Individualized Patient Dosing in Phase I Clinical Trials: The Role of Escalation With Overdose Control in PNU-214936

Cheng, Jonathan D.; Babb, James S.; Langer, Corey J.; Aamdal, Steinar; Robert, Francisco; Engelhardt, Lars; Fernberg, Olov; Schiller, Joan H.; Forsberg, G.; Alpaugh, R. Katherine; Weiner, Louis M.; Rogatko, André

doi:10.1200/jco.2004.12.034

Cited by 72 publications

(53 citation statements)

References 22 publications

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“…Anti-SEA titres determined at each study visit (Table 2) were similar to previous studies (Cheng et al, 2004). There was a 536-fold increase in median titre following the first cycle but this was not boosted by further drug exposure and generally declined after the second cycle.…”

Section: Safety and Immunological Responsesupporting

confidence: 78%

“…In previous studies (Alpaugh et al, 1998b;Cheng et al, 2004), the occurrence of high-systemic levels of IL-2 correlated with toxicity. In the present study, post-infusion IL-2 levels were measured on the first 2 days of treatment as this coincided with the majority of AEs.…”

Section: Discussionmentioning

confidence: 80%

“…In this, SEA has been engineered for reduced MHC class II binding giving it a much improved safety profile compared to fusions with wild-type SEA (Alpaugh et al, 1998a;Brodin et al, 1998;Forsberg et al, 2001;Cheng et al, 2004). The 5T4 oncofoetal antigen is a transmembrane glycoprotein Stern, 1988, 1990).…”

mentioning

confidence: 99%

“…In the phase I study of ABR-214936 in NSCLC, the maximum tolerated dose (MTD) as a function of pre-existing anti-SEA antibody was determined (Cheng et al, 2004). The reported major side effects of ABR-214936 included pyrexia, hypotension, rigours, nausea and lethargy.…”

mentioning

confidence: 99%

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A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

et al. 2007

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In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity.

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Section: Safety and Immunological Responsesupporting

confidence: 78%

Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

et al. 2007

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“…[5][6][7] Superantigen-based antitumor strategies may offer therapeutic promise. 8,9 However, in vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells because superantigens preferentially direct cytotoxicity against MHC II-positive cells. Therefore, successful employment of superantigen in tumor immunotherapy requires targeting superantigen to the site of tumor.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

Sun²,

Li³

et al. 2006

Gene Ther

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Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor b-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by a-fetoprotein (AFP) enhancer/ promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFPproducing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4 + and CD8 + T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.

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Tumor‐Targeted Superantigens

Hedlund¹,

Forsberg²,

Nederman³

et al. 2013

Fusion Protein Technologies for Biopharmaceuticals

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Individualized Patient Dosing in Phase I Clinical Trials: The Role of Escalation With Overdose Control in PNU-214936

Cited by 72 publications

References 22 publications

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

Tumor‐Targeted Superantigens

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