Phase I Clinical Trials of Anti-Cancer Agents

Summary

Principal Investigator: F J Giles
Abstract: DESCRIPTION (provided by applicant): This proposal entitled, "Phase I Clinical Trials of Anti-Cancer Agents," prepared in response to RFA No. CA-02-011, requests support for early stage clinical evaluations, particularly phase I, pharmacological and relevant biological studies, of investigational anti-cancer therapeutics. The greatest advances in the cancer therapy have resulted from the introduction of novel anti-cancer therapeutics and their subsequent optimization (i.e. dosing, scheduling, sequencing, deployment in combination) for clinical practice. The phase I stage represents a crucial step in this developmental process, and the reliability of clinical and supportive pharmacological and biological data may significantly impact on the expedient and optimal development of new therapies. This is especially true for selective rationally-designed, target-based agents. The sheer number investigational candidates is striking relative to available developmental resources, and prioritization of these resources by considering the ultimate impact of the therapeutic represent major developmental challenges that must be overcome. Furthermore, unlike nonspecific cytotoxics, in which anti-cancer activity is often dose-related and, hence, the maximum tolerated dose (MTD) is generally sought, the preponderance of preclinical data with selective target-based therapeutics suggest that maximal biological effects will occur at doses that are substantially lower than the MTD. Selection of a maximal biological dose would likely result in greater therapeutic indices and more "breathing room" for combination development. The preponderance of preclinical data also suggests that the predominant beneficial effects of target-based therapeutics will be tumor growth inhibition, which may not be appreciated in nonrandomized studies. This proposal will describe the San Antonio Drug Development Group's (SADDG) approach to meet these challenges. The specific aims are directed at discerning both traditional phase I study endpoints (e.g. MTD, characterization of toxicity) and relevant biological and pharmacological endpoints (e.g. maximally effective dose.) The latter is particularly important in view of the expectations that many novel anti-cancer agents may not have clear toxicological endpoints, and the prospects for clinical utility may not be known until further evaluations have been completed. Therefore, other specific aims, including the assessment of relevant biological activity at the target level, are of utmost importance to ultimately optimize the therapeutic indices of investigational cancer therapies. The SADDG proposes to perform rigorous and comprehensive toxicological, pharmacological, and biological evaluations in the course of early clinical trials. The results will be synthesized to address therapeutic optimization issues, ascertain proof of principle, and develop assays to discern the relevant effects of the therapy on the target. The development of such assays may be even more crucial for subsequent disease-directed studies to gauge biological targeting and/or tumor growth inhibition in vivo. In addition to the methodology proposed to meet these challenges, the proposal will demonstrate the immense experience, success, and dedication of the SADDG to the comprehensive development of anti-cancer therapeutics, as well as the strong institutional commitment.
Funding Period: 1995-07-01 - 2007-12-16
more information: NIH RePORT

Top Publications

  1. pmc Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study
    Stephen I Shibata
    City of Hope, Duarte, CA 91010, USA
    Clin Cancer Res 19:3631-9. 2013
  2. pmc Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432
    Patricia M LoRusso
    Karmanos Cancer Institute, Detroit, Michigan 48201, USA
    Clin Cancer Res 18:2954-63. 2012
  3. pmc Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study
    Ticiana B Leal
    University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI 53792, USA
    Cancer Chemother Pharmacol 68:1439-47. 2011
  4. ncbi Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors
    Chia Chi Lin
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA
    Cancer Chemother Pharmacol 63:1065-71. 2009
  5. ncbi Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group
    Joseph Gibbons
    Case Comprehensive Cancer Center, Ireland Cancer Center at University Hospitals of Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, USA
    J Clin Oncol 26:570-6. 2008
  6. ncbi Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group
    Ramesh K Ramanathan
    Translational Genomics Research Institute, 13208 E Shea Blvd, Ste 100, Scottsdale, AZ 85259, USA
    J Clin Oncol 26:563-9. 2008
  7. ncbi Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function
    Chris H Takimoto
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245 3217, USA
    Clin Cancer Res 13:4832-9. 2007
  8. ncbi Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study
    Timothy W Synold
    City of Hope Comprehensive Cancer Center, Duarte, California, USA
    Clin Cancer Res 13:3660-6. 2007
  9. ncbi A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma
    Monica M Mita
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA
    Cancer Chemother Pharmacol 59:165-74. 2007
  10. ncbi Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer
    Anthony W Tolcher
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA
    J Clin Oncol 24:2052-8. 2006

