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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Radioimmunotherapy with (111)In/(90)Y-2IT-BAD-m170 for metastatic prostate cancer
R T O'Donnell1, S J DeNardo, A Yuan
1Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis Medical Center, Sacramento, California 95816, USA.rtodonnell@ucdavis.edu
Purpose:
Over 31,000 Americans die of androgen-independent metastatic prostate cancer each year. New strategies that do not involve hormonal manipulation but instead recognize the biochemical and molecular characteristics of prostate cancer are needed. Radioimmunotherapy (RIT) uses a tumor-specific monoclonal antibody to deliver systemic, targeted radiation to cancer. The objectives of this Phase I study of (111)In-2IT-BAD-m170 (for imaging) and (90)Y-2IT-BAD-m170 (for therapy) were to determine the toxicity and maximum tolerated dose (MTD), the specificity for targeting metastatic prostate cancer, and the efficacy for palliation of pain.
Experimental Design:
M170 is a mouse monoclonal antibody that targets adenocarcinomas. Patients with adequate renal and liver function, rising prostate-specific antigen, and androgen-independent metastatic prostate cancer were eligible. After estimation of dosimetry and pharmacokinetics with (111)In-2IT-BAD-m170, a single dose of (90)Y-2IT-BAD-m170 (0.185, 0.370, 0.555, or 0.740 GBq/m(2)) was administered to cohorts of three patients. Pain was assessed objectively by questionnaires before and for 8 weeks after RIT; weekly prostate-specific antigen levels were obtained for 2 months after RIT.
Results:
The MTD of (90)Y-2IT-BAD-m170 was 0.740 GBq/m(2) for patients that had up to 10% of the axial skeleton involved with prostate cancer. Toxicity was almost exclusively confined to reversible myelosuppression. Metastatic prostate cancer was targeted by (111)In-2IT-BAD-m170 in all 17 patients. The mean radiation dose delivered to 39 bone and 18 nodal metastases by (90)Y-2IT-BAD-m170 was 10.5 Gy/GBq (range 2.8-25.1). Thirteen of 17 patients reported pain before (90)Y-2IT-BAD-m170; 7 of these 13 had a partial or complete resolution of pain that lasted an average of 4.3 weeks.
Conclusions:
This study determined the MTD of (111)In/(90)Y-2IT-BAD-m170 in patients with metastatic prostate cancer. The drugs were well tolerated, targeted metastases, and temporarily palliated pain.
Insights
This Phase I study of radioimmunotherapy (RIT) with (111)In/(90)Y-2IT-BAD-m170 found it well-tolerated in metastatic prostate cancer patients. The treatment targeted cancer effectively and provided temporary pain relief, establishing a maximum tolerated dose.
Area of Science:
- Oncology
- Nuclear Medicine
- Immunotherapy
Background:
- Androgen-independent metastatic prostate cancer (mPC) presents a significant unmet need, with over 31,000 annual deaths in the US.
- Novel therapeutic strategies beyond hormonal manipulation are crucial for treating mPC, focusing on its unique biochemical and molecular profiles.
- Radioimmunotherapy (RIT) offers a targeted approach, utilizing tumor-specific monoclonal antibodies to deliver localized radiation therapy.
Purpose of the Study:
- To determine the toxicity and maximum tolerated dose (MTD) of (111)In-2IT-BAD-m170 (imaging) and (90)Y-2IT-BAD-m170 (therapy).
- To assess the specificity of these agents in targeting metastatic prostate cancer.
- To evaluate the efficacy of (90)Y-2IT-BAD-m170 in palliating pain associated with metastatic prostate cancer.
Main Methods:
- A Phase I clinical trial involving patients with androgen-independent mPC and adequate organ function.
- Dosimetry and pharmacokinetics were evaluated using (111)In-2IT-BAD-m170 prior to therapy.
- Single doses of (90)Y-2IT-BAD-m170 were administered at escalating levels (0.185 to 0.740 GBq/m(2)) to cohorts of three patients.
- Pain and prostate-specific antigen (PSA) levels were monitored post-therapy.
Main Results:
- The MTD of (90)Y-2IT-BAD-m170 was established at 0.740 GBq/m(2) for patients with limited axial skeletal involvement.
- Toxicity was primarily reversible myelosuppression.
- (111)In-2IT-BAD-m170 successfully targeted metastatic prostate cancer in all 17 patients.
- Significant radiation doses were delivered to bone and nodal metastases.
- Seven of thirteen patients experiencing pain reported partial or complete pain resolution lasting an average of 4.3 weeks.
Conclusions:
- The study successfully determined the MTD for (111)In/(90)Y-2IT-BAD-m170 in patients with metastatic prostate cancer.
- The RIT agents were well-tolerated, demonstrating specific targeting of metastases.
- (111)In/(90)Y-2IT-BAD-m170 showed potential for temporary pain palliation in metastatic prostate cancer.
