Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen.

Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC.

Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.

PURPOSE: Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS: Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo (Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION: Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

Orteronel for Metastatic Hormone-Sensitive Prostate Cancer: A Multicenter, Randomized, Open-Label Phase III Trial (SWOG-1216).

PURPOSE: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS: Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months (P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION: The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.

Baseline Circulating Tumor Cell Count as a Prognostic Marker of PSA Response and Disease Progression in Metastatic Castrate-Sensitive Prostate Cancer (SWOG S1216).

PURPOSE: In metastatic castrate-sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch circulating tumor cell (CTC) count, an FDA-cleared assay in metastatic castrate-resistant prostate cancer (mCRPC), is a relevant biomarker in mCSPC. EXPERIMENTAL DESIGN: SWOG S1216 is a phase III prospective randomized trial of androgen deprivation therapy (ADT) combined with orteronel or bicalutamide for mCSPC. CellSearch CTC count was measured at registration (baseline). Prespecified CTC cut-off points of 0, 1-4, and ≥5 were correlated with baseline patient characteristics and, in a stratified subsample, were also correlated with two prespecified trial secondary endpoints: 7-month PSA ≤0.2 ng/mL versus 0.2-4.0 versus >4.0 (intermediate endpoint for overall survival); and progression-free survival (PFS) ≤ versus >2 years. RESULTS: A total of 523 patients submitted baseline samples, and CTCs were detected (median 3) in 33%. Adjusting for two trial stratification factors (disease burden and timing of ADT initiation), men with undetectable CTCs had nearly nine times the odds of attaining 7-month PSA ≤ 0.2 versus > 4.0 [OR 8.8, 95% confidence interval (CI), 2.7-28.6, P < 0.001, N = 264] and four times the odds of achieving > 2 years PFS (OR 4.0, 95% CI, 1.9-8.5, P < 0.001, N = 336) compared with men with baseline CTCs ≥5. CONCLUSIONS: Baseline CTC count in mCSPC is highly prognostic of 7-month PSA and 2-year PFS after adjusting for disease burden and discriminates men who are likely to experience poor survival outcomes.

Individualization of Adjuvant Therapy After Radical Prostatectomy for Clinically Localized Prostate Cancer: Current Status and Future Directions.

Radiation therapy indications in the postprostatectomy setting are evolving. Several retrospective series have identified a number of "high-risk" pathologic features associated with an elevated risk of disease recurrence after radical prostatectomy. More recently, several randomized phase III trials demonstrated superior biochemical relapse-free survival for adjuvant radiation therapy after prostatectomy for patients with these high-risk pathologic features, including positive margin status, extraprostatic extension, and/or seminal vesicle invasion. These series further suggested improvement in distant metastasis control and overall survival after 15 years. However, not all patients with high-risk features experience disease recurrence after surgery alone, and some subsets of patients experience suboptimal disease control and survival despite immediate postoperative radiotherapy. Furthermore, some patients without high-risk features will develop recurrence. The present review discusses the current data and potential future directions to improve individualization of therapy after prostatectomy.

Long-term survival after high-dose salvage chemotherapy for germ cell malignancies with adverse prognostic variables.

PURPOSE: Independent prognostic variables for patients undergoing high-dose chemotherapy (HDCT) as salvage modality for germ cell tumors (GCT) were previously described, and a score was created. Patients with more than 2 points had a poor prognosis. However, these data were from patients treated from 1984 to 1993, and most received a single HDCT course. In this study, we evaluated outcomes at Indiana University and determined the applicability of the Beyer score to contemporary poor-risk patients. PATIENTS AND METHODS: We performed a retrospective analysis of patients who received salvage HDCT between 1988 and 2001 and had at least one of the following characteristics: platinum-refractory or absolutely platinum-refractory GCT, primary mediastinal nonseminomatous GCT (PMNSGCT), human chorionic gonadotropin (HCG) > or = 1,000 mU/mL or alpha-fetoprotein (AFP) > or = 1,000 ng/mL before HDCT. Primary end points were overall and 2-year failure-free survival (FFS). RESULTS: Eighty patients were identified. Fifty-six were platinum refractory, 23 had a Beyer score greater than 2, and 13 had PMNSGCT. Fifty-six patients received two HDCT courses. HDCT included carboplatin and etoposide. Forty-three patients received HDCT as first salvage modality. Median overall survival was 14.7 months. The 2-year FFS was 32%. No relapses have occurred after 2 years from HDCT. Patients with greater than 2 points in the Beyer score, platinum-refractory patients, and patients with HCG > or = 1,000 mU/mL, AFP > or = 1,000 ng/mL, and PMNSGCT had 2-year FFS of 30%, 37%, 26%, 18%, and 0%, respectively. CONCLUSION: Results with PMNSGCT remained poor. However, other patients with poor prognosis should not be denied an attempt at curative salvage HDCT.

Phase II study of low-dose topotecan in myelodysplastic syndromes: a Hoosier Oncology Group (HOG) study.

Topotecan has demonstrable activity in high-risk MDS and CMMoL. However, the significant toxicity of topotecan administered at a dose of 2mg/m2 i.v. daily for 5 days as a continuous infusion limits its use in older patients. Therefore, we studied topotecan 1.5mg/m2 per day i.v. over 2 h for three consecutive days in 20 patients with high-risk MDS (12 RAEB; 4 RAEB-T; 4 CMMoL). Cycles were given every 4-6 weeks. Fifteen patients were evaluable for response. Only one patient achieved a durable complete remission (CR). There were three deaths within the first cycle of therapy. Severe myelosuppression was the most common toxicity. Grades 3-4 infections were documented in four patients. We conclude that topotecan administered at this dose and schedule has no clinically significant activity.

Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy.

INTRODUCTION: The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology. METHODS: We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay. RESULTS: At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = -0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001). CONCLUSIONS: Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.

Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206.

PURPOSE: Bevacizumab is an antibody that binds vascular endothelial growth factor and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN-alpha) is the historic standard initial treatment for RCC. A prospective, randomized, phase III trial of bevacizumab plus IFN-alpha versus IFN-alpha monotherapy was conducted. PATIENTS AND METHODS: Patients with previously untreated, metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN-alpha (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN-alpha monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety. RESULTS: Seven hundred thirty-two patients were enrolled. The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-alpha and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-alpha monotherapy (unstratified log-rank P = .097). Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = .069) favoring bevacizumab plus IFN-alpha. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-alpha. Patients who developed HTN on bevacizumab plus IFN-alpha had a significantly improved PFS and OS versus patients without HTN. CONCLUSION: OS favored the bevacizumab plus IFN-alpha arm but did not meet the predefined criteria for significance. HTN may be a biomarker of outcome with bevacizumab plus IFN-alpha.

Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.

PURPOSE: Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted. PATIENTS AND METHODS: Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%). CONCLUSION: Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.