Role of sorafenib in overcoming resistance of chemotherapy-failure castration-resistant prostate cancer.

BACKGROUND: Sorafenib promotes apoptosis through downstream pathways that can be deregulated in CRPC. We hypothesized that sorafenib could overcome chemotherapy resistance in CRPC. PATIENTS AND METHODS: Eligible patients were those whose disease had progressed during chemotherapy (docetaxel or mitoxantrone) or within 12 weeks of stopping either. Patients then continued or resumed their last chemotherapy regimen with the addition of sorafenib 400 mg twice daily. Patients received a maximum of 6 cycles of chemotherapy/sorafenib followed by sorafenib alone until disease progression. The primary end point was combination safety. Secondary end points were overall response, percentage of SD, and time to progression (TTP). RESULTS: Twenty-two patients (21 evaluable) were enrolled (16 patients with Gleason score ≥ 7). Median age was 68 years (range, 59-83 years). Median prostate-specific antigen (PSA) was 142 ng/dL (range, 13.6-9584). Visceral and bone disease were present combined in 9 patients (41%). Ten patients (47.6%) showed biochemical response (19% with > 50% PSA decline) and 16 patients (76%) achieved radiographic stability (according to Response Evaluation Criteria for Solid Tumors) after starting sorafenib for a median duration of 6 months (range, 4-12 months). Grade 3/4 nonhematologic toxicities were fatigue (n = 7, 32%), palmar-plantar erythrodysesthesia (n = 4, 18%). Dose reduction of sorafenib occurred at least once in 15 patients (68%) because of palmar-plantar erythrodysesthesia (22%) and fatigue (22%). With a median follow-up of 19 months (range, 3-46 months), median overall survival was 8 months. TTP according to PSA level was 3 months and TTP according to imaging studies and/or clinically was 6 months. Median number of treatment cycles given was 6 (range, 1-10). CONCLUSION: Sorafenib can be combined safely with chemotherapy and in some patients overcomes chemotherapy resistance.

Lenalidomide monotherapy in chemotherapy-naive, castration-resistant prostate cancer patients: final results of a phase II study.

BACKGROUND: We investigated the activity of lenalidomide, which has antiangiogenic, antineoplastic, and immunomodulatory properties, in chemotherapy-naive, castration-resistant prostate cancer (CRPC) patients. PATIENTS: Patients received 25 mg/d lenalidomide for 21 days in 28-day cycles, until disease progression or unacceptable toxicity developed. Endpoints included overall response rate and clinical benefit (overall response + stable disease), toxicity, time to radiographic progression, and time to prostate-specific antigen (PSA) progression, overall survival, and quality of life. RESULTS: Thirty-two patients were enrolled in the study; of these, 77% (n = 25) had Gleason scores ≥ 7. The median age was 74 years (58-89 y), the median PSA level was 66 ng/mL (2-919 ng/mL), and 5 of 32 patients (17%) had liver or lung involvement. The median number of lenalidomide cycles was 3 (1-16 cycles). Stable disease was seen in 20 patients, for a clinical benefit rate of 63%. The median time to radiographic progression was 4 months (2-16 mo); the median overall survival was 20 months. Of 27 PSA-evaluable patients, 13 (48%) had a decline in PSA level; 3 (11%) had > 50% PSA decrease; the median time to PSA progression was 3 months (2-9 mo). Grade 3/4 hematologic toxicities were the most common adverse events without adverse impact on quality of life. Serious adverse events occurred in 14 patients (44%), including 1 patient (3%) with a rash definitely related to lenalidomide. CONCLUSION: Lenalidomide monotherapy demonstrates modest activity in chemotherapy-naive CRPC.

Bortezomib (Velcade), rituximab, cyclophosphamide, and dexamethasone combination regimen is active as front-line therapy of low-grade non-Hodgkin lymphoma.

OBJECTIVE: To evaluate the efficacy and toxicity of the combination of VRCD (velcade/rituximab/cyclophosphamide/dexamethasone) in chemotherapy-naïve low-grade non-Hodgkin lymphoma or patients with transplantation-ineligible mantle cells. METHODS: The patients were treated with velcade, at 1.6 mg/m(2), on days 1, 8, 15, and 22 on every 35-day cycle. Rituximab was given at 375 mg/m(2) on the same days as velcade during cycle 1 and then only on day 1 in subsequent cycles. Dexamethasone was given orally at 40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. Cyclophosphamide was administered orally at 400 mg/m(2) on days 1-4. The patients had to meet criteria to initiate therapy and had to demonstrate adequate performance status and organ function. RESULTS: Twelve patients were enrolled, after which the study was closed due to a lack of funding. The median age was 68 years (37-83 years), with 83% having stage III/IV disease. Five patients had marginal zone, 4 had follicular, 2 had small lymphocytic, and 1 had mantle cell histologies. The overall response rate was 90% (complete response, 54%). At a median follow-up of 22 months, 9 (75%) patients remain alive, and the median time to progression has not been reached. A third of the patients required dose reductions after a median of 6.5 cycles. No grade 3 or 4 peripheral neuropathy was witnessed. CONCLUSIONS: Although the number of studied patients is small, VRCD appears safe and active as front-line therapy for low-grade non-Hodgkin lymphoma. Further studies are justified.

Efficacy and safety of clofarabine in relapsed and/or refractory non-Hodgkin lymphoma, including rituximab-refractory patients.

