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© 1999 American Society for Clinical Oncology Randomized Phase II Study of BR96-Doxorubicin Conjugate in Patients With Metastatic Breast CancerFrom the British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada; Stony Brook Health Science Center, State University of New York (SUNY), Stony Brook, NY; University of Virginia Health Sciences Center, Charlottesville, VA; University of Alabama, Birmingham, AL; Georgetown University Medical Center, Washington, DC; and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT. Address reprint requests to Anthony W. Tolcher, MD, Institute for Drug Development, Cancer Therapy and Research Center, Suite 250, 8122 Datapoint Dr, San Antonio, TX 78229.
PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease. RESULTS: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent. CONCLUSION: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.
BMS 182248-01 (BR96-doxorubicin immunoconjugate) is an immunoconjugate developed to deliver doxorubicin specifically to tumor cells that express the tumor-associated surface antigen Lewis-Y while sparing normal tissues. The BR96-doxorubicin conjugate is a part human, part mouse chimeric immunoglobulin (Ig) conjugated to approximately eight doxorubicin molecules (Fig 1). In preclinical studies, after BR96-doxorubicin conjugate binds to the Lewis-Y surface antigen, it is rapidly internalized, the doxorubicin molecules are released from the immunoglobulin by hydrolysis of the acid-labile linkage, and cytotoxicity results.1,2 Lewis-Y is abundantly expressed on the surface of many human carcinomas, including breast, lung, colon, and ovary carcinomas.3 Most normal tissues do not express the Lewis-Y antigen, except for epithelial cells of the esophagus, stomach, and proximal small intestine and some acinar cells of the pancreas.3
The BR96-doxorubicin conjugate demonstrated a broad spectrum of antitumor activity in xenograft tumor models, including cures in established L2987 lung, RCA colon, and MCF-7 breast tumors.1,4 This activity was in marked contrast to single-agent doxorubicin, which did not produce cures at its optimal dose and schedule in the same xenograft models.1 Furthermore, equivalent antitumor activity was achieved with the BR96-doxorubicin conjugate at 13% of the comparable free doxorubicin dose. This finding suggests preferential delivery of the doxorubicin to the Lewis-Y–expressing tumor by the immunoconjugate.1 In rodent toxicology studies, the BR96-doxorubicin conjugate was significantly less toxic, including cardiotoxicity, than equivalent doses of doxorubicin.5 An acute enteropathy was observed in dogs that was not observed in rodents and that differed from the toxicity normally associated with doxorubicin.6 The acute enteropathy was believed to be related to the binding of the antibody to Lewis-Y–related antigens expressed by gastrointestinal epithelial cells. Clinical trials were initiated shortly after the broad spectrum of antitumor activity was demonstrated preclinically. In the phase I studies, vomiting with hematemesis was dose-limiting, and an exudative gastritis was found at endoscopy.6,7 Premedication with corticosteroids, 5-hydroxytryptamine-3 antagonists, and a 24-hour infusion schedule led to the recommended phase II dosage of 700 mg/m2 BR96-doxorubicin every 3 weeks (21 mg/m2 conjugated doxorubicin).8 In addition to the reversible gastritis, toxicities included asymptomatic alterations in pancreatic enzymes, most prominently serum lipases, mild hypersensitivity reactions characterized by fever or rash without anaphylactic reactions, modest hematologic toxicity of anemia, and rare cases of neutropenia. No alopecia, mucositis, or cardiomyopathy was reported. During the phase I study of this schedule, two partial responses were observed in patients with breast and gastric carcinoma.8 On the basis of provocative preclinical data and the encouraging phase I study, we initiated a randomized phase II study to determine the antitumor activity of BR96-doxorubicin conjugate in metastatic breast cancer. The randomized phase II design using a single-agent doxorubicin reference arm was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer and confirm the sensitivity of the enrolled population to single-agent doxorubicin. Moreover, this design would permit a rapid determination of the future development of this drug in breast cancer.
