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.
OBJECTIVE
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.


METHODS
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.
Richman
Carol M
CM
University of California-Davis, Sacramento, California 95817, USA. carol.richman@ucdmc.ucdavis.edu
Denardo
Sally J
SJ
O'Donnell
Robert T
RT
Yuan
Aina
A
Shen
Sui
S
Goldstein
Desiree S
DS
Tuscano
Joseph M
JM
Wun
Ted
T
Chew
Helen K
HK
Lara
Primo N
PN
Kukis
David L
DL
Natarajan
Arutselvan
A
Meares
Claude F
CF
Lamborn
Kathleen R
KR
DeNardo
Gerald L
GL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002403:Cathepsins / Q000378:metabolism; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000378:metabolism / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D012983:Soft Tissue Neoplasms / Q000517:prevention & control / Q000556:secondary; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; C434325:MUC-1 monoclonal antibody; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D016572:Cyclosporine; D002403:Cathepsins; D017239:Paclitaxel