0022-5347 /92/1471-0031$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 147, 31-33, January 1992 Printed in U.S.A.
PHASE 1 TRIAL OF ORAL BROPIRIMINE IN SUPERFICIAL BLADDER CANCER MICHAEL F. SAROSDY,* DONALD L. LAMM, RICHARD D. WILLIAMS, TIMOTHY D. MOON, ROBERT C. FLANIGAN, E. DAVID CRAWFORD, NANCY E. WILKS, ROBERT H. EARHART AND JAMES A. MERRITT From the Departments of Urology, University of Texas Health Science Center, San Antonio, Texas; West Virginia University School of Medicine, Morgantown, West Virginia; University of Iowa, Iowa City, Iowa; Tulane Medical Center, New Orleans, Louisiana; Loyola University Medical Center, Maywood, Illinois; University of Colorado Health Sciences Center, Denver, Colorado, and Upjohn Co., Kalamazoo, Michigan
ABSTRACT
A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted. KEY WORDS: BCG vaccine; carcinoma, in situ; bladder neoplasms; carcinoma, transitional cell; interferon inducers
Transitional cell carcinoma of the bladder is diagnosed in more than 45,000 new patients annually in the United States, although the death rate from bladder cancer is beginning to decrease. 1 Part of the reason for the latter finding may be an aggressive approach to the problem of recurrent tumors in those with superficial disease. This has included the use of bacillus Calmette-Guerin (BCG) vaccine in patients who fail intravesical chemotherapy as well as those with carcinoma in situ.2-6 Although BCG is clearly an effective agent, at least 25% of the patients will fail to respond or have relapse and intraves ical therapy with BCG is accompanied by at least moderate side effects. 7 BCG therapy also recently has been identified as the cause of death in at least 7 patients.8 The mechanism of action of BCG appears to be through immune stimulation, primarily of cell-mediated cytotoxicity. Responses to intravesical interferon as well as other biological response modifiers prompted us to investigate other potential immunotherapeutic compounds for activity against transitional cell cancer. Based upon several studies demonstrating activity in murine bladder tumor experiments,9-11 a phase 1 trial was designed to evaluate the oral compound bropirimine in patients with measurable superficial bladder cancer and/or carcinoma in situ. The objectives of the trial were to determine a maxi mally tolerated dose and toxicity of bropirimine when given on 3 consecutive days each week, and to estimate the safety and efficacy of this compound against superficial bladder cancer and carcinoma in situ.
least 1 other agent, including thiotepa, doxorubicin, mitomycin C or BCG. Initially, patients with unresected marker tumors were considered eligible only if they were not candidates for transurethral resection due to over-all health or location of the tumor. This requirement was dropped when bropirimine was recognized to have activity against transitional cell carcinoma. No previous radiotherapy or intravesical chemotherapy within 4 weeks was allowed. All patients were required to have a negative prostatic urethral biopsy, an Eastern Cooperative On cology Group performance status of O to 2, a serum creatinine of less than 2.5 mg./dl., total bilirubin of less than 2.0 and transaminases of less than 1.5 times the upper limit of normal. Institutionally approved informed consent was obtained from all patients. Treatment schedule. Patients were entered consecutively into groups of 5 at progressively higher drug dosage levels following toxicity assessment of patients at previous dosage levels (table 1). Bropirimine was administered in 3 equal doses every 2 hours beginning at suppertime for 3 consecutive days and repeated weekly. Patients obtaining a complete response at 12 weeks were maintained on the same schedule for 1 year, while those with a partial response were maintained on the drug for an additional 12 weeks at the discretion of the treating physician. Patients with no response at 12 weeks were removed from the study and treated at the choice of the physician. Measurement of response. For patients with papillary tumors only cystoscopy was performed after 12 weeks of therapy and the marker tumor was visualized. For patients with carcinoma in situ bladder barbotage was obtained for cytological study,
MATERIALS AND METHODS
Patients. To be eligible for entry patients were required to have pathologically proved carcinoma in situ and/or unresected papillary tumors. Those with carcinoma in situ were required to have a positive cytology study on a barbotage specimen after biopsies were obtained, and were not required to have failed prior intravesical chemotherapy or immunotherapy. Patients with papillary tumors were required to have proved refractory to or to have relapse after prior intravesical therapy with at
TABLE 1. Bropirimine dose levels
Accepted for publication May 17, 1991. * Requests for reprints: Division of Urology, 7703 Floyd Curl Dr., San Antonio, Texas 78284-7845.
Level
Dose (mg.)*
Daily Dose (mg.)
