High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody

Carol M Richman, Sally J. DeNardo, Robert T O'Donnell, Aina Yuan, Sui Shen, Desiree S. Goldstein, Joseph Tuscano, Theodore Wun, Helen K Chew, Primo N Lara, David L. Kukis, Arutselvan Natarajan, Claude F. Meares, Kathleen R. Lamborn, Gerald L Denardo

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. Experimental Design: Patients were imaged with indium-111 ( 111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″, N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 ( 90Y) -m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. Conclusions: 111In/ 90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.

Original languageEnglish (US)
Pages (from-to)5920-5927
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number16
DOIs
StatePublished - Aug 15 2005

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Radioimmunotherapy
Yttrium
Cathepsins
Indium
Paclitaxel
Cyclosporine
Anti-Idiotypic Antibodies
Prostatic Neoplasms
Breast Neoplasms
Neutropenia
MUC-1 monoclonal antibody
Maximum Tolerated Dose
Human Development
Lymphoma
Research Design
Fever
Bone Marrow
Hormones
Hemorrhage
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{1be61105507a4b72b181d7c497f0957d,
title = "High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody",
abstract = "Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. Experimental Design: Patients were imaged with indium-111 ( 111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″, N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 ( 90Y) -m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. Conclusions: 111In/ 90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, {"}fractionated{"} therapy that could enhance clinical response.",
author = "Richman, {Carol M} and DeNardo, {Sally J.} and O'Donnell, {Robert T} and Aina Yuan and Sui Shen and Goldstein, {Desiree S.} and Joseph Tuscano and Theodore Wun and Chew, {Helen K} and Lara, {Primo N} and Kukis, {David L.} and Arutselvan Natarajan and Meares, {Claude F.} and Lamborn, {Kathleen R.} and Denardo, {Gerald L}",
year = "2005",
month = "8",
day = "15",
doi = "10.1158/1078-0432.CCR-05-0211",
language = "English (US)",
volume = "11",
pages = "5920--5927",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

TY - JOUR

T1 - High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody

AU - Richman, Carol M

AU - DeNardo, Sally J.

AU - O'Donnell, Robert T

AU - Yuan, Aina

AU - Shen, Sui

AU - Goldstein, Desiree S.

AU - Tuscano, Joseph

AU - Wun, Theodore

AU - Chew, Helen K

AU - Lara, Primo N

AU - Kukis, David L.

AU - Natarajan, Arutselvan

AU - Meares, Claude F.

AU - Lamborn, Kathleen R.

AU - Denardo, Gerald L

PY - 2005/8/15

Y1 - 2005/8/15

N2 - Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. Experimental Design: Patients were imaged with indium-111 ( 111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″, N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 ( 90Y) -m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. Conclusions: 111In/ 90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.

AB - Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. Experimental Design: Patients were imaged with indium-111 ( 111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″, N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 ( 90Y) -m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. Conclusions: 111In/ 90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.

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U2 - 10.1158/1078-0432.CCR-05-0211

DO - 10.1158/1078-0432.CCR-05-0211

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