BACKGROUND: Currently, no standard therapy exists for patients with relapsed and/or refractory non-Hodgkin lymphoma (NHL) who are ineligible for transplantation or who have failed after bone marrow transplantation. The authors of this report investigated the safety and efficacy of clofarabine (CLO) in these patients. METHODS: In a 2-step, open-label study, CLO (as a 1-hour intravenous infusion given daily for 5 days) was given every 28 days (maximum, 6 cycles). In the phase 1 portion (n = 7; standard 3 + 3 study design), the dose was escalated by 2 mg/m(2) to determine the maximum tolerated dose (MTD). The phase 2 study (n = 26) was initiated at the MTD, and patients were followed until disease progression. RESULTS: Of 33 patients who were enrolled, 31 patients (median age, 69 years) were evaluable; 24% failed after previous stem cell transplantation, and 72% were rituximab-refractory. The MTD for CLO was 4 mg/m(2) . The overall response rate was 42%. Seven patients (23%) achieved a complete response, and 6 patients (19%) achieved a partial response. The median response duration was 5 months. Among the rituximab-refractory patients, the overall response rate was 47% (complete response rate, 28%), and the median response duration was 7 months. At a median follow-up of 14 months, 45% of patients remained alive (median overall survival, 10 months). Toxicity was mainly hematologic (≥60% of patients had neutropenia or thrombocytopenia). Nonhematologic toxicity included tumor lysis syndrome, infection, and renal insufficiency (in 6% of patients each). No treatment-related mortality was observed. CONCLUSIONS: Single-agent CLO was active and was tolerated well in patients with refractory NHL, including patients in a rituximab-refractory subset. Reversible myelosuppression was the major toxicity. Study is registered at www.clinicaltrials.gov (NCT00156013).

A phase II pilot trial investigating the efficacy and activity of single agent granulocyte macrophage colony-stimulating factor as maintenance approach in castration - resistant prostate cancer patients responding to chemotherapy.

PURPOSE: To investigate the toxicity and efficacy of GM-CSF in castration-resistant prostate cancer (CRPC) patients who maximized their response to systemic chemotherapy. MATERIALS AND METHODS: CRPC patients who maximized their response to either docetaxel or mitoxantrone chemotherapy were eligible if they demonstrated adequate performance status, liver, kidney, and bone marrow function. Maximum response to chemotherapy was defined as either receiving at least 8 cycles of chemotherapy without radiographic or biochemical progression, receiving less than 8 cycles as long as the prostate-specific antigen (PSA) changes by less than 10%, or being off chemotherapy for less than 12 weeks without disease progression. Patients received GM-CSF at 250 mcg/m(2) subcutaneously for 14 days followed by 14 days of rest. GM-CSF was continued until disease progression. RESULTS: Fifteen patients were enrolled of which all were evaluable for toxicity and 13 were evaluable for efficacy. Median age was 78 (range 66-96) and 93% of patients had a Gleason score ≥ 7. Biochemically, 2 patients (15.3%) attained partial response (PR) and 4 (30.7%) had stable disease (SD). Median time to PSA progression was 6 months (range 4-12). Radiographically, 9 patients (69.2%) had SD that lasted a median of 6 months (range 2-10). With a median follow-up of 24 months from starting GM-CSF (range 2-38), 2 patients (13.3%) remain alive and well. Median OS from start of any chemotherapy was 21 months (range 10-44). GM-CSF was well-tolerated with minimal expected manageable toxicities. CONCLUSIONS: GM-CSF is active post-chemotherapy in CRPC patients. Further studies with GM-CSF in this setting are warranted.

Erlotinib has moderate single-agent activity in chemotherapy-naïve castration-resistant prostate cancer: final results of a phase II trial.

OBJECTIVES: To investigate the efficacy and toxicity of single-agent erlotinib in chemotherapy-naive castration-resistant prostate cancer. METHODS: Eligible patients received erlotinib at 150 mg daily until disease progression. Toxicity was assessed every 2 weeks and responses every 8 weeks. Primary end point was assessing the overall clinical benefit measured as the sum of stable disease, partial response, and complete response. Secondary end points included time to disease progression, overall survival, and toxicity using the National Cancer Institute Common Toxicity Criteria version 3.0. RESULTS: A total of 29 patients were enrolled in this study. Median age was 77 and median prostate-specific antigen was 66.3 ng/mL. Of 22 evaluable patients, 2 met the criteria for partial response and 5 demonstrated stable disease for an overall clinical benefit of 31%. PSA-doubling time improved in all responding patients to a median of 6 months from 3 months before entry into the study. One patient remained in study at 28 months, and 2 had > 50% decrease in their serum PSA level. Median time to disease progression was 2 months, but at 12 months, 9% of patients were progression-free. Median overall survival was 16.3 months, with 1- and 2-year survival rates of 58% and 27%, respectively. Erlotinib was well tolerated, with only 2 patients requiring dose reductions. Adverse events were as expected with grade 3 or 4 diarrhea, fatigue, and rash occurring in 10%, 6%, and 6% of patients, respectively. CONCLUSIONS: Erlotinib has moderate activity in chemotherapy-naive castration-resistant prostate cancer, with some patients showing biochemical response. Future studies investigating this agent in combination are warranted. (This trial was registered at http://NCI.gov, NCT00272038).