1 2 3 4 5 6
500 750 1,000 1,250 1,500 1,750
1,500 2,250 3,000 3,750 4,500 5,250
* Administered every 2 hours for 3 doses, then daily for 3 consecutive days and repeated weekly for 12 weeks.
31
32
SAROSDY AND ASSOCIATES
and biopsies of previously positive areas, suspicious areas and uninvolved areas were obtained. Responses were classified as complete-complete resolution of carcinoma in situ confirmed by negative biopsy and benign cytology, or disappearance of marker transitional cell carcinomas; partial-significant but incomplete resolution of carcinoma in situ documented by less extensive disease at biopsy but persistent disease on biopsy and cytology, or decrease in size and/or number of papillary tumors but incomplete disappearance, and no response-categories of disease status not defined by the complete and partial response criteria, such as persistent carcinoma in situ with or without transitional cell carcinoma (stage Ta, grade 1 or 2) without a documented significant progression of carcinoma in situ. For patients with a complete response who remained on study, cystoscopy and barbotage for cytological analysis were repeated every 3 months. Toxicity assessment. Patients were followed weekly for the first 4 weeks of therapy with assessment of performance status, complete blood count and serum chemistry studies. The same parameters were then followed monthly until study termination or patient withdrawal. RESULTS
Enrollment and toxicity. Of 34 patients enrolled in the study
32 were evaluable for toxicity, while 26 were evaluable for response. Toxicity was mild among the 32 patients evaluable for side effects. Two patients responded to modest decreases in assigned dosage, 1 for mild increase in liver enzymes that normalized after a 50% dose reduction, and 1 for nausea, vomiting and diarrhea that resolved with a 25% dose reduction. The only withdrawal from the study due to toxicity occurred at 2 months (skin rash probably not due to bropirimine). Other reasons for withdrawal or nonevaluability include 2 patients who refused followup cystoscopy and biopsies after 12 weeks of therapy. Two patients withdrew at their wishes between 4 and 12 weeks. Two patients had not met the eligibility requirements upon later pathological review. One patient was a compassion ate enrollment for unresectable transitional cell cancer of the urethra. Response. Of the 26 patients evaluable for response there were 6 complete and 2 partial responses (table 2). One partial response was in a patient with papillary tumor only and he had no additional tumor reduction with therapy beyond the initial 12-week course. All 6 complete responses were in patients with carcinoma in situ, 1 of whom also had a measurable papillary tumor that disappeared. The over-all response rate was 31% (95% confidence limits 13 to 49%) at 12 weeks, with 45% (95% confidence limits 16 to 75%) of 11 carcinoma in situ patients achieving a complete response. While complete responses in patients with carcinoma in situ were seen over the entire range of dose levels, a dose-response relationship was also evident (table 3). Among the 5 patients with carcinoma in situ only entered at dosage levels 1 and 2, 1 (20%) had a complete response. Among the 6 patients with carcinoma in situ only at higher dose levels 4 (66%) had a complete response. Notably, the only complete response in patients with combined carcinoma in situ and papillary tumor occurred at the highest dose level. Effect of prior therapy on response to bropirimine. Of the 26 patients evaluable for response 19 had received prior therapy with BCG and/or interferon, including 10 with carcinoma in TABLE 2. Responses seen by tumor type after 3 months of therapy
Response Measurable Disease Present Papillary Ca in situ only Ca in situ and papillary Ca Totals
Complete
Partial
None
0 5 1 6
1 1 0
9 5 4
2
18
Total No.
