A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer.

OBJECTIVES: Epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases may be involved in activation of androgen receptor and progression of prostate cancer. They represent potential therapeutic targets in prostate cancer. Lapatinib is an oral inhibitor of EGFR and HER-2. The objective of this study is to assess the preliminary clinical efficacy of lapatinib in the therapy of castration-resistant prostate cancer. METHODS: In this multicenter, open-label trial, patients with rising PSA on androgen deprivation therapy and not having received chemotherapy were eligible. They were treated with lapatinib at a dose of 1,500 mg once daily. The primary end point was a >50% confirmed PSA decline from baseline; safety, tolerability, and time to PSA progression were secondary outcomes. RESULTS: Twenty-nine patients enrolled in the study had a median age of 73 years and a baseline PSA of 21.6 ng/ml. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both. Treatment was well tolerated with only grade 3 treatment-related toxicities being diarrhea (14%) and rash (3%). One of 21 evaluable patients had >50% reduction in PSA, while another patient had 47% reduction in PSA with an ongoing duration of response of 45+ months. The median time to PSA progression was 29 days. CONCLUSIONS: Lapatinib showed single agent activity in a small subset of unselected patients with castration-resistant prostate cancer, as measured by PSA. Future trials should explore a trial design with time-to-event end points and predictive biomarkers and a combination with other agents.

Neoadjuvant docetaxel/estramustine prior to radical prostatectomy or external beam radiotherapy in high risk localized prostate cancer: a phase II trial.

BACKGROUND: Patients with locally advanced or organ confined, high risk, prostate cancer are at significant risk of having disease recurrence despite definitive local therapy. We evaluated the 2-year progression-free survival of subjects treated with chemotherapy administered prior to definitive therapy with surgery or radiation. PATIENTS AND METHODS: Patients (n = 24) with locally advanced and high risk localized prostate cancer were treated with neoadjuvant docetaxel 36 mg/m2 i.v. weekly for 3 weeks and estramustine 140 mg orally 3 times daily for 3 consecutive days every 28 days prior to definitive treatment with prostatectomy or radiation. RESULTS: All evaluable patients, except 1, completed the proposed cycles of neoadjuvant chemotherapy with minimal dose reductions or delays. Of the 22 evaluable patients, 12 underwent radical prostatectomy and 10 underwent external beam radiation therapy. Twenty-one of 22 patients achieved a prostate-specific antigen (PSA) reduction > 25%. There were no pathologic complete responses. With a median follow-up of 24 months, the 2-year progression-free survival was 45%. CONCLUSIONS: Our findings support the safety, tolerability, and efficacy of neoadjuvant chemotherapy in patients with men with high risk, locally advanced prostate adenocarcinoma, although the relative contributions of androgen deprivation therapy and docetaxel cannot be determined. The effectiveness of neoadjuvant chemotherapy in preventing prostate cancer relapses should be studied in a randomized trial.

Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma.

PURPOSE: The multitargeted tyrosine kinase inhibitor sorafenib is used for the treatment of advanced-stage renal cell carcinoma. However, the safety and efficacy of this agent have yet to be evaluated in the preoperative period, where there may be potential advantages including tumor downstaging. This prospective trial evaluates the safety and feasibility of sorafenib in the preoperative setting. PATIENTS AND METHODS: Thirty patients with clinical stage II or higher renal masses, selected based on their candidacy for nephrectomy, underwent preoperative treatment with sorafenib. Toxicities, surgical complications, and tumor responses were monitored. RESULTS: Of the thirty patients enrolled, 17 patients had localized disease and 13 had metastatic disease. After a course of sorafenib therapy (median duration, 33 days), a decrease in primary tumor size (median, 9.6%) and radiographic evidence of loss of intratumoral enhancement, quantified using a methodology similar to Choi criteria (median, 13%), was also observed. According to Response Evaluation Criteria in Solid Tumors, of the 28 patients evaluable for response, two patients had a partial response and 26 had stable disease, with no patients progressing on therapy. Toxicities from sorafenib were similar to that expected with this class of medication. All patients were able to proceed with nephrectomy and no surgical complications related to sorafenib administration were observed. CONCLUSION: The administration of preoperative sorafenib therapy can impact the size and density of the primary tumor and appears safe and feasible. Further studies are required to determine if preoperative systemic therapy improves outcomes in patients undergoing nephrectomy for renal cell carcinoma.

