Gayle Grigson

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.

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.

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.

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

Study Type – Therapy (cohort)
Level of Evidence 2b

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.

A phase II trial of neo-adjuvant docetaxel (D) and estramustine (E) in patients with high risk/locally advanced prostate cancer

4753 Background: Biochemical failure rates after radiation therapy (RT) or radical prostatectomy (RP) in patients (pts) with high risk/locally advanced prostate cancer approach 30% after two years. We evaluated the efficacy and safety of weekly neoadjuvant D and E chemotherapy in patients with high risk/locally advanced prostate cancer. METHODS We report the interim results of a phase II trial of neoadjuvant chemotherapy in high risk/locally advanced prostate cancer examining PSA response to chemotherapy, pathologic stage after RP, and 2 year progression free survival. Eligibility criteria were clinical stage T3, T1-2 + Gleason Score (GS) 8-10, or T1-2 + GS 7 + PSA>10 ng/mL. Three cycles of D (36 mg/m2) days 2, 9, & 16 and E (140 mg TID) on days 1-3 q28 days were administered followed by either RT or RP. All pts were placed on warfarin 2 mg/day. Pathologic response was evaluated after RP. RESULTS Out of 24 anticipated subjects, 12 pts with a median age of 64 years and PSA of 26 (range 10 - 53) were evaluable. Three pts had clinical stage T1, 7 T2, and 2 T3. GS was ≤7 in 7 pts and ≥8 in 5 pts. All three cycles of chemotherapy were administered to all pts, except for one who died during the first cycle from an unknown cause. Median testosterone baseline and nadir levels were 290 and 10 ng/mL. Therapy was well tolerated. The most common toxicities were grade III dyspnea (17%) and grade III fatigue (17%). All pts had a response by PSA criteria with a median nadir of 0.5 ng/mL. None of the 3 patients undergoing RP were pathological stage P0. Seven pts had RT. CONCLUSIONS Neoadjuvant weekly docetaxel and estramustine is well tolerated, potentially active, and deserves further study in high risk/locally advanced prostate cancer pts. Supported by Aventis. [Table: see text].