10 11 5
26
TABLE 3. Distribution of complete responses in patients with
carcinoma in situ after 3 months of therapy
Fraction With Complete Responses Dose Level
Ca in Situ Only
Ca in Situ and Papillary Tumor
1
1/4 0/1
0/2
2
3 4 5 6
1/2 1/1 1/1 1/2
0/0
0/0 0/2
0/0 1/1
situ only. One patient who previously had been rendered free of disease on intravesical interferon had relapse while off interferon and then attained a complete response to bropiri mine. Of 7 patients who failed BCG therapy 3 attained a complete response to bropirimine. One of 2 patients who had received both agents attained a complete response. In light of this dose-response relationship the 6 patients with carcinoma in situ only at dosage levels 3 through 6 were examined for prior therapy. Of the 4 patients who attained a complete response 3 had received prior BCG therapy and 1 had received no prior therapy. Of the 2 nonresponders 1 had failed BCG and 1 had received no prior therapy. Thus, of 4 patients who had failed prior BCG therapy 3 attained a complete re sponse to bropirimine at these higher dose levels. Durability of response. At the time of this report two-thirds of the patients have completed 12 months of therapy or had treatment terminated due to lack of response. Durability after completion of 12 months of therapy in those who were complete responders is not yet evaluable for the entire group. Table 4 represents the status of all patients who had experienced com plete response at least 3 months in duration at the time of this report. Patients 1 and 19 have completed 12 months of therapy and their treatment has been discontinued. Patient 1 remained free of disease with a negative cytology study 9 months after bropirimine was stopped. Patient 19 has just begun followup off of the drug. Patient 11 had evidence of recurrent disease at 12 months. Patient 21 was free of carcinoma in situ at 6 months but a papillary tumor developed and he was removed from the study. Patient 31 was free of all disease at 6 months but was switched to BCG due to anxiety. DISCUSSION
This phase 1 trial of oral bropirimine in patients with meas urable papillary transitional cell cancer or cytologically con firmed residual carcinoma in situ has demonstrated that bro pirimine is well tolerated at a dosage schedule that is clearly effective against carcinoma in situ and possibly effective against papillary tumors. Importantly, bropirimine was effective in some patients who had failed prior BCG therapy, as well as patients who had received prior immunotherapy with intraves ical interferon. This salvage effect of bropirimine was particu larly evident at the higher dose levels in which 3 of 4 patients who had failed BCG attained a complete response to bropiri mine. Bropirimine is an aryl pyrimidinone shown to have multiple immunostimulatory properties, including stimulation of endo genous interferon production, and antiviral and antitumor ac tivity.12-14 Bropirimine has been shown to potentiate cell-me diated cytotoxicity in multiple compartments, including the spleen, peritoneal exudate, lung, liver, peripheral blood and bone marrow. This activity has been shown by means of block ing studies and target cell discrimination to be natural killer cell-dependent as well as macrophage-dependent. Bropirimine induced natural killer cell activation may take place even in the absence of increased serum levels of interferon. It is possible
ORAL INTERFERON INDUCER IN CARCINOMA IN SITU OF BLADDER
33
TABLE 4. Durability of complete response in patients with carcinoma in situ only
Evaluation Point During Therapy (mos.) Pt. No
3
6
9
12
Complete response
Complete response
Complete response
Complete response
11 19
Complete response Complete response
Complete response Complete response
Complete response Complete response
Recurrence Complete response
21 31
Complete response Complete response
Complete responset
Present Status Remains in complete remission after 9 mos. off drug Just starting long-term followup
* Taken off study when a papillary tumor occurred, but still a complete response in regard to carcinoma in situ. t Still complete response but switched to BCG due to anxiety of patient and referring urologist.
that interferon, interleukin-1 and possibly other cytokines act synergistically to augment natural killer cell activity. A series of phases 1 and 2 trials of bropirimine in human cancers has demonstrated that bropirimine is capable of induc ing regression in some advanced cancers, some of these complete and long-lasting. 