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Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials

Shivaani Kummar1, Khanh Do1, Geraldine O'Sullivan Coyne1

  • 1National Cancer Institute, National Institutes of Health, Bethesda, MD.

Seminars in Oncology
|September 25, 2016
PubMed

Insights

Designing early-phase clinical trials for molecularly targeted cancer therapies requires demonstrating proof-of-mechanism. Challenges in assessing target modulation in tumor biopsies must be addressed for successful anti-cancer agent development.

Area of Science:

  • Oncology
  • Clinical Pharmacology

Background:

  • Molecularly targeted therapies rely on target modulation and anti-tumor effects for clinical development.
  • Early-phase clinical trials are crucial for establishing safety, maximum tolerated dose, and proof-of-mechanism.

Purpose of the Study:

  • To discuss the challenges in applying pharmacodynamic studies in early-phase clinical trials of anti-cancer agents.
  • To highlight the importance of demonstrating target modulation in tissues of interest.

Main Methods:

  • Review of challenges in assessing target modulation in paired tumor biopsies from patients with solid tumors.
  • Consideration of procedural, ethical, logistical, and technological factors in pharmacodynamic studies.

Main Results:

  • Assessing target modulation faces challenges including patient safety, ethical concerns, and sample handling.
  • Biomarker assay technology, resource availability, and real-time analysis are critical for study success.

Conclusions:

  • Practical application of pharmacodynamic studies in early-phase anti-cancer trials presents significant challenges.
  • Addressing these challenges is essential for the successful clinical development of molecularly targeted therapies.
Keywords:
BiomarkersBiopsy surrogate tissuesDrug evaluationPharmacodynamicsPhase I

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