Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma

Chong, Geoffrey; Lee, Fook Thean; Hopkins, Wendie; Tebbutt, Niall C.; Cebon, Jonathan; Mountain, A.; Chappell, Bridget; Papenfuss, Anthony T.; Schleyer, Paul; Paul, Udo; Murphy, Roger; Wirth, Veronika; Smyth, Fiona E; Potasz, Nicole; Poon, Aurora; Davis, Ian D.; Saunder, Timothy; O’Keefe, Graeme; Burgess, Antony W.; Hoffman, Eric W.; Old, Lloyd J.; Scott, Andrew M.

doi:10.1158/1078-0432.ccr-04-2330

Cited by 74 publications

(58 citation statements)

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“…huA33 was radiolabeled using an established radiolabeling technique (13,19). Antibody preparations equal to or better than 95% isotope bound to protein were used, and binding of 131 I-huA33 to A33-positive cells was shown to reduce by only 13% after a 7-d incubation in human serum at 37°C.…”

Section: Radiolabeling Of Hua33mentioning

confidence: 99%

“…The humanized IgG1 antibody huA33 has high affinity for its target antigen (9), is internalized on binding, and is safe and tolerable when given to patients alone (10,11), in combination with chemotherapy (12), and when radiolabeled (13). 131 I-huA33 can cause targeted delivery of radiation to colon cancer cells and is retained in the tumor for 6 wk (13). Elimination from normal colonocytes in around 5 d (with basal turnover) minimizes toxicity to normal gut epithelium.…”

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confidence: 99%

“…Elimination from normal colonocytes in around 5 d (with basal turnover) minimizes toxicity to normal gut epithelium. The dose of radiation delivered to the tumor by 1.48GBq/m 2 of 131 I-huA33 is equivalent to approximately 8-10 Gy (13).…”

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confidence: 99%

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Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of ¹³¹I-huA33 with Concurrent Capecitabine

et al. 2014

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huA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and more than 95% of human colon cancers but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 wk but eliminated from normal colonocytes within days. This phase I study used radiolabeled huA33 in combination with capecitabine to target chemoradiation to metastatic colorectal cancer. The primary objective was safety and tolerability of the combination of capecitabine and 131 I-huA33. Pharmacokinetics, biodistribution, immunogenicity, and tumor response were also assessed. Methods: Eligibility included measurable metastatic colorectal cancer, adequate hematologic and biochemical function, and informed consent. An outpatient scout 131 I-huA33 dose was followed by a single-therapy infusion 1 wk later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the 12-wk trial. Tumor targeting was assessed using a γ camera and SPECT imaging. Results: Nineteen eligible patients were enrolled. The most frequently observed toxicity included myelosuppression, gastrointestinal symptoms, and asymptomatic hyperbilirubinemia. Biodistribution analysis demonstrated excellent tumor targeting of the known tumor sites, expected transient bowel uptake, but no other normal tissue uptake. 131 I-huA33 demonstrated a mean terminal half-life and serum clearance suited to radioimmunotherapy (T 1/2 β, 100.24 ± 20.92 h, and clearance, 36.72 ± 8.01 mL/h). The mean total tumor dose was 13.8 ± 7.6 Gy (range, 5.1-26.9 Gy). One patient had a partial response, and 10 patients had stable disease. Conclusion: 131 I-huA33 achieves specific targeting of radiotherapy to colorectal cancer metastases and can be safely combined with chemotherapy, providing an opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients.

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Section: Radiolabeling Of Hua33mentioning

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Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of ¹³¹I-huA33 with Concurrent Capecitabine

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“…Currently, only 131 I and 90 Y appear to fulfill the present requirements for commercial development. Direct radioiodination ( 131 I, 125 I, 124 I, and 123 I) is well established, and tositumomab, the Ab in Bexxar®, is radiolabeled with 131 I by this means.…”

Section: Radiolabeling Protocolsmentioning

confidence: 99%

“…Examples of matched β + /β − (imaging/therapy) pairs include 124 I/ 131 I, 86 Y/ 90 Y, and 64 Cu/ 67 Cu. Bremsstrahlung imaging of 90 Y is sub-optimal, and although 111 In can be used as a surrogate, PET imaging using 86 Y provides the advantage of matched chemistry.…”

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confidence: 99%

Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view

Boswell

Brechbiel

2007

Nuclear Medicine and Biology

218

213

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Only a handful of radiolabeled antibodies (Abs) have gained FDA approval for use in clinical oncology, including four immunodiagnostic agents and two targeted radioimmunotherapeutic agents. Despite the advent of non-immunogenic Abs and availability of a diverse library of radionuclides, progress beyond early Phase II RIT studies in solid tumors has been marginal. Furthermore, 18 F-FDG continues to dominate the molecular imaging domain, underscored by a decade-long absence of any newly approved antibody-based imaging agents (none since 1996!). Why has the development of clinically successful Abs for RIT been limited to lymphoma? What obstacles must be overcome to allow the FDA-approval of immunoPET imaging agents? How can we address the unique challenges that have thus far prevented the introduction of Ab-based imaging agents and therapeutics for solid tumors? Many poor decisions have been made regarding radiolabeled Abs, but useful insight can be gained from these mistakes. The following review addresses physical, chemical, biological, clinical, regulatory, and financial limitations that impede the progress of this increasingly important class of drugs. OverviewThe following review illustrates key components of a successful radiolabeled diagnostic or therapeutic antibody (Ab) from the inside out -that is, starting from the unstable nucleus itself and moving outwards. For each sequential topic, relevant theory will be examined and related to the practical use of various radiolabeled Abs that have succeeded to varying degrees in the clinic. This approach will present each important aspect of a rather complex multidisplinary phenomenon in a logical, stepwise manner: I. The radionuclide itselfPhysical properties of the unstable nucleus II. The radionuclide's chemical surroundingsChemical attachment of the radiometal or radiohalogen III. The antibodyBiological issues of the radioimmunoconjugate † Portions of this article were highlighted during a presentation at the Workshop on Molecular Imaging: After Bench to Bedside: Impact on Clinical Outcome Feb. [23][24][25] 2007. *Correspondence to: Martin W. Brechbiel, Ph.D., Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, NCI, NIH, Building 10, Room 1B40, 10 Center Drive, Bethesda, MD 20892-1088, Fax: (301) 402-1923, e-mail: martinwb@mail.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNucl Med Biol. Author manuscript; available in PMC 2008 October 1. Published in final edited form as:Nucl Med Biol. 2007 October ; 34(7): 757-778. NIH-PA Author ManuscriptNIH-PA...

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Radioimmunotherapy: Current Status and Future Directions

Pandit‐Taskar

Divgi

2009

Therapeutic Monoclonal Antibodies

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Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma

Cited by 74 publications

References 23 publications

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of ¹³¹I-huA33 with Concurrent Capecitabine

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of ¹³¹I-huA33 with Concurrent Capecitabine

Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view

Radioimmunotherapy: Current Status and Future Directions

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Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma

Cited by 74 publications

References 23 publications

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of 131I-huA33 with Concurrent Capecitabine

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of 131I-huA33 with Concurrent Capecitabine

Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view

Radioimmunotherapy: Current Status and Future Directions

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Product

Resources

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Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of ¹³¹I-huA33 with Concurrent Capecitabine

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of ¹³¹I-huA33 with Concurrent Capecitabine