5 Responses have been seen at relatively nontoxic doses, such as in this trial in bladder cancer. Inter feron induction does occur within hours and may be boosted or primed by prolonged administration of the drug. Induction of circulating interferon is not necessary for responses to occur, since several have been seen in the absence of interferon induction. Stimulation of antibody-dependent cell-mediated cytolysis and natural killer cytolytic activity seen in animals has been shown to occur in patients in whom it was measured. In other trials bropirimine was seen to be relatively nontoxic when compared to other cytotoxic agents and biological re sponse modifiers of comparable clinical efficacy. Toxicity is generally dose and schedule dependent, and is similar in nature to symptoms associated with exogenous interferon administra tion. An association of higher grades of these toxicities with the detection of interferon suggests that much of the toxicity of bropirimine is related to its interferon-inducing potential. With the FANFT-induced transplantable murine transi tional cell carcinoma MBT-2, several in vivo studies have demonstrated activity of bropirimine. With intralesional injec tions directly into subcutaneously growing tumors in C3H mice, Simmons et al reported an antitumor effect approaching that of BCG. 9 Also, using the subcutaneous model in C3H mice but with oral administration of bropirimine Sidky et al demon strated a significant dose-dependent decrease in the tumor growth rate. 0 Sarosdy and Kierum reported a synergistic an titumor effect when BCG and bropirimine were administered in combination intraperitoneally using the MBT model devised by Pang and Morales. 1 1 Additionally, that study demonstrated a greater potentiation of cell-mediated cytotoxicity by bropiri mine than by BCG, with that response occurring earlier, lasting longer and being of greater magnitude. Several reports of the activity of intravesically administered recombinant a-2 interferon have confirmed that superficial bladder cancer may be an immunotherapeutically responsive tumor. 1 6• While the side effects of intravesical interferon are remarkably low, the drug cost required to obtain the 45% complete response rate in carcinoma in situ that was seen in 1 study might make this form of therapy impractical on a routine basis. An oral agent that is effective against superficial bladder cancer is highly desirable. Clearly, a phase 2 trial in patients with carcinoma in situ is warranted to corroborate the results obtained in our pilot study. If the activity of bropirimine against carcinoma in situ is confirmed, then its value as either a front line agent before BCG therapy or a second-line agent in BCG failures should be investigated. Based upon the synergy seen in the murine trial of combination therapy with bropirimine and BCG, this compound is presently also the leading candidate for 1
1
17
a clinical trial of BCG in combination with any currently available immunotherapeutic agent. REFERENCES
1. Silverberg, E. and Lubera, J. A.: Cancer statistics. CA, 38: 5, 1988. 2. Lamm, D. L.: Bacillus Calmette-Guerin immunotherapy for blad der cancer. J. Urol., 134: 40, 1985. 3. Brosman, S. A.: The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ. J. Urol., 134: 36, 1985. 4. Herr, H. W., Pinsky, C. M., Whitmore, W. F., Jr., Sogani, P. C., Oettgen, H. F. and Melamed, M. R.: Long-term effect of intraves ical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J. Urol., 135: 265, 1986. 5. Catalana, W. J., Hudson, M. A., Gillen, D. P., Andriole, G. L. and Ratliff, T. L.: Risks and benefits of repeated courses of intraves ical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 137: 220, 1987. 6. Sarosdy, M. F. and Lamm, D. L.: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 142: 719, 1989. 7. Lamm, D. L., Stogdill, V. D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1985. 8. Rawls, W. H., Lamm, D. L., Lowe, B. A., Crawford, E. D., Sarosdy, M. F., Montie, J.E., Grossman, B. H. and Scardino, P.: Fatal sepsis following intravesical bacillus Calmette-Guerin adminis tration for bladder cancer. J. Urol., 144: 1328, 1990. 9. Simmons, W. B., Reichert, D. F., Lucio, R. M. and Lamm, D. L.: Pyrimidinone interferon inducers in the treatment of murine transitional cell carcinoma. J. Urol., part 2, 129: 169, abstract 309, 1983. 10. Sidky, Y. A., Borden, E. C., Wierenga, W. and Bryan, G. T.: Inhibitory effects of interferon-inducing pyrimidinones on the growth of transplantable mouse bladder tumors. Cancer Res., 46: 3798, 1986. 11. Sarosdy, M. F. and Kierum, C. A.: Combination immunotherapy of murine transitional cell carcinoma using BCG and an inter feron-inducing pyrimidinone. J. Urol., 142: 1376, 1989. 12. Wierenga, W.: Antiviral and other bioactivities of pyrimidinones. Pharmacol. Ther., 30: 67, 1985. 13. Chang, A. Y.-C., Chuang, C., Pandya, K. J. and Wierenga, W.: Chemoprevention of 7,12-dimethylbenz-(alpha) anthracene (DMBA) induced rat mammary tumors by 2-amino-5-bromo-6phenyl-4(3H)-pyrimidinone (ABPP). J. Biol. Response Modi fiers, 5: 112, 1986. 14. Lotzova, E., Savary, C. A., Khan, A. and Stringfellow, D. A.: Stimulation of natural killer cells in two random-bred strains of athymic rats by interferon-inducing pyrimidinone. J. lmmunol., 132: 2566, 1984. 15. Rios, A., Stringfellow, D. A., Fitzpatrick, F. A., Reele, S. B., Gutknecht, G. D. and Hersh, E. M.: Phase I study of 2-amino5-bromo-6-phenyl-4 (3H)-pyrimidinone (ABPP), an oral inter feron inducer, in cancer patients. J. Biol. Response Modifers, 5: 330, 1986. 16. Williams, R., Sarosdy, M., Catalona, W., Chodak, G., Vogelzang, N., Freiha, F. and Torti, F.: Randomized trial of high vs. low dose intravesical interferon alpha 2-B (IFN-A2B) treatment of bladder carcinoma-in-situ (CIS). In: Proceedings of the 24th Annual Meeting of the American Society of Clinical Oncology, p. 121, abstract 467, May 1988. 17. Glashan, R. W.: A randomized controlled study of intravesical a2b-interferon in carcinoma in situ of the bladder. J. Urol., 144: 658, 1990.
