Phase II Trial of Murine Monoclonal Antibody D612 Combined with Recombinant Human Monocyte Colony-stimulating Factor (rhM-CSF) in Patients with Metastatic Gastrointestinal Cancer

Mansoor N. Saleh, M. B. Khazaeli, Richard H. Wheeler, Tiepu Liu, Michael P. Everson, Albert F. LoBuglio, R. Pat Bucy, Jeff Schlom, David H Munn

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Abstract

In a Phase II study, 14 patients with metastatic gastrointestinal cancer received the mAb D612 (40 mg/m2, days 4,7, and 11) in combination with recombinant human monocyte colony-stimulating factor [(rhM-CSF) 80 ug/kg/days 1–14]. The combined treatment was well tolerated and resulted in characteristic biological activity associated with each of the agents. Thus, 10 of 14 patients experienced D612-associated secretory diarrhea, which responded to the prostaglandin inhibitor Indomethacin in 5 of 7 patients. rhM-CSF therapy was associated with peripheral monocytosis (peak absolute monocyte count, 1444 ± 394/mm3) and thrombocytopenia (nadir count, 78 ± 10/mm3). Monocyte surface marker analysis revealed a high baseline expression of CD16+ cells in our patient population with an additional increase with rhM-CSF therapy. We observed a correlation between the degree of thrombocytopenia and the pretreatment CD16+ monocyte count Of the plasma cytokines assayed, serum Neop-terin demonstrated the most consistent increase during rhM-CSF therapy. There was a significant difference in the half-life of the first and last dose of D612 (35.8 ± 2 versus 27 ± 2.9 h; P < 0.05). Eleven of fourteen patients developed low-moderate levels of anti-D612 antibody. Despite the observed biological activity of both rhM-CSF and D612 and the previously described in vitro synergy, no clinical antitumor responses were observed in this Phase II study.

Original languageEnglish (US)
Pages (from-to)4339-4346
Number of pages8
JournalCancer Research
Volume55
Issue number19
StatePublished - Oct 1 1995

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Colony-Stimulating Factors
Gastrointestinal Neoplasms
Monocytes
Monoclonal Antibodies
Thrombocytopenia
Prostaglandin Antagonists
Therapeutics
Indomethacin
Half-Life
Anti-Idiotypic Antibodies
Diarrhea
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II Trial of Murine Monoclonal Antibody D612 Combined with Recombinant Human Monocyte Colony-stimulating Factor (rhM-CSF) in Patients with Metastatic Gastrointestinal Cancer. / Saleh, Mansoor N.; Khazaeli, M. B.; Wheeler, Richard H.; Liu, Tiepu; Everson, Michael P.; LoBuglio, Albert F.; Bucy, R. Pat; Schlom, Jeff; Munn, David H.

In: Cancer Research, Vol. 55, No. 19, 01.10.1995, p. 4339-4346.

Research output: Contribution to journalArticle

Saleh, MN, Khazaeli, MB, Wheeler, RH, Liu, T, Everson, MP, LoBuglio, AF, Bucy, RP, Schlom, J & Munn, DH 1995, 'Phase II Trial of Murine Monoclonal Antibody D612 Combined with Recombinant Human Monocyte Colony-stimulating Factor (rhM-CSF) in Patients with Metastatic Gastrointestinal Cancer', Cancer Research, vol. 55, no. 19, pp. 4339-4346.
Saleh, Mansoor N. ; Khazaeli, M. B. ; Wheeler, Richard H. ; Liu, Tiepu ; Everson, Michael P. ; LoBuglio, Albert F. ; Bucy, R. Pat ; Schlom, Jeff ; Munn, David H. / Phase II Trial of Murine Monoclonal Antibody D612 Combined with Recombinant Human Monocyte Colony-stimulating Factor (rhM-CSF) in Patients with Metastatic Gastrointestinal Cancer. In: Cancer Research. 1995 ; Vol. 55, No. 19. pp. 4339-4346.
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abstract = "In a Phase II study, 14 patients with metastatic gastrointestinal cancer received the mAb D612 (40 mg/m2, days 4,7, and 11) in combination with recombinant human monocyte colony-stimulating factor [(rhM-CSF) 80 ug/kg/days 1–14]. The combined treatment was well tolerated and resulted in characteristic biological activity associated with each of the agents. Thus, 10 of 14 patients experienced D612-associated secretory diarrhea, which responded to the prostaglandin inhibitor Indomethacin in 5 of 7 patients. rhM-CSF therapy was associated with peripheral monocytosis (peak absolute monocyte count, 1444 ± 394/mm3) and thrombocytopenia (nadir count, 78 ± 10/mm3). Monocyte surface marker analysis revealed a high baseline expression of CD16+ cells in our patient population with an additional increase with rhM-CSF therapy. We observed a correlation between the degree of thrombocytopenia and the pretreatment CD16+ monocyte count Of the plasma cytokines assayed, serum Neop-terin demonstrated the most consistent increase during rhM-CSF therapy. There was a significant difference in the half-life of the first and last dose of D612 (35.8 ± 2 versus 27 ± 2.9 h; P < 0.05). Eleven of fourteen patients developed low-moderate levels of anti-D612 antibody. Despite the observed biological activity of both rhM-CSF and D612 and the previously described in vitro synergy, no clinical antitumor responses were observed in this Phase II study.",
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