Eligibility Patients aged 18 years or older with histologically confirmed, measurable metastatic breast cancer were eligible for this study. Patients were permitted to have had one prior chemotherapy regimen in either the adjuvant or metastatic setting. Prior chemotherapy for metastatic disease could not contain anthracyclines. However, prior adjuvant chemotherapy could include an anthracycline if the patient had relapsed more than 12 months after the completion of the chemotherapy and the cumulative dose was equal to or less than 300 mg/m2 doxorubicin. Patients who received nonanthracycline-containing adjuvant chemotherapy must have relapsed more than 3 months after treatment completion. Patients were permitted prior hormone therapy for adjuvant and metastatic disease; however, patients who had previously responded to hormone therapy had to have discontinued it at least 4 weeks before randomization and tumor evaluation was repeated after a 4-week washout interval. Prior radiotherapy was acceptable if it was completed 4 weeks before study entry. Before randomization, all patients were required to have a breast cancer specimen positive for Lewis-Y antigen by immunohistochemistry, a normal left ventricular ejection fraction, an Eastern Cooperative Oncology Group performance status of 0 or 1, or a Karnofsky performance status of more than 80%. Laboratory requirements included the following: a hemoglobin count of more than 10 g/dL; a granulocyte count of 1,500 cells/µL or higher; blood urea nitrogen and serum creatinine levels within 1.25 times the upper limit of normal; a bilirubin level of less than 1.5 mg/dL; AST and ALT levels within 2.5 times the institutional upper limit of normal; and serum lipase or amylase levels that were less than twice the institutional upper limit. Alkaline phosphatase elevations of more than 2.5 times the upper limit of normal were permitted if bone metastases were documented. Women of child-bearing potential were required to have a negative serum or urine pregnancy test result within 72 hours before the start of study medication and to practice contraception. Patients were excluded if they had been exposed to therapeutic or diagnostic murine, murine/human chimeric, or humanized monoclonal antibodies within 6 months before randomization. A history of neoplasm other than breast cancer within 5 years of study entry was a reason for exclusion, with the exception of nonmelanoma skin cancer or curatively treated carcinoma-in-situ of the cervix. Patients were not permitted to have CNS metastases that required active treatment or receive concomitant cytotoxic, hormone, radiation, or investigational therapy while participating in this study. The study was approved by each participating institution's institutional review board, and written informed consent according to the guidelines of the participating institutions was obtained from patients before study entry.
Study Design BR96-doxorubicin conjugate (BMS-182248-01; Bristol-Myers Squibb, Wallingford, CT) was administered by continuous IV infusion over 24 hours once every 21 days. The full calculated dose was divided into four equal doses and prepared in 250 ml of normal saline or 5% dextrose water; each of the four doses was administered over 6 hours. Premedication consisted of oral dexamethasone 20 mg daily starting 2 days before the start of infusion and continued for 2 days after therapy. Antiemetics, including 5-hydroxytryptamine-3 antagonists, were administered according to institutional policy. Lorazepam 1 to 2 mg orally (PO) or IV was administered at least 30 minutes before the start of infusion. Vital signs were monitored in all patients receiving the BR96-doxorubicin conjugate immediately before, 15 minutes and 1 hour after the start, and at the completion of the infusion. Doxorubicin was reconstituted with sodium chloride injection USP (0.9% normal saline) or sterile water for injection. Doxorubicin was given as a bolus injection IV once every 3 weeks. Vitals signs were monitored before treatment and at completion of the infusion.
Toxicity Evaluation and Dose Modifications The drug dose was reduced 25% when febrile neutropenia occurred or a platelet transfusion was required. Failure to recover the absolute neutrophil count to 1,000/µL or higher or the platelet count to 100,000 cells/µL or higher required a delay of treatment until recovery and a 25% dose reduction. Grade 3 or 4 nausea and vomiting for more than 48 hours' duration required a 25% dose reduction. If symptoms persisted at the planned time of re-treatment, patient participation was delayed until recovery. Gastrointestinal hemorrhage up to grade 1 was permitted as long as patients had recovered by the day of re-treatment. Grade 2 or greater gastrointestinal hemorrhage required discontinuation of therapy. Pancreatic toxicity was defined as elevations of serum amylase or lipase with or without symptoms consistent with pancreatic inflammation. Any grade 4 pancreatic toxicity, or the presence of symptoms regardless of grade, required a 25% dose reduction and a resolution of the biochemical toxicity to grade 0 to 3 with resolution of symptoms before re-treatment. All other grade 3 or 4 nonhematologic toxicities, with the exception of alopecia, warranted a 25% dose modification with resolution of toxicity to grade 0 or 1 by the date of re-treatment. Grade 1 cardiovascular toxicities were permitted provided that patients recovered by the time of re-treatment. Any grade 2 or greater cardiovascular toxicity required discontinuation from further treatment.
