Christopher W. Ryan

Phase II Trial of PS-341 in Patients With Renal Cell Cancer: A University of Chicago Phase II Consortium Study

PURPOSE Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. PATIENTS AND METHODS PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. RESULTS Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively). CONCLUSION Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era

BACKGROUND Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that are characterized by constitutive overexpression of the tyrosine kinase receptor KIT (CD117). Imatinib mesylate is a selective inhibitor of tyrosine kinase-mediated activity. This study reports a single-institution experience of surgical resection and the use of imatinib in the treatment of GIST. METHODS A retrospective review from 1995 to 2002 identified 57 patients (M:F, 29:28; median age, 61 years) with GIST who were treated at the University of Chicago. Twenty-eight patients underwent exploratory surgery with curative intent; 29 patients were referred for treatment of metastatic disease after surgery at outside institutions. Twenty-nine patients were treated with oral imatinib for either metastatic disease (n=26 patients) or in the adjuvant setting after complete resection (n=3 patients). RESULTS Resections were performed in 53 patients, and metastatic disease was identified in 17 patients at the time of exploratory surgery. Immunohistochemical staining for CD117 was positive in 96% of patients. A size larger than 5 cm, a mitotic rate larger than 1/10 high-power field, and tumor necrosis predicted recurrence in patients after resection. The median follow-up period was 18 months (range, 4-81 months). Twenty-three patients (40%) are alive without disease; 22 patients (39%) are alive with disease; 7 patients died, and 5 patients are lost to follow-up. Among the 26 patients with metastatic disease who were treated with imatinib, 5 deaths have occurred, and disease stabilization or tumor regression was observed initially in 22 patients, with a median duration of response of 19 months. CONCLUSIONS Complete surgical extirpation remains the only curative treatment of GIST. Imatinib-targeted therapy of metastatic disease yields encouraging clinical responses. The true efficacy of imatinib in this setting, as induction therapy or as an adjuvant treatment in patients with GIST, is unknown pending the completion of ongoing prospective trials.

A Randomized Phase II Trial of the Antiangiogenic Agent SU5416 in Hormone-Refractory Prostate Cancer

Purpose: To assess the activity of the antiangiogenic agent and VEGFR2 inhibitor SU5416 in hormone-refractory prostate cancer. Patients and Methods: Thirty-six chemotherapy naïve patients were randomized to treatment with SU5416 (145 mg/m2) and dexamethasone premedication or dexamethasone alone. Patients in the control arm could cross over to experimental therapy after progression. Prostate-specific antigen (PSA) was measured every 2 weeks, and radiological evaluation was performed every 8 weeks. In vitro assessment of SU5416 on PSA secretion was assessed in the LNCaP cell line. Baseline serum basic fibroblast growth factor and plasma vascular endothelial growth factor (VEGF) were explored as prognostic factors. Results: VEGF receptor-2 expression is detectable in prostate cancer cell lines, and SU5416 inhibited in vitro PSA secretion. No effect of SU5416 on PSA secretion or time to progression is detectable in patients. VEGF and basic fibroblast growth factor were not prognostic. Headache and fatigue were the most common SU5416 toxicities, but hyperglycemia, hyponatremia, lymphopenia, infection, and adrenal suppression, all attributable to steroids and the required central line, were common. Conclusion: No disease modifying effects of SU5416 were detectable in this small study. Modest toxicity, an inconvenient administration schedule, and availability of other VEGFR-targeted agents support the decision to halt further evaluation of SU5416 in prostate cancer.

Docetaxel and exisulind in hormone-refractory prostate cancer

Single-agent docetaxel has been shown to produce a significant decrease in prostate-specific antigen (PSA) levels among patients with hormone-refractory prostate cancer (HRPC). A recent study also showed that exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug sulindac, lengthens the median PSA doubling time in men who had increasing PSA levels after radical prostatectomy. Furthermore, exisulind has shown significant antineoplastic activity in prostate cancer cell lines in vitro and in nude mouse xenograft models. Because preclinical studies have suggested synergistic interactions between docetaxel and exisulind, a phase I/II clinical trial combining these agents has been initiated in patients with HRPC. The primary objective of this study is to determine PSA response and measurable disease response rate of the combination therapy; secondary objectives include toxicity assessment and determination of time to disease progression, duration of response, and overall survival. Accrual is ongoing.

A phase I study of liposomal doxorubicin (Doxil) with topotecan.

New therapies are needed for patients with advanced ovarian cancer who relapse after initial treatment with platinum and/or paclitaxel-based regimens. This study sought to determine the toxicities of combined liposomal doxorubicin (Doxil) and topotecan, and to determine a regimen for future phase II testing in ovarian cancer. Nine patients with advanced malignancies were treated with topotecan 1.0 mg/m2/day X 5 days followed by liposomal doxorubicin at a starting dose of 30 mg/m2 on day 5. Cycles were repeated every 28 days. A total of 13 cycles of therapy were administered. Grade IV neutropenia and grade IV thrombocytopenia developed in both of the two patients treated at the first dose level. Subsequent patients received only 20 mg/m2 liposomal doxorubicin. At that dose level, three patients experienced dose-limiting toxicity (one grade IV neutropenia, two grade IV neutropenia and thrombocytopenia). No responses were observed. These data indicate that the described regimen of liposomal doxorubicin and topotecan is not feasible because of excessive hematologic toxicity. Escalation to doses of liposomal doxorubicin or topotecan that have previously demonstrated antitumor activity was not possible. Future strategies to minimize such toxicity may include limiting eligibility to patients with minimal prior therapy, reducing the number of days of topotecan administration, or use of oral topotecan.

