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Clin Lymphoma Myeloma Leuk. 2013 Aug;13(4):385-91. doi: 10.1016/j.clml.2013.03.010. Epub 2013 Jun 10.

Phase I trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies.

Author information

1
Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Nishitha.reddy@vanderbilt.edu

Abstract

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/m(2) to 74 mg/m(2) 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/m(2) for 21/28 days was generally well tolerated with reversible toxicity. The responses observed in myeloma and lymphoma patients are encouraging.

KEYWORDS:

Clinical trial; Heat shock protein; Pharmacokinetics

PMID:
23763921
DOI:
10.1016/j.clml.2013.03.010
[Indexed for MEDLINE]

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