Vol. 147, 31-33, January 1992 Printed in U.S.A.
PHASE 1 TRIAL OF ORAL BROPIRIMINE IN SUPERFICIAL BLADDER CANCER MICHAEL F. SAROSDY,* DONALD L. LAMM, RICHARD D. WILLIAMS, TIMOTHY D. MOON, ROBERT C. FLANIGAN, E. DAVID CRAWFORD, NANCY E. WILKS, ROBERT H. EARHART AND JAMES A. MERRITT From the Departments of Urology, University of Texas Health Science Center, San Antonio, Texas; West Virginia University School of Medicine, Morgantown, West Virginia; University of Iowa, Iowa City, Iowa; Tulane Medical Center, New Orleans, Louisiana; Loyola University Medical Center, Maywood, Illinois; University of Colorado Health Sciences Center, Denver, Colorado, and Upjohn Co., Kalamazoo, Michigan
ABSTRACT
A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted. KEY WORDS: BCG vaccine; carcinoma, in situ; bladder neoplasms; carcinoma, transitional cell; interferon inducers
Transitional cell carcinoma of the bladder is diagnosed in more than 45,000 new patients annually in the United States, although the death rate from bladder cancer is beginning to decrease. 1 Part of the reason for the latter finding may be an aggressive approach to the problem of recurrent tumors in those with superficial disease. This has included the use of bacillus Calmette-Guerin (BCG) vaccine in patients who fail intravesical chemotherapy as well as those with carcinoma in situ.2-6 Although BCG is clearly an effective agent, at least 25% of the patients will fail to respond or have relapse and intraves ical therapy with BCG is accompanied by at least moderate side effects. 7 BCG therapy also recently has been identified as the cause of death in at least 7 patients.8 The mechanism of action of BCG appears to be through immune stimulation, primarily of cell-mediated cytotoxicity. Responses to intravesical interferon as well as other biological response modifiers prompted us to investigate other potential immunotherapeutic compounds for activity against transitional cell cancer. Based upon several studies demonstrating activity in murine bladder tumor experiments,9-11 a phase 1 trial was designed to evaluate the oral compound bropirimine in patients with measurable superficial bladder cancer and/or carcinoma in situ. The objectives of the trial were to determine a maxi mally tolerated dose and toxicity of bropirimine when given on 3 consecutive days each week, and to estimate the safety and efficacy of this compound against superficial bladder cancer and carcinoma in situ.
least 1 other agent, including thiotepa, doxorubicin, mitomycin C or BCG. Initially, patients with unresected marker tumors were considered eligible only if they were not candidates for transurethral resection due to over-all health or location of the tumor. This requirement was dropped when bropirimine was recognized to have activity against transitional cell carcinoma. No previous radiotherapy or intravesical chemotherapy within 4 weeks was allowed. All patients were required to have a negative prostatic urethral biopsy, an Eastern Cooperative On cology Group performance status of O to 2, a serum creatinine of less than 2.5 mg./dl., total bilirubin of less than 2.0 and transaminases of less than 1.5 times the upper limit of normal. Institutionally approved informed consent was obtained from all patients. Treatment schedule. Patients were entered consecutively into groups of 5 at progressively higher drug dosage levels following toxicity assessment of patients at previous dosage levels (table 1). Bropirimine was administered in 3 equal doses every 2 hours beginning at suppertime for 3 consecutive days and repeated weekly. Patients obtaining a complete response at 12 weeks were maintained on the same schedule for 1 year, while those with a partial response were maintained on the drug for an additional 12 weeks at the discretion of the treating physician. Patients with no response at 12 weeks were removed from the study and treated at the choice of the physician. Measurement of response. For patients with papillary tumors only cystoscopy was performed after 12 weeks of therapy and the marker tumor was visualized. For patients with carcinoma in situ bladder barbotage was obtained for cytological study,
MATERIALS AND METHODS
Patients. To be eligible for entry patients were required to have pathologically proved carcinoma in situ and/or unresected papillary tumors. Those with carcinoma in situ were required to have a positive cytology study on a barbotage specimen after biopsies were obtained, and were not required to have failed prior intravesical chemotherapy or immunotherapy. Patients with papillary tumors were required to have proved refractory to or to have relapse after prior intravesical therapy with at
TABLE 1. Bropirimine dose levels
Accepted for publication May 17, 1991. * Requests for reprints: Division of Urology, 7703 Floyd Curl Dr., San Antonio, Texas 78284-7845.
Level
Dose (mg.)*
Daily Dose (mg.)