A phase II trial of sequential chemotherapy with docetaxel and methotrexate followed by gemcitabine and cisplatin for metastatic urothelial cancer

Administration of noncross-resistant agents in a sequential fashion may improve outcome by targeting tumor cells with different sensitivity profiles. We evaluated the toxicity and response rate of docetaxel and methotrexate (DM) followed by gemcitabine and cisplatin (GC) in patients with metastatic or unresectable transitional cell carcinoma of the urothelium. Patients received 3 cycles of DM (40 mg/m2 methotrexate on days 1 and 8 and 100 mg/m2 docetaxel on day 8 repeated every 21 days) followed by GC (1000 mg/m2 gemcitabine on days 1 and 8 and 75 mg/m2 cisplatin on day 1 repeated every 21 days). The most common toxicities were hematologic, with grade 3/4 neutropenia and thrombocytopenia observed in 4 and 2 patients, respectively. Four partial responses were observed after DM (4 of 12, 33% response rate) and 6 responses (3 partial response, 3 complete response, 6 of 9, 67% response rate) after GC for an overall response rate of 7 of 13 (54%). Three patients who progressed on DM responded to GC and 3 responders to DM achieved further response to GC. The median overall survival was 13.6 months. Although we do not recommend this particular sequence of chemotherapy for further study, the uncompromised median survival and the ability to salvage responses with GC suggest that testing of novel agents in sequence with GC is a feasible strategy.

A Phase Ii Trial of Uft and Leucovorin in Women 65 Years and Older With Advanced Breast Cancer

The incidence of breast cancer increases with age. This trial evaluated the efficacy and safety of oral UFT (ftorafur plus uracil) plus leucovorin in elderly patients with advanced breast cancer. Eligibility criteria included age ≥65 years, locally advanced or metastatic breast cancer, ≤1 prior chemotherapy regimens in the setting of metastatic disease, performance status 0–2, and adequate end-organ function. UFT at 300 mg/m2 per day as 2 divided doses and 30 mg leucovorin with each dose were administered orally daily for 21 days, followed by a 7-day rest period. Ten patients were accrued. Six patients received treatment in their first relapse and 3 in their second. One patient was chemotherapy-naive. The dose-limiting toxicity was diarrhea with grade 3 or 4 diarrhea occurring more often in the oldest patients (1 of 6 patients between 65 and 69 vs. 3 of 4 patients ≥70 years old). Protocol treatment was discontinued in 2 patients (ages 78 and 83) secondary to severe gastrointestinal toxicity. One patient achieved a partial response. Although UFT/leucovorin had efficacy in 1 patient, toxicity in the patients over 70 years of age was increased. Careful evaluation of anticancer drug toxicity in very elderly patients is important as our population ages.

Angiosarcoma masquerading as embryonal carcinoma in the metastasis from a mature testicular teratoma

Sarcoma can arise within a germ cell tumor (GCT) from a malignant transformation of teratomatous elements or as late sequelae to radiation therapy. Angiosarcoma as a malignant component in testicular GCTs has rarely been reported and is often misdiagnosed as embryonal carcinoma. We report the case of a 23-year-old man with mature teratoma of the testis and retroperitoneal metastasis exhibiting components of mature teratoma intermingled with high-grade angiosarcoma. It is important to recognize the presence of a high-grade sarcomatous component within a GCT because of its aggressive clinical behavior and different response to therapy.

CI-980 in advanced melanoma and hormone refractory prostate cancer.

Introduction: CI-980 is a novel chemotherapeutic agent thatinhibits polymerization of tubulin. Preclinical studies haveindicated a high level activity of this agent against various tumorcell lines. Methods: 13 malignant melanoma patients who hadfailed prior chemotherapy and/or immunotherapy and 13 hormonerefractory prostate cancer patients, including 4 who had receivedprior chemotherapy, were treated in 2 separate NCI-supportedclinical trials. Subjects received a recommended phase II dose ofCI-980 of 4.5 mg/m2/day by continuous infusion for 72 hoursevery 3 weeks. Results: No activity was seen in either study.Toxicity was tolerable with neutropenia being the most common,significant toxicity. Among the melanoma patients, 15% and 31%developed grade 3 and grade 4 neutropenia, while 7% and 38% ofthe prostate patients developed grade 3 and grade 4 neutropenia,respectively. Conclusions: CI-980 at this dose and scheduleis ineffective against malignant melanoma and hormone refractoryprostate cancer.

Gemcitabine in the treatment of bladder cancer

New agents are available for the treatment of metastatic transitional cell carcinoma of the bladder. In the US, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) remains the standard chemotherapy regimen for advanced bladder cancer. Gemcitabine (2′,2′-difluorodeoxycytidine [dFdC]) is a relatively new agent with a favourable toxicity profile that has demonstrated activity against a number of solid tumours in both preclinical and clinical studies. Single-agent gemcitabine has shown activity in bladder cancer in both pretreated and chemotherapy-naïve patients. The combination of gemcitabine plus cisplatin is a regimen with significant activity and moderate toxicity in bladder cancer patients. A randomised trial of gemcitabine plus cisplatin versus M-VAC has completed accrual but has not yet been reported. New combination studies of gemcitabine with other chemotherapy agents, including the taxanes, are ongoing.