Treatment Duration and Cross-Over Criteria Patients were permitted to cross-over to the alternate treatment arm if they demonstrated either disease progression or stable disease after four cycles and if it was considered in the patient's best interest by the treating physician. Cross-over was permitted only if the patient met the original eligibility criteria. All patients who received one dose of the study drug were assessable for toxicity. All patients who received at least two cycles of treatment were considered assessable for response. A complete response (CR) was defined as disappearance of all clinically evident tumor, including normalization of any tumor markers determined by two observations not less than 4 weeks apart. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of the bidimensional measurements of the measured lesions determined by two observations not less than 4 weeks apart. No simultaneous increase in the size of any lesion or appearance of new lesions could occur. Nonmeasurable lesions were required to remain stable or regress to meet the PR criterion. Stable disease was defined as a decrease of less than 50% in total tumor size up to an increase of less than 25% in the total tumor size. To meet the stable disease criterion, no new lesions could develop. Progressive disease was the unequivocal increase of at least 25% from the best response or baseline in one or more measurable lesions. The appearance of new lesions constituted progressive disease.
Anti-Immunoconjugate Antibody Assessment (Human Anti-Mouse Antibody)
Statistical Analysis The toxicities (hematologic and biochemical) experienced by the two treatment groups were compared on the first cycle, and worst toxicity (both hematologic and nonhematologic) was compared over all cycles, using a two-sided Monte Carlo simulation, a permutation of a Wilcoxon rank sum statistic. The Bonferroni method was used because a large number of variables were compared, and the significance level of each variable was set at .002 to ensure a 0.05 experiment-wise error rate.
A total of 25 patients were entered onto this study: 10 patients were randomized to receive the BR96-doxorubicin conjugate, and 10 patients were randomized to single-agent doxorubicin. After the protocol was amended, five additional patients received the BR96-doxorubicin conjugate without randomization. Two randomized patients (one patient in each treatment arm) were never treated. One of these patients refused their assigned single-agent doxorubicin treatment, and one patient rapidly deteriorated from disease before BR96-doxorubicin conjugate treatment. The median age of patients entered was 52 years (range, 25 to 65 years), and they had a median of two sites of metastatic disease. Thirteen patients had received prior chemotherapy (eight patients in the BR96-doxorubicin conjugate arm and five in the doxorubicin arm). Two patients treated with BR96-doxorubicin conjugate and one patient randomized to the doxorubicin arm had received prior adjuvant doxorubicin. All patients treated were assessable for response and toxicity. Patient characteristics are listed in Table 1.
Forty-five cycles were administered to the 14 patients treated initially with BR96-doxorubicin. In addition, 25 cycles were administered to four patients who crossed over to receive BR96-doxorubicin conjugate after progression or persistently stable disease during single-agent doxorubicin treatment. Forty-one cycles of single-agent doxorubicin were administered to the nine randomized patients, whereas two cycles of doxorubicin were given to one patient who crossed over after disease progressed during BR96-doxorubicin treatment. Patients treated with the BR96-doxorubicin conjugate as initial therapy received a median of three cycles of therapy (range, two to five cycles), whereas patients treated with single-agent doxorubicin initially received a median of four cycles (range, two to six cycles). In the four patients who crossed over to receive BR96-doxorubicin conjugate after disease progression during doxorubicin treatment, the median number of courses was five (range, one to 14 courses).