1 2 3 4 5 6
500 750 1,000 1,250 1,500 1,750
1,500 2,250 3,000 3,750 4,500 5,250
* Administered every 2 hours for 3 doses, then daily for 3 consecutive days and repeated weekly for 12 weeks.
31
32
SAROSDY AND ASSOCIATES
and biopsies of previously positive areas, suspicious areas and uninvolved areas were obtained. Responses were classified as complete-complete resolution of carcinoma in situ confirmed by negative biopsy and benign cytology, or disappearance of marker transitional cell carcinomas; partial-significant but incomplete resolution of carcinoma in situ documented by less extensive disease at biopsy but persistent disease on biopsy and cytology, or decrease in size and/or number of papillary tumors but incomplete disappearance, and no response-categories of disease status not defined by the complete and partial response criteria, such as persistent carcinoma in situ with or without transitional cell carcinoma (stage Ta, grade 1 or 2) without a documented significant progression of carcinoma in situ. For patients with a complete response who remained on study, cystoscopy and barbotage for cytological analysis were repeated every 3 months. Toxicity assessment. Patients were followed weekly for the first 4 weeks of therapy with assessment of performance status, complete blood count and serum chemistry studies. The same parameters were then followed monthly until study termination or patient withdrawal. RESULTS
Enrollment and toxicity. Of 34 patients enrolled in the study
32 were evaluable for toxicity, while 26 were evaluable for response. Toxicity was mild among the 32 patients evaluable for side effects. Two patients responded to modest decreases in assigned dosage, 1 for mild increase in liver enzymes that normalized after a 50% dose reduction, and 1 for nausea, vomiting and diarrhea that resolved with a 25% dose reduction. The only withdrawal from the study due to toxicity occurred at 2 months (skin rash probably not due to bropirimine). Other reasons for withdrawal or nonevaluability include 2 patients who refused followup cystoscopy and biopsies after 12 weeks of therapy. Two patients withdrew at their wishes between 4 and 12 weeks. Two patients had not met the eligibility requirements upon later pathological review. One patient was a compassion ate enrollment for unresectable transitional cell cancer of the urethra. Response. Of the 26 patients evaluable for response there were 6 complete and 2 partial responses (table 2). One partial response was in a patient with papillary tumor only and he had no additional tumor reduction with therapy beyond the initial 12-week course. All 6 complete responses were in patients with carcinoma in situ, 1 of whom also had a measurable papillary tumor that disappeared. The over-all response rate was 31% (95% confidence limits 13 to 49%) at 12 weeks, with 45% (95% confidence limits 16 to 75%) of 11 carcinoma in situ patients achieving a complete response. While complete responses in patients with carcinoma in situ were seen over the entire range of dose levels, a dose-response relationship was also evident (table 3). Among the 5 patients with carcinoma in situ only entered at dosage levels 1 and 2, 1 (20%) had a complete response. Among the 6 patients with carcinoma in situ only at higher dose levels 4 (66%) had a complete response. Notably, the only complete response in patients with combined carcinoma in situ and papillary tumor occurred at the highest dose level. Effect of prior therapy on response to bropirimine. Of the 26 patients evaluable for response 19 had received prior therapy with BCG and/or interferon, including 10 with carcinoma in TABLE 2. Responses seen by tumor type after 3 months of therapy
Response Measurable Disease Present Papillary Ca in situ only Ca in situ and papillary Ca Totals
Complete
Partial
None
0 5 1 6
1 1 0
9 5 4
2
18
Total No.
