Atrasentan in Patients With Advanced Renal Cell Carcinoma: A Phase 2 Trial of the ECOG-ACRIN Cancer Research Group (E6800)

Abstract

Objectives Atrasentan, an oral endothelin-A receptor antagonist, demonstrated Phase I activity in patients with renal cell cancer (RCC). A phase II study was undertaken in patients with measurable or bone only metastatic RCC in the pre-VEGF/TKI era. Methods and Materials Patients were stratified on disease status and prior immunotherapy. Eligible patients had no prior chemotherapy, 0-1 prior immunotherapies, and ECOG PS 0 - 2. Patients received atrasentan 10 mg/day until progression. The primary endpoint was progression-free (PF) rate at 6 months. Rates of 25% among patients treated with prior immunotherapy and 45% among patients with no prior immunotherapy were considered promising. A two-stage design was used for cohorts without prior immunotherapy. Results From 2003 to 2005, 98 patients were registered. Median treatment duration was 9.9 weeks (range, 0.3 - 107 weeks). Toxicities were mild; 71% of patients reported no Grade 3 or higher treatment-related events. Grade 4 events included neutropenia (n=3), dyspnea (n=2), thrombosis, and arrhythmia (n=1 each). Two grade 5 events (dyspnea and constitutional) were possibly treatment-related. Six-month PF rates (90% CI) were 14% (6 - 25%), 0% (0 – 39%), 8% (1 – 23%) and 22% (8 – 44%) respectively for patients with prior immunotherapy/measurable disease (n=44), prior immunotherapy/bone metastases (n=6), no prior immunotherapy/measurable disease (n=25), and no prior immunotherapy/bone metastases (n=18). Median PF survival was 2.3 months (95% CI, 2.0 – 3.5 months). Conclusions While well tolerated, atrasentan did not yield 6-month PF rates supporting its use as first-line monotherapy in patients with advanced RCC.

Endothelin type A receptors mediate pain in a mouse model of sickle cell disease

“…At the dosages used, ABT-627 produced pain relief that persisted for the entire testing period (at least 7 hours) with no noticeable side effects. Given that ABT-627 and similar ET A receptor antagonists have been used in phase II/III clinical trials for cancer treatment 18 , 19 and are beneficial for SCD-related pulmonary hypertension, 16 targeting DRG ET A receptors may have potential therapeutic value for SCD-associated pain management.…”

“… 17 However, whether and how this elevated ET-1 in SCD DRG contributes to SCD-associated pain remains elusive. Given that ET A receptor antagonists have been used in phase II/III clinical trials for cancer treatment 18 , 19 and SCD-related pulmonary hypertension, 16 identifying the role of ET-1 and its ET A receptors in SCD-associated pain may provide a new avenue for treatment of SCD-associated pain in patients.…”

Bone Pain and Muscle Weakness in Cancer Patients

“…The ET1A receptor antagonist atrasentan is under phase II trials for bone metastates in renal carcinoma patients. [60] However, a meta-analysis of its use in prostate cancer showed a significant decrease in CIBP and SRE with a delayed rise in PSA and bone alkaline phosphatase. [61]…”

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

“…Other genes associated with the angiogenic process were observed to contribute to tumor dormancy, including tropomyosin, transforming growth factor beta 2 (TGF-b2), Eph receptor A5 (EphA5), histone H2BK, proline 4-hydroxylase alpha polypeptide I, and insulin-like growth factor binding protein 5 (IGFBP-5) [ 123 ]. Several studies not including UM investigated the role of MSGs in preventing the formation of metastases and favoring dormancy [ 124 , 125 , 141 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 ]. Specifically, the MSGs KISS1, RhoG-DI2, and Nm23-H1 showed to be able to suppress the development of distant metastases without significantly affecting tumor growth at the primary site [ 124 , 125 ].…”