Scientific Experts

  • Anthony W Tolcher
  • Chris H Takimoto
  • Alejandro D Ricart
  • R K Ramanathan
  • John Sarantopoulos
  • Heinz Josef Lenz
  • Sridhar Mani
  • Stephen I Shibata
  • S Percy Ivy
  • Anne Hamilton
  • Daniel L Mulkerin
  • Timothy W Synold
  • Scot C Remick
  • Monica M Mita
  • Afshin Dowlati
  • Michelle A Rudek
  • Patricia M LoRusso
  • Karthik Venkatakrishnan
  • Rachel Neuwirth
  • Daniel Mulkerin
  • Ticiana B Leal
  • Merrill J Egorin
  • Patricia A LoRusso
  • Stephen Shibata
  • Percy Ivy
  • Chia Chi Lin
  • Joseph Gibbons
  • Alain C Mita
  • Amita Patnaik
  • M M Mita
  • S Cecilia Lau
  • Shivaani Kummar
  • Edward M Newman
  • Jeffrey A Longmate
  • Chandra P Belani
  • Anne L Hamilton
  • Lone H Ottesen
  • Patricia LoRusso
  • A Benjamin Suttle
  • BERT H O'NEIL
  • R Donald Harvey
  • Vincent Chung
  • Leena Gandhi
  • Dixie Lee Esseltine
  • James Mier
  • Lisa von Moltke
  • John J Wright
  • Angela Davies
  • I Tien Yeh
  • Theresa Mays
  • Janet E Dancey
  • Emiliano Calvo
  • Glenn G Preston
  • Helen Chen
  • Kyriakos P Papadopoulos
  • Jordi Rodon
  • Pat O'Rourke
  • Anthony J Murgo
  • Pingfu Fu
  • Jean L Grem
  • Anna Pavlick
  • Susan M Flick
  • Robert A Parise
  • Yanfeng Wang
  • Sherrie Reynolds
  • Theodore F Lagattuta
  • Eric K Rowinsky
  • Kristin Berg
  • Lisa A Hammond
  • Paul Simmons
  • Leonardo Forero
  • James H Doroshow
  • Jeffrey Longmate
  • David Gandara
  • Bennett M Kaufman
  • Johann S de Bono
  • Martin Graham
  • Sunil Sharma
  • Elzbieta Izbicka
  • Muralidhar Beeram
  • Geoffrey R Weiss
  • S Gail Eckhart
  • E K Rowinsky
  • A Patnaik
  • L A Hammond
  • L Ochoa
  • E Izbicka
  • G Schwartz
  • I T Yeh
  • J Kuhn

Detail Information

Publications13

  1. pmc Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study
    Stephen I Shibata
    City of Hope, Duarte, CA 91010, USA
    Clin Cancer Res 19:3631-9. 2013
    ..The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction...
  2. pmc Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432
    Patricia M LoRusso
    Karmanos Cancer Institute, Detroit, Michigan 48201, USA
    Clin Cancer Res 18:2954-63. 2012
    ..This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations...
  3. pmc Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study
    Ticiana B Leal
    University of Wisconsin Carbone Cancer Center, 600 Highland Ave, Madison, WI 53792, USA
    Cancer Chemother Pharmacol 68:1439-47. 2011
    ..To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population...
  4. ncbi Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors
    Chia Chi Lin
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA
    Cancer Chemother Pharmacol 63:1065-71. 2009
    ....
  5. ncbi Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group
    Joseph Gibbons
    Case Comprehensive Cancer Center, Ireland Cancer Center at University Hospitals of Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, USA
    J Clin Oncol 26:570-6. 2008
    ....
  6. ncbi Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group
    Ramesh K Ramanathan
    Translational Genomics Research Institute, 13208 E Shea Blvd, Ste 100, Scottsdale, AZ 85259, USA
    J Clin Oncol 26:563-9. 2008
    ..To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD)...
  7. ncbi Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function
    Chris H Takimoto
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245 3217, USA
    Clin Cancer Res 13:4832-9. 2007
    ..To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function...
  8. ncbi Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study
    Timothy W Synold
    City of Hope Comprehensive Cancer Center, Duarte, California, USA
    Clin Cancer Res 13:3660-6. 2007
    ..To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population...
  9. ncbi A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma
    Monica M Mita
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA
    Cancer Chemother Pharmacol 59:165-74. 2007
    ....
  10. ncbi Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer
    Anthony W Tolcher
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA
    J Clin Oncol 24:2052-8. 2006
    ....
  11. ncbi Phase I and pharmacokinetic study of sequences of the rebeccamycin analogue NSC 655649 and cisplatin in patients with advanced solid tumors
    Alejandro D Ricart
    Institute for Drug Development, Cancer Therapy and Research Center, and Department of Pharmacology, University of Texas Health Science Center at San Antonio 78229, USA
    Clin Cancer Res 11:8728-36. 2005
    ..Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed...
  12. ncbi A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer
    M M Mita
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA
    Ann Oncol 17:313-21. 2006
    ....
  13. ncbi A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer
    Anthony W Tolcher
    Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA
    Clin Cancer Res 11:3854-61. 2005
    ....