10 11 5
26
TABLE 3. Distribution of complete responses in patients with
carcinoma in situ after 3 months of therapy
Fraction With Complete Responses Dose Level
Ca in Situ Only
Ca in Situ and Papillary Tumor
1
1/4 0/1
0/2
2
3 4 5 6
1/2 1/1 1/1 1/2
0/0
0/0 0/2
0/0 1/1
situ only. One patient who previously had been rendered free of disease on intravesical interferon had relapse while off interferon and then attained a complete response to bropiri mine. Of 7 patients who failed BCG therapy 3 attained a complete response to bropirimine. One of 2 patients who had received both agents attained a complete response. In light of this dose-response relationship the 6 patients with carcinoma in situ only at dosage levels 3 through 6 were examined for prior therapy. Of the 4 patients who attained a complete response 3 had received prior BCG therapy and 1 had received no prior therapy. Of the 2 nonresponders 1 had failed BCG and 1 had received no prior therapy. Thus, of 4 patients who had failed prior BCG therapy 3 attained a complete re sponse to bropirimine at these higher dose levels. Durability of response. At the time of this report two-thirds of the patients have completed 12 months of therapy or had treatment terminated due to lack of response. Durability after completion of 12 months of therapy in those who were complete responders is not yet evaluable for the entire group. Table 4 represents the status of all patients who had experienced com plete response at least 3 months in duration at the time of this report. Patients 1 and 19 have completed 12 months of therapy and their treatment has been discontinued. Patient 1 remained free of disease with a negative cytology study 9 months after bropirimine was stopped. Patient 19 has just begun followup off of the drug. Patient 11 had evidence of recurrent disease at 12 months. Patient 21 was free of carcinoma in situ at 6 months but a papillary tumor developed and he was removed from the study. Patient 31 was free of all disease at 6 months but was switched to BCG due to anxiety. DISCUSSION
This phase 1 trial of oral bropirimine in patients with meas urable papillary transitional cell cancer or cytologically con firmed residual carcinoma in situ has demonstrated that bro pirimine is well tolerated at a dosage schedule that is clearly effective against carcinoma in situ and possibly effective against papillary tumors. Importantly, bropirimine was effective in some patients who had failed prior BCG therapy, as well as patients who had received prior immunotherapy with intraves ical interferon. This salvage effect of bropirimine was particu larly evident at the higher dose levels in which 3 of 4 patients who had failed BCG attained a complete response to bropiri mine. Bropirimine is an aryl pyrimidinone shown to have multiple immunostimulatory properties, including stimulation of endo genous interferon production, and antiviral and antitumor ac tivity.12-14 Bropirimine has been shown to potentiate cell-me diated cytotoxicity in multiple compartments, including the spleen, peritoneal exudate, lung, liver, peripheral blood and bone marrow. This activity has been shown by means of block ing studies and target cell discrimination to be natural killer cell-dependent as well as macrophage-dependent. Bropirimine induced natural killer cell activation may take place even in the absence of increased serum levels of interferon. It is possible
ORAL INTERFERON INDUCER IN CARCINOMA IN SITU OF BLADDER
33
TABLE 4. Durability of complete response in patients with carcinoma in situ only
Evaluation Point During Therapy (mos.) Pt. No
3
6
9
12
Complete response
Complete response
Complete response
Complete response
11 19
Complete response Complete response
Complete response Complete response
Complete response Complete response
Recurrence Complete response
21 31
Complete response Complete response
Complete responset
Present Status Remains in complete remission after 9 mos. off drug Just starting long-term followup
* Taken off study when a papillary tumor occurred, but still a complete response in regard to carcinoma in situ. t Still complete response but switched to BCG due to anxiety of patient and referring urologist.
that interferon, interleukin-1 and possibly other cytokines act synergistically to augment natural killer cell activity. A series of phases 1 and 2 trials of bropirimine in human cancers has demonstrated that bropirimine is capable of induc ing regression in some advanced cancers, some of these complete and long-lasting. 