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

Nishitha Reddy, Peter M. Voorhees, Brett E. Houk, Nicoletta Brega, James M. Hinson, Anand Jillella

Research output: Contribution to journalArticle

18 Citations (Scopus)

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/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.

Original languageEnglish (US)
Pages (from-to)385-391
Number of pages7
JournalClinical Lymphoma, Myeloma and Leukemia
Volume13
Issue number4
DOIs
StatePublished - Aug 1 2013

Fingerprint

Hematologic Neoplasms
Thrombocytopenia
Lymphoma
HSP90 Heat-Shock Proteins
Maximum Tolerated Dose
PF 04929113
Pruritus
Multiple Myeloma
Nausea
Fatigue
Diarrhea
Cell Survival
Pharmacokinetics
Therapeutics
Growth

Keywords

  • Clinical trial
  • Heat shock protein
  • Pharmacokinetics

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Phase i trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies. / Reddy, Nishitha; Voorhees, Peter M.; Houk, Brett E.; Brega, Nicoletta; Hinson, James M.; Jillella, Anand.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 13, No. 4, 01.08.2013, p. 385-391.

Research output: Contribution to journalArticle

Reddy, Nishitha ; Voorhees, Peter M. ; Houk, Brett E. ; Brega, Nicoletta ; Hinson, James M. ; Jillella, Anand. / Phase i trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies. In: Clinical Lymphoma, Myeloma and Leukemia. 2013 ; Vol. 13, No. 4. pp. 385-391.
@article{f1cab917896b4c1c89d213f7a06b5213,
title = "Phase i trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies",
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/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.",
keywords = "Clinical trial, Heat shock protein, Pharmacokinetics",
author = "Nishitha Reddy and Voorhees, {Peter M.} and Houk, {Brett E.} and Nicoletta Brega and Hinson, {James M.} and Anand Jillella",
year = "2013",
month = "8",
day = "1",
doi = "10.1016/j.clml.2013.03.010",
language = "English (US)",
volume = "13",
pages = "385--391",
journal = "Clinical Lymphoma, Myeloma and Leukemia",
issn = "2152-2650",
publisher = "Cancer Media Group",
number = "4",

}

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 - Jillella, Anand

PY - 2013/8/1

Y1 - 2013/8/1

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

UR - http://www.scopus.com/inward/record.url?scp=84880739009&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880739009&partnerID=8YFLogxK

U2 - 10.1016/j.clml.2013.03.010

DO - 10.1016/j.clml.2013.03.010

M3 - Article

C2 - 23763921

AN - SCOPUS:84880739009

VL - 13

SP - 385

EP - 391

JO - Clinical Lymphoma, Myeloma and Leukemia

JF - Clinical Lymphoma, Myeloma and Leukemia

SN - 2152-2650

IS - 4

ER -