Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma

John P. Leonard, Brian K. Link, Christos Emmanouilides, Stephanie A. Gregory, Daniel Weisdorf, Jeffrey Andrey, John Hainsworth, Joseph A. Sparano, Donald E. Tsai, Sandra Horning, Arthur M. Krieg, George J. Weiner

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Abstract

Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. Experimental Design: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

Original languageEnglish (US)
Pages (from-to)6168-6174
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number20
DOIs
StatePublished - Oct 15 2007

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Toll-Like Receptor 9
Non-Hodgkin's Lymphoma
ProMune
Rituximab
Therapeutics
B-Cell Lymphoma
Neutropenia
Oligonucleotides
Antineoplastic Agents
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma. / Leonard, John P.; Link, Brian K.; Emmanouilides, Christos; Gregory, Stephanie A.; Weisdorf, Daniel; Andrey, Jeffrey; Hainsworth, John; Sparano, Joseph A.; Tsai, Donald E.; Horning, Sandra; Krieg, Arthur M.; Weiner, George J.

In: Clinical Cancer Research, Vol. 13, No. 20, 15.10.2007, p. 6168-6174.

Research output: Contribution to journalArticle

Leonard, JP, Link, BK, Emmanouilides, C, Gregory, SA, Weisdorf, D, Andrey, J, Hainsworth, J, Sparano, JA, Tsai, DE, Horning, S, Krieg, AM & Weiner, GJ 2007, 'Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma', Clinical Cancer Research, vol. 13, no. 20, pp. 6168-6174. https://doi.org/10.1158/1078-0432.CCR-07-0815
Leonard, John P. ; Link, Brian K. ; Emmanouilides, Christos ; Gregory, Stephanie A. ; Weisdorf, Daniel ; Andrey, Jeffrey ; Hainsworth, John ; Sparano, Joseph A. ; Tsai, Donald E. ; Horning, Sandra ; Krieg, Arthur M. ; Weiner, George J. / Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 20. pp. 6168-6174.
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title = "Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma",
abstract = "Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. Experimental Design: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80{\%} of patients. Treatment-related adverse events occurred in 11 of 19 (58{\%}) i.v. patients, 15 of 19 (79{\%}) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24{\%}) patients overall and in 6 of 12 (50{\%}) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.",
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T1 - Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non-Hodgkin's lymphoma

AU - Leonard, John P.

AU - Link, Brian K.

AU - Emmanouilides, Christos

AU - Gregory, Stephanie A.

AU - Weisdorf, Daniel

AU - Andrey, Jeffrey

AU - Hainsworth, John

AU - Sparano, Joseph A.

AU - Tsai, Donald E.

AU - Horning, Sandra

AU - Krieg, Arthur M.

AU - Weiner, George J.

PY - 2007/10/15

Y1 - 2007/10/15

N2 - Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. Experimental Design: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

AB - Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. Experimental Design: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

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