Toxicity Data No clinically significant hypersensitivity reactions occurred in patients randomized initially to the BR96-doxorubicin conjugate. Fever was noted in three patients and wheezing was observed in two patients treated with the BR96-doxorubicin conjugate. One patient who crossed over and received the BR96-doxorubicin conjugate experienced four hypersensitivity reactions on successive cycles, with symptoms characterized by cough and wheezing. This patient could be re-treated safely after temporary interruption of the infusion. The toxicities are summarized in Tables 2 and 3.
Treatment Modification and Delay
HAMA Analysis
Response Data The response duration was 3 months for the patient treated initially with BR96-doxorubicin conjugate and 6 and 6+ months for the patients who responded to BR96-doxorubicin after cross-over. The response durations for the four patients randomized to doxorubicin and who responded were 2, 4, 10, and 15 months.
The immunoconjugate BR96-doxorubicin was developed to selectively deliver doxorubicin to tumors that express the tumor-associated surface antigen Lewis-Y while avoiding doxorubicin's systemic toxicity. We determined that the BR96-doxorubicin conjugate on this schedule and dose has modest antitumor activity in metastatic breast cancer. This is in contrast to the doxorubicin arm, which as part of this randomized study, demonstrated a 44% response rate, including one CR. These results, therefore, do not confirm the preclinical data, which show that the immunoconjugate was superior to single-agent doxorubicin1. The failure of BR96-doxorubicin to produce a clinically significant number of responses, despite the strong preclinical evidence, deserves examination. The patient population entered should have been sensitive to doxorubicin because they were minimally pretreated and were not eligible if they were refractory to adjuvant doxorubicin. The response rate in the doxorubicin reference arm supports this contention; therefore, the failure of BR96-doxorubicin was not due to intrinsic doxorubicin resistance. We believe that the relatively low dose of doxorubicin contained in the immunoconjugate treatment (approximately one fourth of the dose in the free doxorubicin arm) should not have limited the antitumor activity significantly. In preclinical models, equivalent antitumor activity was achieved with the BR96-doxorubicin immunoconjugate at one eighth of the dose of free doxorubicin, and superior activity was noted for the BR96-doxorubicin immunoconjugate at doses above this level. The HAMA response to the murine F(ab') fragment was modest, as would be expected in a chimeric part human, part murine immunoglobulin. Data from the prior phase I clinical trial demonstrated bound antibody to tumor cells in tumor biopsy specimens and the presence of doxorubicin in tumor cell nuclei, with the absence of a significant HAMA response. This suggests that targeting, binding, and delivery of doxorubicin by the chimeric immunoconjugate to Lewis-Y–expressing target cells was possible.10 The toxicities observed with the BR96-doxorubicin conjugate in this study, however, provide indirect evidence for the limited clinical antitumor activity observed. The toxicity associated with the BR96-doxorubicin conjugate differed markedly from that of the single-agent doxorubicin reference arm and was predominantly gastrointestinal (ie, nausea and vomiting, including hematemesis, abdominal pain, and pancreatic enzyme abnormalities). Although the BR96 immunoglobulin targets the tumor-associated antigen Lewis-Y, this antigen is also expressed by a few normal tissues, including the gastric mucosa, small intestine, and pancreas. These gastrointestinal toxicities undoubtedly represent the binding of the immunoconjugate to these gastrointestinal sites. This is further supported by immunohistochemical evidence of bound BR96 immunoglobulin to gastric mucosa in one patient where the immunoglobulin alone was administered, and bound BR96-doxorubicin immunoconjugate to the gastric mucosa at endoscopy in the phase I study which was seen in earlier dog toxicology studies.6,11 Moreover, the presence of Lewis-Y antigen expression on the gastrointestinal tract may act as an "antigen sink," binding the immunoconjugate and preventing sufficient immunoconjugate from reaching the metastatic tumor deposits. As mice do not express Lewis-Y on their cells, this sequestration of the BR96-doxorubicin conjugate away from the implanted tumor cells would not have occurred in