A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results.

OBJECTIVE: To evaluate the clinicopathological efficacy of neoadjuvant erlotinib (an epidermal growth factor receptor, EGFR, inhibitor) for invasive bladder cancer in patients undergoing radical cystectomy (RC) as despite definitive surgical therapy, only half of patients undergoing RC will have long-term disease-free survival, and effective adjunctive therapies, especially using agents with lower toxicity, would be a significant advance in the treatment of invasive bladder cancer. PATIENTS AND METHODS: The primary endpoint of this phase II trial is to determine the effect of neoadjuvant erlotinib (150 mg once daily for 4 weeks) before RC on the pathological complete response rate (pT0 rate) in RC specimens. In addition, the safety of therapy with erlotinib was also evaluated. Patients selected for study included those with histologically confirmed muscle-invasive bladder cancer who had undergone initial transurethral resection. RESULTS: In all, 20 patients with clinical stage T2 disease had neoadjuvant erlotinib therapy followed by RC. On surgical pathology, five patients (25%) were pT0; in addition, seven (35%) were clinically down-staged (< or = pT1) and 15 (75%) had organ-confined disease at surgical pathology. At a mean follow-up of 24.8 months, 10 patients remain alive and with no evidence of disease, four with organ-confined disease had progression and nine died, including six from disease and three from other causes. Erlotinib was tolerated in all patients, with drug rash being the most common side-effect, in 15 patients (75%). Interestingly, all pT0 and pTis/T1 patients had a rash. CONCLUSIONS: The EGFR inhibitor erlotinib, when administered in the neoadjuvant setting, can have beneficial effects in terms of surgical pathology and short-term clinical outcomes in patients undergoing RC for invasive bladder cancer. Analyses are underway to examine the molecular correlates of the apparent clinical effect of neoadjuvant therapy in these patients.

Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer.

PURPOSE: We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN-alpha-2b) as first- or second-line therapy in metastatic renal cell cancer (RCC). PATIENTS AND METHODS: Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN-alpha-2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN-alpha-2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity. RESULTS: The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) -treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients. CONCLUSION: The combination of sorafenib and IFN-alpha-2b has substantial activity in treatment-naïve and IL-2-treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.

Phase II trial of celecoxib in prostate-specific antigen recurrent prostate cancer after definitive radiation therapy or radical prostatectomy.

OBJECTIVES: Recent evidence has shown that cyclooxygenase-2 (COX-2) inhibitors have potent antitumor activity in prostate cancer both in vitro and in vivo. However, human trials are absent. This study evaluated the efficacy of the COX-2 inhibitor celecoxib in prostate-specific antigen (PSA) recurrent prostate cancer after radiation therapy (X-ray therapy or XRT) or radical prostatectomy. METHODS: Forty patients who had biochemical relapse after XRT or radical prostatectomy were treated with celecoxib 400 mg twice per day. Follow-up PSA levels were obtained at 3, 6, 12, and 18 months and subsequently every 6 months thereafter. Data were evaluated by calculating PSA doubling times and by calculating the slope of the curve of log(PSA) versus time to assess rate of PSA increase before and after celecoxib treatment for each patient. RESULTS: Thirty-six of 40 (90%) patients had a slowing effect on their rate of PSA after 3 months, including 11 of 40 with a decline and 8 of 40 with stabilization of PSA. Short-term responses at 3 months continued at 6, 12, 18 months. Comparison of rate of PSA increase before versus after celecoxib treatment showed significant flattening of slope of log(PSA) versus time from pretreatment for each of the time points. There was no significant change in testosterone levels, suggesting an androgen-independent mechanism. CONCLUSIONS: COX-2 inhibitors may have an effect on serum PSA levels in patients with biochemical progression after XRT or radical prostatectomy. These results suggest that COX-2 inhibitors may help delay or prevent disease progression in these patients and thereby help extend the time until androgen deprivation therapy.