TY - JOUR
T1 - Phase i trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies
AU - Reddy, Nishitha
AU - Voorhees, Peter M.
AU - Houk, Brett E.
AU - Brega, Nicoletta
AU - Hinson, James M.
AU - Jillela, Anand
N1 - Funding Information:
P.M. Voorhees participated in an Advisory Board for MedImmune in 2011; previously participated in Speakers Bureaus for Celgene and Millennium Pharmaceuticals (2008); received research funding from Pfizer (for this study), and from Merck and Johnson & Johnson (small levels of support for running various myeloma trials). J.M. Hinson was a medical consultant to Serenex, Inc, and Pfizer Inc, during the development of the compound. B. Houk and N. Brega are both employees of Pfizer. N. Reddy and A. Jillela has no conflicts of interest.
Funding Information:
Research support for N.R. provided by NCRR/NIH , and 5K-12 CA090625-09 . This study was sponsored by Pfizer Inc . Editorial support was provided by Rachel Mason at ACUMED (Tytherington, UK) with funding from Pfizer Inc.
PY - 2013/8
Y1 - 2013/8
N2 - Background: Heat shock protein (HSP)90 regulates the function of proteins responsible for cell growth and survival, is overexpressed in many cancers and is an attractive therapeutic target. We undertook a phase 1 trial of PF-04929113 (SNX-5422), a novel oral HSP90 inhibitor, to estimate the maximum tolerated dose and describe the pharmacokinetic and toxicity profiles. Patients and Methods: Patients with relapsed, refractory, hematologic malignancies and adequate organ function were eligible. PF-04929113 was administered orally every other day for 21 days of a 28-day cycle. Twenty-five patients were treated, with dose escalation ranging from 5.32 mg/m2 to 74 mg/m2 using a 3 plus 3 trial design. Results: All 25 patients enrolled were evaluable for toxicity. Most common toxicities included prolonged QTc interval, diarrhea, pruritus, thrombocytopenia, fatigue, and nausea. Grade 3/4 treatment-related adverse events were experienced by 7/25 patients (28%); thrombocytopenia was the most common (n = 3 grade 3; n = 2 grade 4). Partial response was experienced by a patient with transformed lymphoma, and prolonged stabilization of disease was observed in a patient with multiple myeloma. Conclusion: Alternate-day oral dosing of PF-04929113 at 74 mg/m2 for 21/28 days was generally well tolerated with reversible toxicity. The responses observed in myeloma and lymphoma patients are encouraging.
AB - Background: Heat shock protein (HSP)90 regulates the function of proteins responsible for cell growth and survival, is overexpressed in many cancers and is an attractive therapeutic target. We undertook a phase 1 trial of PF-04929113 (SNX-5422), a novel oral HSP90 inhibitor, to estimate the maximum tolerated dose and describe the pharmacokinetic and toxicity profiles. Patients and Methods: Patients with relapsed, refractory, hematologic malignancies and adequate organ function were eligible. PF-04929113 was administered orally every other day for 21 days of a 28-day cycle. Twenty-five patients were treated, with dose escalation ranging from 5.32 mg/m2 to 74 mg/m2 using a 3 plus 3 trial design. Results: All 25 patients enrolled were evaluable for toxicity. Most common toxicities included prolonged QTc interval, diarrhea, pruritus, thrombocytopenia, fatigue, and nausea. Grade 3/4 treatment-related adverse events were experienced by 7/25 patients (28%); thrombocytopenia was the most common (n = 3 grade 3; n = 2 grade 4). Partial response was experienced by a patient with transformed lymphoma, and prolonged stabilization of disease was observed in a patient with multiple myeloma. Conclusion: Alternate-day oral dosing of PF-04929113 at 74 mg/m2 for 21/28 days was generally well tolerated with reversible toxicity. The responses observed in myeloma and lymphoma patients are encouraging.
KW - Clinical trial
KW - Heat shock protein
KW - Pharmacokinetics
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U2 - 10.1016/j.clml.2013.03.010
DO - 10.1016/j.clml.2013.03.010
M3 - Article
C2 - 23763921
AN - SCOPUS:84880739009
SN - 2152-2650
VL - 13
SP - 385
EP - 391
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 4
ER -