Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.

PURPOSE: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. EXPERIMENTAL DESIGN: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. RESULTS: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade>2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P=0.6268), dose (P=0.4602), or cohort (P=0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). CONCLUSIONS: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Phase II study of CT-2103 in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

PURPOSE: To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-L-glutamic acid, in heavily pretreated patients with recurrent ovarian, fallopian tube, or peritoneal cancer. PATIENTS AND METHODS: Ninety-nine patients with measurable disease received intravenous CT-2103 at 175 mg/m2 of conjugated paclitaxel over 10 minutes every 3 weeks without routine premedications. Platinum-sensitive (n = 42) and platinum-refractory or platinum-resistant patients (n = 57) were enrolled. Thirty-nine patients (39%) had received one or two prior regimens, and 60 patients (61%) had received between three and 12 regimens. RESULTS: In 99 patients, the median number of cycles was three (range, one to 14 cycles). The response rate (RR) for all patients was 10% (10 of 99 patients), with median time to disease progression (TTP) of 2 months. The RR (partial response) in platinum-sensitive and platinum-resistant patients was 14% (six of 42 patients) and 7% (four of 57 patients), respectively. In patients with only one or two prior regimens, the RR in platinum-sensitive and platinum-resistant patients was 28% (five of 18 patients) and 10% (two of 21 patients), with a median TTP of 4 and 2 months, respectively. Grade 2 (15 patients) or 3 (15 patients) neuropathy was reported in 30 patients (30%). Grade 2 hypersensitivity occurred in eight patients (8%) who were subsequently treated with premedications; one patient had grade 3 hypersensitivity and was removed. Grade 2 alopecia was absent. CONCLUSION: CT-2103 is active in patients with recurrent ovarian cancer. Neurotoxicity in these heavily pretreated patients was more frequent than predicted from phase I trials. Further study to define toxicity and efficacy in patients with less prior therapy is ongoing.

Intraperitoneal cisplatin with intraperitoneal gemcitabine in patients with epithelial ovarian cancer: results of a phase I/II Trial.

PURPOSE: The aims of this study were to determine the dose and schedule of i.p. cisplatin with i.p. gemcitabine in patients with persistent disease at second-look assessment, the toxicity of this regimen, and the time to treatment failure and overall survival. EXPERIMENTAL DESIGN: We performed a Phase I/II evaluation of i.p. cisplatin at 75 mg/m(2) on day 1 with planned gemcitabine at 500, 750, 1000, or 1250 mg/m(2) i.p. on days 1, 8, and 15 on a 28-day schedule for four courses. Eligible patients completed surgical cytoreduction followed by adjuvant platinum-based chemotherapy. They had second-look assessment showing microscopic or macroscopic (< or =1 cm) disease, followed by i.p. port placement. RESULTS: The Phase I dose-limiting toxicity was grade 3 thrombocytopenia at day 15 on dose level 1 (n = 5). The protocol was amended, and the Phase II portion accrued to 30 patients, who were given i.p. cisplatin (75 mg/m(2)) on day 1 and gemcitabine at 500 mg/m(2) on days 1 and 8 on a 21-day schedule for four courses. Nine patients were removed from the study: one each for hypersensitivity, cellulitis, and i.p. port malfunction; two for progression of disease; and four for renal toxicity. Other toxicities included grade 3 nausea (7%) and transient grade 3 neuropathy (3%). Grade 1 or 2 neuropathy was frequently seen (80%). Five patients (17%) returned to the operating room at a median of 6 months (range, 1-20 months) after i.p. therapy for evaluation of abdominal pain; two patients had recurrence, and all had areas of fibrous tissue with encasement of the bowel. In two patients, the fibrous tissue was causing partial bowel obstruction. No other patients had symptoms prompting surgical exploration. Pharmacokinetic (PK) studies showed a median area under the curve (AUC) i.p. of 3041 h. micro M (range, 676-5702 h. micro M) and AUC in plasma of 4.0 h. micro M (range, 0.92-8.2 h. micro M) reached between 120 and 240 min; the pharmacological advantage was 759-fold (range, 217-1415-fold) for i.p. versus plasma drug levels. The mean residence time of gemcitabine with i.p. administration was 4.7 h. The median time to progression of the intent to treat population was 15.93 months (95% confidence interval, 9.13-25.9 months), with a median overall survival of 43.5 months [95% confidence interval, (34.66- infinity)]. No statistical differences were seen with respect to overall survival if patients were grouped in terms of optimal debulking or not (median not reached versus 34.8 months, respectively; P = 0.16) or whether visible disease was present or not at the start of i.p. therapy (34.8 versus 47.7 months; P = 0.47). With regard to time to treatment failure, a statistical difference favored patients with optimal versus nonoptimal primary debulking (25.2 versus 10.2 months, respectively; P = 0.03). CONCLUSIONS: The median time to treatment failure and overall survival of 15.9 months and 43.5 months, respectively, are consistent with our historical data in patients receiving i.p. platinum-based regimens for consolidation. The fibrotic changes seen in explored patients suggest local toxicity of this combination. The absolute benefit of i.p. consolidation requires randomized trials to assess efficacy.