Fever-range whole-body thermal therapy combined with cisplatin, gemcitabine, and daily interferon-α: A description of a phase I-II protocol

PURPOSE A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 131-labeled monoclonal antibody (mAb) A33 (131I-mAb A33) administered intravenously, its limiting organ toxicity, and its radioisotope retention in tumors, and to develop preliminary evidence of antitumor activity. PATIENTS AND METHODS Patients (N = 23) with colorectal cancer who had failed to respond to conventional chemotherapy but had not received prior radiotherapy were treated with escalating doses of 131I-mAb A33. Three or more patients were entered at each dose level, starting at 30 mCi/m2, with increments of 15 mCi/m2 to a maximal dose of 90 mCi/m2. Radiolabeling was performed to maintain a specific activity of 30 mCi/m2/4 mg mAb A33 (projected maximum, 15 mCi/mg). Patients were under strict isolation precautions until whole-body radiation levels decreased to less than 5 mrem/h at 1 m. Serial radioimmunoscintigrams were performed in some cases for up to 3 weeks after 131I-mAb A33 administration. RESULTS All 20 patients with radiologic evidence of disease showed localization of radioisotope to sites of disease. Two patients with elevated carcinoembryonic antigen (CEA) levels and negative radiologic tests did not have positive antibody scans. One patient with a small-bowel cancer also had a negative antibody scan. The major toxicity was hematologic and was more pronounced in patients with compromised bone marrow due to prior chemotherapy. Of five patients who received 78 to 84 mCi/m2 131I-mAb A33, one had grade 3 and one grade 4 toxicity; of six patients treated with 86 to 94 mCi/m2 131I-mAb A33, two had grade 4 and one grade 1 toxicity. The MTD was determined to be 75 mCi/m2 in these heavily pretreated patients. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild (n = 8) or absent. No major responses were observed; however, three patients had evidence of mixed responses, and CEA levels decreased in two patients without clinical or radiologic measurable disease. Immunoreactivity of radiolabeled mAb A33 decreased at the highest dose levels in preparations in which specific activity exceeded 18 mCi/mg. CONCLUSION The A33 antigen appears to be a promising target for radioimmunotherapy of colon cancer. The modest antitumor activity of 131I-mAb A33 in heavily pretreated patients is encouraging because of its lack of toxicity in the bowel, the only antigen-positive normal tissue.

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Phase I Trial of Sunitinib Malate plus Interferon-α for Patients with Metastatic Renal Cell Carcinoma

Clinical Genitourinary Cancer ◽

10.3816/cgc.2009.n.005 ◽

2009 ◽

Vol 7 (1) ◽

pp. 28-33 ◽

Cited By ~ 52

Author(s):

Robert J. Motzer ◽

Gary Hudes ◽

George Wilding ◽

Lawrence H. Schwartz ◽

Subramanian Hariharan ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Phase I ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Phase I Trial ◽

Interferon Α ◽

Sunitinib Malate

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Phase I/II trial of subcutaneous interleukin-2, granulocyte-macrophage colony-stimulating factor and interferon-α in patients with metastatic renal cell carcinoma

BJU International ◽

10.1111/j.1464-410x.2010.10011.x ◽

2011 ◽

Vol 109 (1) ◽

pp. 63-69 ◽

Cited By ~ 7

Author(s):

Jorge A. Garcia ◽

Tarek Mekhail ◽

Paul Elson ◽

Laura Wood ◽

Ronald M. Bukowski ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Phase I ◽

Cell Carcinoma ◽

Renal Cell ◽

Interleukin 2 ◽

Interferon Α ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Phase I Evaluation of Doxorubicin and Whole-body Hyperthermia in Dogs with Lymphoma

Journal of Veterinary Internal Medicine ◽

10.1111/j.1939-1676.1992.tb00346.x ◽

1992 ◽

Vol 6 (4) ◽

pp. 245-249 ◽

Cited By ~ 3

Author(s):

C. A. Novotney ◽

R. L. Page ◽

D. W. Macy ◽

M. W. Dewhirst ◽

G. K. Ogilvie ◽

...

Keyword(s):

Phase I ◽

Whole Body ◽

Whole Body Hyperthermia

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A phase I trial of 5-day continuous infusion cisplatin and interferon α

Cancer Chemotherapy and Pharmacology ◽

10.1007/s002800050365 ◽

1995 ◽

Vol 37 (1-2) ◽

pp. 39-46

Author(s):

Michael P. Gosland ◽

Susan Goodin ◽

Robert A. Yokel ◽

Marietta Smith ◽

W. J. John

Keyword(s):

Phase I ◽

Continuous Infusion ◽

Phase I Trial ◽

Interferon Α

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Outcomes of the miltuximab first in human trial and proposed study design for a phase I trial 89Zr/177Lu theranostic trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.261 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 261-261 ◽

Cited By ~ 1

Author(s):

Douglas Campbell ◽

Dhanusha Sabanathan ◽

Howard Gurney ◽

David Gillatt ◽

Marko Trifunovic ◽

...

