned and presumed used, exceeded 92% of expected. More than 80% compliance as measured by bottle count was obtained in 29 of 32 subjects (90.6%).
Standard Laboratory Test Changes.
No evidence of toxicity was identified in the serum tests performed
after BBIC administration. The majority of laboratory values (SMA-20
and complete blood count) were within the test reference ranges both
before and after treatment, and there were no patterns of major shifts
in normal pretreatment serum values to abnormal values after BBIC
treatment. Compared with the respective pretreatment values, the mean
serum sodium increased from 137.8 to 139.0 meq/l (n =
24; P < 0.04), mean serum glucose decreased from 119.5
to 92.4 mg/dl (n = 24; P < 0.03), and
mean serum lipase decreased from 13.3 to 9.6 units/dl
(n = 25; P < 0.04). One subject had a
marked decrease of an elevated serum glucose level from above the
reference range before treatment (327 mg/dl) to below reference range
after treatment (68 mg/dl) that accounted for the majority of the shift
in the mean value of the group seen for this test.
Micronutrients.
The serum levels of ß-carotene, vitamin E, and retinol did not change
significantly after 1 month of treatment with BBIC either as a function
of dose or across all doses combined (P > 0.23 for all
three). No relationship was observed between the percentage of
reduction in lesion area and change in or initial value of
ß-carotene, vitamin E, or retinol (P > 0.17 for
all).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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It has been reported that leukoplakia can respond to treatment with retinol or other retinoids, and/or vitamin E (34, 35, 36) . In the present trial, the decrease in oral lesion areas observed after BBIC treatment was not related to alterations in levels of these three compounds because no relationship between changes in these micronutrients and clinical response was observed.
There appeared to be a possible direct interaction between the
pretreatment oral mucosal cell PA level and clinical response (Fig. 4)
.
Patients with lower initial PA levels tended to have an overall greater
clinical response than patients with elevated PA (Fig. 4)
. Because
these data suggest that the baseline PA may affect clinical response to
BBIC, an ordinary, simultaneous least-squares multiple regression was
performed on the data, where clinical response was modeled by an
intercept, baseline PA, and dose to adjust for initial PA level
(37)
. The model estimates coefficients for dose and for
baseline PA, each adjusted for the effects of the other. The model was
used to generate predicted values of clinical response as a function of
dose, fixing the baseline PA at the average value for all patients in
the study for whom we have data, regardless of dose. The predicted
results, shown in Fig. 6
, demonstrate that after accounting for the effect of initial PA level,
the dose-response relationship remained intact.
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was identified. This finding suggests that BBIC may reduce
elevated levels of PA but does not affect PA levels when they are
within a normal range. This is consistent with previous observations
that BBI or BBIC can lower elevated levels of other biomarkers such as
c-fos (38
, 39)
and c-myc
(39
, 40) when they are abnormally elevated, while not
affecting to a significant degree the normal levels of expression of
these biomarkers (see Ref. 6
for a review).
The mechanisms of BBI chemopreventive activity remain unknown. PA is a
potentially useful biomarker for chemoprevention trials using BBIC.
Although a possible relationship between lowered initial PA and
relative decrease in total lesion area was seen (Fig. 4)
, no
correlation between change in PA and clinical response was found. There
are several possible reasons for this. One likely reason is the short
duration of this trial, which is a standard length for these types of
studies. The tissues undergo dynamic changes secondary to drug
administration and may not have reached a steady state by the end of
the study. We would anticipate that the effects on biomarkers would be
more pronounced with more prolonged drug administration. This problem
is inherent with the phase IIa study design, which has the dual purpose
of identifying toxicities and determining whether there is sufficient
clinical response or change in other biomarkers to warrant a longer
term randomized placebo controlled trial.
Another confounding factor may be that the oral mucosal cell harvest technique did not collect a high proportion of dislodged epithelial cells from the clinically observed lesions. Because the oral mucosal cell brushings represent cells obtained throughout the oral cavity, it is possible that the changes of SEBMs in cells collected from the lesions were masked by a lack of change in the same SEBMs in uninvolved epithelial cells. In future trials, this issue could be addressed by collecting oral scrapings (35 , 41) directly from lesion sites as well, but we have found that this is surprisingly difficult to do for a number of technical reasons and may not be reliable. The biological heterogeneity of clinically observed lesions may also contribute to the apparent lack of correlation between cellular PA levels and clinical response.
No significant histological changes were identified in this trial. This is not surprising given the short duration of the trial. The population had a very low incidence of dysplasia, present in only 2 of 32 subjects. However, the absence of dysplasia does not adequately predict that patients will have a low risk of eventually developing malignancy (42 , 43) . After the BBIC trial, two patients were known to have subsequently developed cancers. One subject developed a T1N2cM0 squamous cell carcinoma of the soft palate 4 months after study completion, and a second subject developed a T1N0M0 squamous cell carcinoma of the oral tongue 16 months after study completion. Both tumors developed at the sites of documented lesions. Review of biopsy specimens from both cases confirmed absence of dysplasia in all pre- and posttreatment biopsy specimens. The development of two malignant transformations is within the range observed in "studies of oral premalignancy." Published malignant transformation rates are variable for oral leukoplakia, and range from 0.13% in an Indian population to >6% in a series in the United States (42 , 44) . Transformation rates are also dependent on the location in the oral cavity as well (42 , 43) . Both subjects that developed squamous cell carcinoma had lesions at high-risk sites for malignant transformation. Given the fact that BBI is an extract of a food product that was administered in doses near that ingested in the Japanese diet, it is extremely unlikely that BBI acted as a procarcinogen.
BBIC was well tolerated by the patients, with an over 90% overall compliance rate. The palatability of BBIC suspension did not affect compliance, and no clinical or laboratory evidence of toxicity or drug allergy was observed other than infrequent reporting of nausea, diarrhea, or epigastric discomfort, which did not seem related to drug ingestion. The population in this trial was extremely motivated, and it is expected that the compliance over a longer term of administration in future trials will not change significantly. Although statistically significant changes in mean sodium, glucose, and lipase values were seen for the group as a whole, the changes were not clinically significant and do not appear to represent clinical toxicity to BBIC. These results suggest that BBIC is safe to be used as a cancer chemopreventive agent at the doses tested in this trial.
Chemoprevention is an important and viable strategy to decrease cancer incidence and mortality. In this short-term clinical trial, BBIC demonstrated clinical activity on oral leukoplakia lesions with no dose-limiting toxicity. The analysis of SEBMs tested in this trial support our hypothesis that BBIC acts through modulation of PA in premalignant cells. Subsequent trials are planned to better define the utility of PA as a candidate biomarker. The dose-dependent decrease in oral leukoplakia lesion area and the lack of clinical toxicity observed after BBIC treatment indicate that this compound should be assessed in a randomized clinical trial.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by Grants U01-CA46496 and
P30CA 62203 from the National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at Chao Family Comprehensive Cancer Center, 101 The City
Drive South, Orange, CA 92868. E-mail: FLMeyske{at}UCI.edu
3 The abbreviations used are: BBI, Bowman-Birk
inhibitor; BBIC, BBI concentrate; SEBM, surrogate end point biomarker;
PA, protease activity; CIU, chymotrypsin inhibitory unit(s); PR,
partial response; CR, complete response.
Received 7/ 3/00; revised 9/21/00; accepted 9/26/00.
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