the xenograft mouse models in which dramatic antitumor activity was observed. To avoid the potential for immunoconjugate sequestration on normal tissues, targeting of tumor-specific rather than tumor-associated antigens will be required for continued and improved immunoconjugate therapy development. Although the response in two of four patients who crossed over and received the BR96-doxorubicin conjugate after persistently stable and progressive disease on single-agent doxorubicin is of clinical and biologic interest, the small number of patients in this subset limits the interpretation of this result. Possible hypotheses include delayed response to prior doxorubicin therapy, perturbation of the metastatic deposit, rendering it more susceptible to immunoconjugate therapy, and chance alone. A randomized phase II design offered several advantages for testing this novel agent. In a standard phase II study, the single response in 14 patients could have been interpreted as due to either unfavorable disease or patient characteristics. Subsequent continuation of accrual beyond 15 patients may have occurred, despite the initial criterion of a 30% response rate of interest. In this study, which used a randomized study design, once nine patients had been randomized to each arm, it became clear that there was a low likelihood that a 30% response rate would be missed in the experimental arm if we ceased the study. In contrast, this level of activity was clearly satisfied in the doxorubicin reference arm. The experimental arm therefore would not meet a level of antitumor activity needed for continued interest. This analysis provided the justification to discontinue further clinical development of BR96-doxorubicin in breast cancer. In summary, the BR96-doxorubicin conjugate has definite but limited antitumor activity against metastatic breast cancer with this dose and schedule and has a markedly different toxicity profile compared with doxorubicin. Although the concept of targeted cytotoxic immunotherapy has considerable interest, further work identifying tumor specific-antigen targets is necessary before this immunoconjugate approach can be used for the delivery of cytotoxic chemotherapy.
Supported by Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660.
1. Trail PA, Willner D, Lasch SJ, et al: Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates [published erratum appears in Science 263:1076, 1994] Science 261:212-215, , 1993 2. Garrigues J, Garrigues U, Hellstrom I, et al: Ley specific antibody with potent anti-tumor activity is internalized and degraded in lysosomes. Am J Pathol 142:607-622, 1993[Abstract]
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Hellstrom I, Garrigues HJ, Garrigues U, et al: Highly tumor-reactive, internalizing, mouse monoclonal antibodies to Le(Y)-related cell surface antigens. Cancer Res 50:2183-2190, 1990
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Sjogren HO, Isaksson M, Willner D, et al: Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats. Cancer Res 57:4530-4536, 1997
5.
Comereski CR, Peden WM, Davidson TJ, et al: BR96-doxorubicin conjugate (BMS-182248) versus doxorubicin: A comparative toxicity assessment in rats. Toxicol Pathol 22:473-488, 1994 6. Saleh M, LoBuglio A, Sugarman S, et al: Gastrointestinal effects of chimeric BR96-doxorubicin (DOX) conjugate. Proc Am Assoc Cancer Res 36:A2876, 1995 (abstr) 7. Sugarman S, Murray JL, Saleh M, et al: A phase I study of BR96-doxorubicin (BR96-Dox) in patients with advanced carcinoma expressing the Lewis(Y) antigen. Proc Am Soc Clin Oncol 14:A1532, 1995 (abstr) 8. Slichenmyer WJ, Saleh MN, Bookman MA, et al: Phase I studies of BR96 doxorubicin in patients with advanced solid tumors that express the Lewis Y antigen. Anti-Cancer Treatment, Sixth International Congress, 1996, pp 95:6-9, (abstr) 9. Gehan E: The determination of the number of patients required in a preliminary and follow-up trial of a new chemotherapeutic agent. J Chronic Dis 13:346-353, 1961[Medline] 10. Trail PA, Onetto N, Lasch S, et al: Tumor penetration and functional activity of BMS-182248 following administration in a phase I clinical trial. Proc Am Assoc Cancer Res 36:A2974, 1995 (abstr) 11. Saleh ML, LoBuglio AF, Trail PA: Monoclonal antibody-based immunoconjugate therapy for cancer: Studies with BR96-doxorubicin, Grossbard J (ed): Monoclonal Antibody-Based Therapy of Cancer397-416, 1998 Submitted May 1, 1998; accepted October 22, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5%, beta).