5 Responses have been seen at relatively nontoxic doses, such as in this trial in bladder cancer. Inter feron induction does occur within hours and may be boosted or primed by prolonged administration of the drug. Induction of circulating interferon is not necessary for responses to occur, since several have been seen in the absence of interferon induction. Stimulation of antibody-dependent cell-mediated cytolysis and natural killer cytolytic activity seen in animals has been shown to occur in patients in whom it was measured. In other trials bropirimine was seen to be relatively nontoxic when compared to other cytotoxic agents and biological re sponse modifiers of comparable clinical efficacy. Toxicity is generally dose and schedule dependent, and is similar in nature to symptoms associated with exogenous interferon administra tion. An association of higher grades of these toxicities with the detection of interferon suggests that much of the toxicity of bropirimine is related to its interferon-inducing potential. With the FANFT-induced transplantable murine transi tional cell carcinoma MBT-2, several in vivo studies have demonstrated activity of bropirimine. With intralesional injec tions directly into subcutaneously growing tumors in C3H mice, Simmons et al reported an antitumor effect approaching that of BCG. 9 Also, using the subcutaneous model in C3H mice but with oral administration of bropirimine Sidky et al demon strated a significant dose-dependent decrease in the tumor growth rate. 0 Sarosdy and Kierum reported a synergistic an titumor effect when BCG and bropirimine were administered in combination intraperitoneally using the MBT model devised by Pang and Morales. 1 1 Additionally, that study demonstrated a greater potentiation of cell-mediated cytotoxicity by bropiri mine than by BCG, with that response occurring earlier, lasting longer and being of greater magnitude. Several reports of the activity of intravesically administered recombinant a-2 interferon have confirmed that superficial bladder cancer may be an immunotherapeutically responsive tumor. 1 6• While the side effects of intravesical interferon are remarkably low, the drug cost required to obtain the 45% complete response rate in carcinoma in situ that was seen in 1 study might make this form of therapy impractical on a routine basis. An oral agent that is effective against superficial bladder cancer is highly desirable. Clearly, a phase 2 trial in patients with carcinoma in situ is warranted to corroborate the results obtained in our pilot study. If the activity of bropirimine against carcinoma in situ is confirmed, then its value as either a front line agent before BCG therapy or a second-line agent in BCG failures should be investigated. Based upon the synergy seen in the murine trial of combination therapy with bropirimine and BCG, this compound is presently also the leading candidate for 1
1
17
a clinical trial of BCG in combination with any currently available immunotherapeutic agent. REFERENCES
1. Silverberg, E. and Lubera, J. A.: Cancer statistics. CA, 38: 5, 1988. 2. Lamm, D. L.: Bacillus Calmette-Guerin immunotherapy for blad der cancer. J. Urol., 134: 40, 1985. 3. Brosman, S. A.: The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ. J. Urol., 134: 36, 1985. 4. Herr, H. W., Pinsky, C. M., Whitmore, W. F., Jr., Sogani, P. C., Oettgen, H. F. and Melamed, M. R.: Long-term effect of intraves ical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J. Urol., 135: 265, 1986. 5. Catalana, W. J., Hudson, M. A., Gillen, D. P., Andriole, G. L. and Ratliff, T. L.: Risks and benefits of repeated courses of intraves ical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 137: 220, 1987. 6. Sarosdy, M. F. and Lamm, D. L.: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 142: 719, 1989. 7. Lamm, D. L., Stogdill, V. D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1985. 8. Rawls, W. H., Lamm, D. L., Lowe, B. A., Crawford, E. D., Sarosdy, M. F., Montie, J.E., Grossman, B. H. and Scardino, P.: Fatal sepsis following intravesical bacillus Calmette-Guerin adminis tration for bladder cancer. J. Urol., 144: 1328, 1990. 9. Simmons, W. B., Reichert, D. F., Lucio, R. M. and Lamm, D. L.: Pyrimidinone interferon inducers in the treatment of murine transitional cell carcinoma. J. Urol., part 2, 129: 169, abstract 309, 1983. 10. Sidky, Y. A., Borden, E. C., Wierenga, W. and Bryan, G. T.: Inhibitory effects of interferon-inducing pyrimidinones on the growth of transplantable mouse bladder tumors. Cancer Res., 46: 3798, 1986. 11. Sarosdy, M. F. and Kierum, C. A.: Combination immunotherapy of murine transitional cell carcinoma using BCG and an inter feron-inducing pyrimidinone. J. Urol., 142: 1376, 1989. 12. Wierenga, W.: Antiviral and other bioactivities of pyrimidinones. Pharmacol. Ther., 30: 67, 1985. 13. Chang, A. Y.-C., Chuang, C., Pandya, K. J. and Wierenga, W.: Chemoprevention of 7,12-dimethylbenz-(alpha) anthracene (DMBA) induced rat mammary tumors by 2-amino-5-bromo-6phenyl-4(3H)-pyrimidinone (ABPP). J. Biol. Response Modi fiers, 5: 112, 1986. 14. Lotzova, E., Savary, C. A., Khan, A. and Stringfellow, D. A.: Stimulation of natural killer cells in two random-bred strains of athymic rats by interferon-inducing pyrimidinone. J. lmmunol., 132: 2566, 1984. 15. Rios, A., Stringfellow, D. A., Fitzpatrick, F. A., Reele, S. B., Gutknecht, G. D. and Hersh, E. M.: Phase I study of 2-amino5-bromo-6-phenyl-4 (3H)-pyrimidinone (ABPP), an oral inter feron inducer, in cancer patients. J. Biol. Response Modifers, 5: 330, 1986. 16. Williams, R., Sarosdy, M., Catalona, W., Chodak, G., Vogelzang, N., Freiha, F. and Torti, F.: Randomized trial of high vs. low dose intravesical interferon alpha 2-B (IFN-A2B) treatment of bladder carcinoma-in-situ (CIS). In: Proceedings of the 24th Annual Meeting of the American Society of Clinical Oncology, p. 121, abstract 467, May 1988. 17. Glashan, R. W.: A randomized controlled study of intravesical a2b-interferon in carcinoma in situ of the bladder. J. Urol., 144: 658, 1990.
