TY - JOUR
T1 - Phase 1/1B trial of the heat shock protein 90 inhibitor NVP-AUY922 as monotherapy or in combination with bortezomib in patients with relapsed or refractory multiple myeloma
AU - Seggewiss-Bernhardt, Ruth
AU - Bargou, Ralf C.
AU - Goh, Yeow Tee
AU - Stewart, A. Keith
AU - Spencer, Andrew
AU - Alegre, Adrian
AU - Bladé, Joan
AU - Ottmann, Oliver G.
AU - Fernandez-Ibarra, Cristina
AU - Lu, Hong
AU - Pain, Scott
AU - Akimov, Mikhail
AU - Iyer, Swaminathan Padmanabhan
N1 - Publisher Copyright:
© 2015 American Cancer Society.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - BACKGROUND NVP-AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP-AUY922 alone and with bortezomib in patients with relapsed or refractory MM. METHODS Dose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP-AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP-AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP-AUY922. RESULTS Twenty-four patients received NVP-AUY922 monotherapy at doses of 8 to 70 mg/m2. One dose-limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m2); no MTD was reached. The recommended phase 2 dose was 70 mg/m2. The most frequent drug-related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (≥45 mg/m2). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP-AUY922 (which was started at 50 mg/m2) plus bortezomib (1.3 mg/m2). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP-AUY922 plus bortezomib was not established. CONCLUSIONS This study showed disease stabilization with NVP-AUY922 in patients with relapsed or refractory MM. The MTD for NVP-AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP-AUY922 was not tolerated. Cancer 2015;121:2185-2192.
AB - BACKGROUND NVP-AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP-AUY922 alone and with bortezomib in patients with relapsed or refractory MM. METHODS Dose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP-AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP-AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP-AUY922. RESULTS Twenty-four patients received NVP-AUY922 monotherapy at doses of 8 to 70 mg/m2. One dose-limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m2); no MTD was reached. The recommended phase 2 dose was 70 mg/m2. The most frequent drug-related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (≥45 mg/m2). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP-AUY922 (which was started at 50 mg/m2) plus bortezomib (1.3 mg/m2). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP-AUY922 plus bortezomib was not established. CONCLUSIONS This study showed disease stabilization with NVP-AUY922 in patients with relapsed or refractory MM. The MTD for NVP-AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP-AUY922 was not tolerated. Cancer 2015;121:2185-2192.
KW - AUY922
KW - bortezomib
KW - heat shock protein 90
KW - heat shock protein 90 inhibitors
KW - proteasome inhibitor
KW - relapsed or refractory multiple myeloma
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UR - http://www.scopus.com/inward/citedby.url?scp=84931069759&partnerID=8YFLogxK
U2 - 10.1002/cncr.29339
DO - 10.1002/cncr.29339
M3 - Article
C2 - 25809731
AN - SCOPUS:84931069759
VL - 121
SP - 2185
EP - 2192
JO - Cancer
JF - Cancer
SN - 0008-543X
IS - 13
ER -