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Clinical Trials: Immunotherapy

Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors

Osama E. Rahma, Joshua E. Reuss, Anita Giobbie-Hurder, Ghazaleh Shoja E Razavi, Osama Abu-Shawer, Pooja Mehra, Seema Gupta, Richard Simon and Samir N. Khleif
Osama E. Rahma
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2Harvard Medical School, Boston, Massachusetts.
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Joshua E. Reuss
3Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Anita Giobbie-Hurder
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
4Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Ghazaleh Shoja E Razavi
5Cumming School of Medicine, University of Calgary, Calgary, Canada.
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Osama Abu-Shawer
2Harvard Medical School, Boston, Massachusetts.
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Pooja Mehra
6University of Virginia, Charlottesville, Virginia.
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  • ORCID record for Pooja Mehra
Seema Gupta
7Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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Richard Simon
8R Simon Consulting, Potomac, Maryland.
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Samir N. Khleif
7Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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  • For correspondence: snk48@georgetown.edu
DOI: 10.1158/1078-0432.CCR-20-2669 Published January 2021
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Abstract

Purpose: Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.

Experimental Design: We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3–5 adverse events (G3–5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.

Results: A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3–5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3–5 AEs was 20.1% which was lower in non–small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose–response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3–5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC.

Conclusions: Our analysis shows a lack of consistent dose-toxicity or dose–response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:485–91

  • Received July 15, 2020.
  • Revision received September 21, 2020.
  • Accepted October 16, 2020.
  • Published first October 20, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (2)
January 2021
Volume 27, Issue 2
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Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors
Osama E. Rahma, Joshua E. Reuss, Anita Giobbie-Hurder, Ghazaleh Shoja E Razavi, Osama Abu-Shawer, Pooja Mehra, Seema Gupta, Richard Simon and Samir N. Khleif
Clin Cancer Res January 15 2021 (27) (2) 485-491; DOI: 10.1158/1078-0432.CCR-20-2669

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Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors
Osama E. Rahma, Joshua E. Reuss, Anita Giobbie-Hurder, Ghazaleh Shoja E Razavi, Osama Abu-Shawer, Pooja Mehra, Seema Gupta, Richard Simon and Samir N. Khleif
Clin Cancer Res January 15 2021 (27) (2) 485-491; DOI: 10.1158/1078-0432.CCR-20-2669
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Clinical Cancer Research
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