Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II consortium study.
OBJECTIVE
Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer.


METHODS
PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) 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).


CONCLUSIONS
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.
Davis
Nancy B
NB
Section of Hematology/Oncology, University of Chicago Medical Center, 5841 S Maryland Avenue, MC 2115, Chicago, IL 60637, USA.
Taber
David A
DA
Ansari
Rafat H
RH
Ryan
Christopher W
CW
George
Christopher
C
Vokes
Everett E
EE
Vogelzang
Nicholas J
NJ
Stadler
Walter M
WM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000069286:Bortezomib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009362:Neoplasm Metastasis; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome
D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex