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e-Posters

9P - Late phase 1 studies: concepts and outcomes of a new clinical trial design

Date

06 Oct 2021

Session

e-Posters

Presenters

Jose Carlos Benitez Montanez

Citation

Annals of Oncology (2021) 32 (suppl_6): S1345-S1371. 10.1016/annonc/annonc740

Authors

J.C. Benitez Montanez1, A. Geraud2, M. Texier2, C. Massard2, A. Paci2, J. Soria2, B. Besse2

Author affiliations

  • 1 Gustave Roussy - Cancer Campus, Villejuif, Cedex/FR
  • 2 Gustave Roussy - Cancer Campus, 94805 - Villejuif/FR
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Abstract 9P

Background

Targeted therapies have become cornerstone treatments for many cancers harboring oncogenic addictions. The emergence of tumor-resistant mechanisms paved the way for next-generation inhibitors. Insufficient concentrations of targeted therapies is a frequent but poorly explored mechanism of treatment failure. We propose a new concept in clinical development, the late phase I trial, to restore drug efficacy at the time of failure at the standard dose.

Methods

The primary goal of these studies is to define a new maximal tolerated dose (MTD) of a drug in chronically-exposed patients (MTDc). Eligible patients (pts) must be still on treatment with the standard dose of the drug, experienced initial benefit and subsequently progressed without an identified resistance alteration. Groups composed of six pts will assess the best MTDc as a new late phase I recommended standard dose. The first group will initially be treated with a ‘dose level 1’, corresponding to the standard approved dose by regulatory agencies plus a predetermined dose increase. If no dose limiting toxicity (DLT) is reported after one DLT assessment window (DAW), these first six pts will move forward to dose level 2, and six new pts will be included at the second dose escalation level moving forward to dose level 3 (dose level 2 dose plus predetermined increase dose) after one DAW without reporting any DLT. Groups of six pts will start the study from sequentially established dose levels until the maximal determined late dose. The highest dose escalation level is defined by the highest administered dose experimental drug with unacceptable toxicity (≥33% of DLT events among 12 patients) and represents the last dose increase level. Unique DLTcs will be described for each subgroup.

Results

Along with the definition of MTDc, these trials will determine a late effective dose (LED) in pts, defining the optimal scheme for a rapid intra-patient dose escalation and hopefully reverse drug resistance.

Conclusions

Late phase I trials could be a new approach to restore the response to a drug by intra-patient dose escalation in cases of relapse without evidence of resistance mutations.

Legal entity responsible for the study

Gustave Roussy Cancer Center.

Funding

Has not received any funding.

Disclosure

C. Massard: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer. A. Paci: Financial Interests, Personal, Advisory Board: Fresenius; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Expert Testimony: Servier. J-C. Soria: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Funding: Gritstone; Financial Interests, Personal, Advisory Board: Hookipa Pharmaceuticals. B. Besse: Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Amgen; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Grant: MSD. All other authors have declared no conflicts of interest.

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