Keyword(s):

Prostate Cancer ◽

Phase I ◽

Phase 1 ◽

Standard Of Care ◽

The Body ◽

Whole Body ◽

Chimeric Antibody ◽

Pharmacokinetic Data ◽

Post Dose ◽

Before And After

261 Background: Miltuximab is a chimeric antibody targeting Glypican-1 which is overexpressed in prostate cancer. Miltuximab has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. Methods: Metastatic patients (prostate, pancreatic and bladder) were dosed with unlabelled Miltuximabfollowed by the infusion of 1 mg/250MBq 67Ga-Miltuximab. Patients underwent whole body gamma and SPECT/CT scans up to 144 hours post-infusion. Standard of care imaging was performed at least 14 days before and after participation. Safety was evaluated by an external monitoring committee. Total organ exposure was determined by dosimetry of whole-body gamma scans. Antibody pharmacokinetics were also determined. Results: 12 patients were enrolled into the trial. Miltuximabwas well tolerated and did not elicit any drug-related adverse reactions. Liver and spleen uptake of 67Ga-Miltuximabwas observed from 30 min to 72 hours post dose. Pre-infusion of unlabelled Miltuximab resulted in reduced liver accumulation and increased distribution in the rest of the body. Miltuximab targeting to sites of active progressive disease was observed in certain prostate cancer patients who had failed enzalutamide treatment. Dosimetry analysis combined with antibody pharmacokinetic data was used to establish safe dose limits for a Phase 1 study. Conclusions: This study is the first in human for Miltuximaband demonstrates its potential for further clinical evaluation as a theranostic in prostate cancers and formed the basis for a Phase I imaging and therapy study planned for 2019. This study will use 89Zr-labelled Miltuximab to screen eligible patients and confirm tumour localisation, followed by treatment with 177Lu-labelled Miltuximab. Clinical trial information: ACTRN12616000787482.

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Can polymetastatic disease be arrested using SABR? A dosimetric analysis to inform development of a phase I trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21567 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21567-e21567

Author(s):

Mark Thomas Corkum ◽

Hatim Fakir ◽

David A. Palma ◽

Timothy K. Nguyen ◽

Glenn Bauman

Keyword(s):

Clinical Trial ◽

Phase I ◽

Dose Level ◽

Phase I Trial ◽

The Body ◽

Phase Iii ◽

Whole Body ◽

Stereotactic Ablative Radiotherapy ◽

Test Cases ◽

Dose Escalation Study

e21567 Background: Phase II randomized trials suggest that stereotactic ablative radiotherapy (SABR) improves progression-free and overall survival in patients with oligometastatic cancer, with phase III trials currently testing SABR in up to 10 metastases. Whether SABR could provide similar benefits in polymetastatic disease ( > 10 metastases) is unknown. A critical first step is to determine the feasibility of planning SABR for a large number of metastases throughout the body while maintaining acceptable organ at risk (OAR) doses. Therefore, we sought to evaluate the dosimetric feasibility of using SABR in polymetastatic disease ( > 10 sites) while adhering to OAR constraints to be used in a phase I trial (ARREST). Methods: Five craniospinal CT simulations were utilized to retrospectively contour 24 (n = 2), 30 (n = 2) and 50 (n = 1) tumour targets not present on the initial scan. Standard PTV margins were added based on institutional immobilization practices. OAR constraints from published clinical trial protocols were used. Radiotherapy plans for the highest dose level in our planned phase I trial (30Gy in 5 fractions) were created utilizing a minimum number of isocentres. Plans were created using Raystation (RaySearch Laboratories, Stockholm, Sweden) for delivery on linear accelerators using volumetric modulated arc therapy. Results: The gross tumour volumes (GTVs) ranged from 134.8– 184.2cm3 in our five test cases. The first two cases with 24 GTVs have been planned and were deemed to be clinically acceptable. PTV volumes were 483.0cm3 and 417.4cm3, utilizing five and six isocentres for treatment respectively. Median PTV D95 was 29.7Gy and 29.0Gy, whole body V10 was 21.2% and 17.4%, and V5 was 41.8% and 44.8%. All OAR goals were met, though low-dose conformality was less than traditional SABR treatment plans (R100 of 1.04 and 0.93; R50 of 9.90 and 6.98, respectively). The remainder of the test cases will be presented. Conclusions: In our test cases, planning SABR in polymetastatic disease appears dosimetrically feasible. Our phase I clinical trial (ARREST) is under development, which will evaluate the feasibility and toxicity of delivering SABR in polymetastatic disease in a 3+3 dose escalation study. The starting dose level will be 12Gy in 2 weekly fractions, escalating the dose by adding 6Gy weekly until our target dose of 30Gy in 5 weekly fractions. Our study population will include > 10 sites of disease, all tumour types, and patients must have exhausted standard lines of systemic therapy.

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