TY - JOUR
T1 - Phase II trial of PS-341 in patients with renal cell cancer
T2 - A University of Chicago phase II consortium study
AU - Davis, Nancy B.
AU - Taber, David A.
AU - Ansari, Rafat H.
AU - Ryan, Christopher W.
AU - George, Christopher
AU - Vokes, Everett E.
AU - Vogelzang, Nicholas J.
AU - Stadler, Walter M.
PY - 2004
Y1 - 2004
N2 - Purpose: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods: PS-341 1.5 mg/m2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.
AB - Purpose: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods: PS-341 1.5 mg/m2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.
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U2 - 10.1200/JCO.2004.07.165
DO - 10.1200/JCO.2004.07.165
M3 - Article
C2 - 14701773
AN - SCOPUS:2442510143
SN - 0732-183X
VL - 22
SP - 115
EP - 119
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 1
ER -