Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation

A. Dowlati, J. Haaga, S. C. Remick, T. P. Spiro, S. L. Gerson, L. Liu, S. J. Berger, N. A. Berger, J. K V Willson

Research output: Contribution to journalArticle

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Abstract

Purpose: In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attributed to modulation of the intended target in early phase trials in human subjects. This paradigm of target modulation allows us to determine a Phase II or III dose (optimal biochemical/biological modulatory dose) that may not necessarily be the maximum tolerated dose. A major obstacle to target-based (often cytostatic) drug development has been obtaining relevant tumor tissue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect. Experimental Design: From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory dose in human tumor tissues (not surrogate tissue). Eligibility enrollment required that patients have a biopsiable lesion either with computerized tomography (CT) guidance or direct visualization and consent to sequential (pre and posttreatment) biopsies. Results: A total of 192 biopsies were performed in 107 patients. All but 8 patients had sequential pre and posttreatment biopsies. Seventy-eight (73%) of the 107 patients had liver lesion biopsies. In eight patients, either one or both biopsies contained insufficient viable tumor tissue or no tumor tissue at all for analysis. Of a total of 99 patients in whom we attempted to obtain paired biopsies, a total of 87 (88%) were successful. Reasons for failure included patient refusal for a second biopsy (n=2), vasovagal reaction with first biopsy precluding a second biopsy (n=1), subcapsular hepatic bleeding (n=1), and most commonly obtaining necrotic tumor, fibrous, or normal tissue in one of the two sequential biopsies (n=8). Conclusions: This is the first and largest reported series demonstrating that with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.

Original languageEnglish (US)
Pages (from-to)2971-2976
Number of pages6
JournalClinical Cancer Research
Volume7
Issue number10
StatePublished - 2001

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Antineoplastic Agents
Clinical Trials
Biopsy
Neoplasms
Maximum Tolerated Dose
Liver
Cytostatic Agents
Pharmaceutical Preparations
Research Design
Tomography
Hemorrhage

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dowlati, A., Haaga, J., Remick, S. C., Spiro, T. P., Gerson, S. L., Liu, L., ... Willson, J. K. V. (2001). Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clinical Cancer Research, 7(10), 2971-2976.

Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. / Dowlati, A.; Haaga, J.; Remick, S. C.; Spiro, T. P.; Gerson, S. L.; Liu, L.; Berger, S. J.; Berger, N. A.; Willson, J. K V.

In: Clinical Cancer Research, Vol. 7, No. 10, 2001, p. 2971-2976.

Research output: Contribution to journalArticle

Dowlati, A, Haaga, J, Remick, SC, Spiro, TP, Gerson, SL, Liu, L, Berger, SJ, Berger, NA & Willson, JKV 2001, 'Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation', Clinical Cancer Research, vol. 7, no. 10, pp. 2971-2976.
Dowlati A, Haaga J, Remick SC, Spiro TP, Gerson SL, Liu L et al. Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clinical Cancer Research. 2001;7(10):2971-2976.
Dowlati, A. ; Haaga, J. ; Remick, S. C. ; Spiro, T. P. ; Gerson, S. L. ; Liu, L. ; Berger, S. J. ; Berger, N. A. ; Willson, J. K V. / Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 10. pp. 2971-2976.
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AU - Dowlati, A.

AU - Haaga, J.

AU - Remick, S. C.

AU - Spiro, T. P.

AU - Gerson, S. L.

AU - Liu, L.

AU - Berger, S. J.

AU - Berger, N. A.

AU - Willson, J. K V

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N2 - Purpose: In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attributed to modulation of the intended target in early phase trials in human subjects. This paradigm of target modulation allows us to determine a Phase II or III dose (optimal biochemical/biological modulatory dose) that may not necessarily be the maximum tolerated dose. A major obstacle to target-based (often cytostatic) drug development has been obtaining relevant tumor tissue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect. Experimental Design: From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory dose in human tumor tissues (not surrogate tissue). Eligibility enrollment required that patients have a biopsiable lesion either with computerized tomography (CT) guidance or direct visualization and consent to sequential (pre and posttreatment) biopsies. Results: A total of 192 biopsies were performed in 107 patients. All but 8 patients had sequential pre and posttreatment biopsies. Seventy-eight (73%) of the 107 patients had liver lesion biopsies. In eight patients, either one or both biopsies contained insufficient viable tumor tissue or no tumor tissue at all for analysis. Of a total of 99 patients in whom we attempted to obtain paired biopsies, a total of 87 (88%) were successful. Reasons for failure included patient refusal for a second biopsy (n=2), vasovagal reaction with first biopsy precluding a second biopsy (n=1), subcapsular hepatic bleeding (n=1), and most commonly obtaining necrotic tumor, fibrous, or normal tissue in one of the two sequential biopsies (n=8). Conclusions: This is the first and largest reported series demonstrating that with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.

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