A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer

M. Aglietta, C. Barone, M. B. Sawyer, M. J. Moore, W. H. Miller, C. Bagalà, F. Colombi, C. Cagnazzo, L. Gioeni, E. Wang, B. Huang, K. D. Fly, F. Leone

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Abstract

Background: Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyteassociated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, openlabel, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. Patients and methods: Gemcitabine (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. Results: From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). Conclusion: Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.

Original languageEnglish
Article numbermdu205
Pages (from-to)1750-1755
Number of pages6
JournalAnnals of Oncology
Volume25
Issue number9
DOIs
Publication statusPublished - 2014

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gemcitabine
Pancreatic Neoplasms
Drug Therapy
Viral Tumor Antigens
tremelimumab
Safety
Asthenia
Maximum Tolerated Dose

Keywords

  • Gemcitabine chemotherapy
  • Immunotherapy
  • Metastatic pancreatic cancer
  • Tremelimumab

ASJC Scopus subject areas

  • Oncology
  • Hematology
  • Medicine(all)

Cite this

A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. / Aglietta, M.; Barone, C.; Sawyer, M. B.; Moore, M. J.; Miller, W. H.; Bagalà, C.; Colombi, F.; Cagnazzo, C.; Gioeni, L.; Wang, E.; Huang, B.; Fly, K. D.; Leone, F.

In: Annals of Oncology, Vol. 25, No. 9, mdu205, 2014, p. 1750-1755.

Research output: Contribution to journalArticle

Aglietta, M. ; Barone, C. ; Sawyer, M. B. ; Moore, M. J. ; Miller, W. H. ; Bagalà, C. ; Colombi, F. ; Cagnazzo, C. ; Gioeni, L. ; Wang, E. ; Huang, B. ; Fly, K. D. ; Leone, F. / A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. In: Annals of Oncology. 2014 ; Vol. 25, No. 9. pp. 1750-1755.
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title = "A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer",
abstract = "Background: Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyteassociated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, openlabel, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. Patients and methods: Gemcitabine (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. Results: From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8{\%}) and nausea (8.8{\%}). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95{\%} confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5{\%}). Conclusion: Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.",
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author = "M. Aglietta and C. Barone and Sawyer, {M. B.} and Moore, {M. J.} and Miller, {W. H.} and C. Bagal{\`a} and F. Colombi and C. Cagnazzo and L. Gioeni and E. Wang and B. Huang and Fly, {K. D.} and F. Leone",
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T1 - A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer

AU - Aglietta, M.

AU - Barone, C.

AU - Sawyer, M. B.

AU - Moore, M. J.

AU - Miller, W. H.

AU - Bagalà, C.

AU - Colombi, F.

AU - Cagnazzo, C.

AU - Gioeni, L.

AU - Wang, E.

AU - Huang, B.

AU - Fly, K. D.

AU - Leone, F.

PY - 2014

Y1 - 2014

N2 - Background: Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyteassociated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, openlabel, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. Patients and methods: Gemcitabine (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. Results: From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). Conclusion: Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.

AB - Background: Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyteassociated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, openlabel, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. Patients and methods: Gemcitabine (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. Results: From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). Conclusion: Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.

KW - Gemcitabine chemotherapy

KW - Immunotherapy

KW - Metastatic pancreatic cancer

KW - Tremelimumab

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