A Phase I Study of Combined Modality 90 Yttrium-CC49 Intraperitoneal Radioimmunotherapy for Ovarian Cancer 1 Ronald D. Alvarez, 2 Warner K. Huh, M. B. Khazaeli, Ruby F. Meredith, Edward E. Partridge, Larry C. Kilgore, William E. Grizzle, Sui Shen, J. Max Austin, Mack N. Barnes, Delicia Carey, Jeffrey Schlom, and Albert F. LoBuglio Departments of Obstetrics and Gynecology [R. D. A., W. K. H., E. E. P., L. C. K., J. M. A., M. N. B.], Radiation Oncology [M. B. K., R. F. M., S. S.], Pathology [W. E. G.], Biostatistics [D. C.], and Medicine [A. F. L.], University of Alabama at Birmingham Cancer Center, Birmingham, Alabama 35233, and National Cancer Institute, Bethesda, Maryland 20892 [J. S.] ABSTRACT Purpose: The purpose of this study was to determine the feasibility and maximum tolerated dose of 90 Yttrium-CC49 ( 90 Y-CC49) as the radioimmunotherapy (RIT) component of an i.p. combined modality treatment for recurrent ovarian cancer. Experimental Design: A Phase I trial of 90 Y-CC49 RIT was conducted in ovarian cancer patients who had persistent or recurrent intra-abdominal disease, had failed one or two prior chemotherapy regimens, and demonstrated TAG-72 expression. Patients were treated with a previously estab- lished combined modality treatment protocol of s.c. IFN 2b, i.p. paclitaxel, and increasing dosages of i.p. 90 Y-CC49. Patients were monitored for toxicity, generation of human antimouse antibody response, and clinical efficacy. Results: Twenty eligible patients were treated per study specifications. All patients had been treated with debulking and paclitaxel/carboplatin-based chemotherapy at initial di- agnosis. The patients included 11 patients with persistent disease at the time of second look laparotomy and 9 patients with delayed recurrence. Patients were treated with i.p. 90 Y-CC49 given in combination with s.c. IFN 2b (dose of 3  10 6 units for a total of four doses) and i.p. paclitaxel (dose of 100 mg/m 2 ). RIT treatment was associated with primarily hematological toxicity. The maximum tolerated dose of i.p. 90 Y-CC49 was established at 24.2 mCi/m 2 in this combined regimen. Of nine patients with measurable dis- ease, two had partial responses lasting 2 and 4 months. Of 11 patients with nonmeasurable disease, median time to pro- gression was 6 months in 7 patients who recurred; 4 of these patients remain no evidence of disease at 9, 18, 19, and 23 months. Conclusions: 90 Yttrium-CC49-based RIT in combina- tion with IFN 2b and i.p. paclitaxel is feasible and well tolerated at a dose of <24.2 mCi/m 2 . INTRODUCTION Despite advances in therapy for ovarian cancer, failure to control intra-abdominal disease remains the primary reason for poor overall outcome. We and others have investigated the utility of i.p. administration of radiolabeled monoclonal anti- bodies as a strategy for achieving long-term disease control in ovarian cancer patients. For our initial Phase I study, the mono- clonal antibody CC49, which targets the tumor-associated anti- gen TAG-72.3, was conjugated to the novel radioisotope 177 Lu- tetium ( 177 Lu) and administered i.p. to patients with recurrent or persistent ovarian cancer. The results of this Phase I trial dem- onstrated tumor regression in one patient with gross measurable disease and extended disease-free survival for others with small volume residual disease (1, 2). We were subsequently able to demonstrate the feasibility of a combined modality strategy of i.p. 177 Lu-CC49 adminis- tered with s.c. IFN 2b and i.p. paclitaxel with little need for RIT 3 dose attenuation (3). IFN 2b has been shown to enhance expression of TAG-72 tumor antigen and improve localization of radiolabeled antibody to tumor cells (4, 5). Paclitaxel has activity against ovarian cancer, is a known radiation sensitizer, and has been demonstrated to sensitize ovarian cancer cells to the cytotoxic effects of ionizing radiation (6). This strategy was well tolerated because of nonoverlapping marrow suppression by paclitaxel (14 days) and RIT (6 weeks). We then sought to determine whether this combined mo- dality strategy was applicable to 90 Yttrium ( 90 Y), a pure  emitter that has higher  energy (E avg  935 KeV) and depth of penetration (range, 1–2 mm) in comparison with 177 Lu (E avg  133 KeV; range, 0.2– 0.3 mm). Furthermore, 90 Y has a shorter physical half-life (2.7 days) and does not produce  emissions. The current study was thus designed to identify the MTD, the Received 2/13/02; revised 5/9/02; accepted 5/20/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by National Cancer Institute Grant CM 87215 and NIH Grants 1R01 CA OD6782801 and M01 RR00032. 2 To whom requests for reprints should be addressed, at 618 20th Street South, OHB Room 538, Division of Gynecologic Oncology, Birming- ham, Alabama 35233. Phone: (205) 934-4986; Fax: (205) 975-6174; E-mail: rdalvarez@aol.com. 3 The abbreviations used are: RIT, radioimmunotherapy; HAMA, hu- man antimouse antibody; MTD, maximum tolerated dose; E avg , average energy; CT, computed tomography; UAB, University of Alabama at Birmingham; TTP, time to progression; DOTA, 1,4,7,10-tetra-azacy- lododecane N,N,N,N-tetraacetic acid. 2806 Vol. 8, 2806 –2811, September 2002 Clinical Cancer Research Research. on December 9, 2021. © 2002 American Association for Cancer clincancerres.aacrjournals.org Downloaded from