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Predicting success in regulatory approval from Phase I results

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Abstract

Purpose

Drug development in oncology is resource intensive and has a high failure rate. In this exploratory analysis, we aimed to identify the characteristics and outcomes of published Phase I studies associated with future Food and Drug Administration (FDA) approval.

Methods

Phase I studies of approved and non-approved anticancer agents between 2000 and 2013 were retrospectively examined. Fisher’s exact and chi-squared tests were used to compare the potential predictive measures.

Results

Phase I studies of 88 anticancer agents (54 approved and 34 non-approved by the FDA), treating a total of 4,423 subjects, were examined. The median number of patients in Phase I trials of approved and non-approved agents was 44.5 and 32, respectively. A total of 423 subjects (86 reporting studies) had a complete responses, and 342 subjects (80 reporting studies) had a partial responses (PR). A higher number of PR (P < 0.001), PR rate (P = 0.003) and longer PR duration (P = 0.001) were predictive of regulatory success.

Conclusions

These preliminary findings indicate that objective responses in Phase I trials may have predictive value for later regulatory approval.

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References

  1. Von Hoff DD (1998) There are no bad anticancer agents, only bad clinical trial designs–twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Cancer Res 4(5):1079–1086

    Google Scholar 

  2. Czerepak EA, Ryser S (2008) Drug approvals and failures: implications for alliances. Nat Rev Drug Discov 7 (3):197–198. http://www.nature.com/nrd/journal/v7/n3/suppinfo/nrd2531_S1.html

  3. Walker I, Newell H (2009) Do molecularly targeted agents in oncology have reduced attrition rates? Nat Rev Drug Discov 8 (1):15–16. http://www.nature.com/nrd/journal/v8/n1/suppinfo/nrd2758_S1.html

  4. U.S. Food and Drug Administration (2014) http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm. Accessed March 2014

  5. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47(1):207–214

    Article  PubMed  CAS  Google Scholar 

  6. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  PubMed  CAS  Google Scholar 

  7. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. doi:10.1016/j.ejca.2008.10.026

    Article  PubMed  CAS  Google Scholar 

  8. Goel S, Mita AC, Mita M, Rowinsky EK, Chu QS, Wong N, Desjardins C, Fang F, Jansen M, Shuster DE, Mani S, Takimoto CH (2009) A Phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res 15(12):4207–4212. doi:10.1158/1078-0432.ccr-08-2429

    Article  PubMed  CAS  Google Scholar 

  9. Holden SN, Eckhardt SG, Basser R, de Boer R, Rischin D, Green M, Rosenthal MA, Wheeler C, Barge A, Hurwitz HI (2005) Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 16(8):1391–1397. doi:10.1093/annonc/mdi247

    Article  PubMed  CAS  Google Scholar 

  10. McDonald AC, Vasey PA, Adams L, Walling J, Woodworth JR, Abrahams T, McCarthy S, Bailey NP, Siddiqui N, Lind MJ, Calvert AH, Twelves CJ, Cassidy J, Kaye SB (1998) A Phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 4(3):605–610

    PubMed  CAS  Google Scholar 

  11. Mukohara T, Nagai S, Mukai H, Namiki M, Minami H (2012) Eribulin mesylate in patients with refractory cancers: a Phase I study. Invest New Drugs 30(5):1926–1933. doi:10.1007/s10637-011-9741-2

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Tamura T, Minami H, Yamada Y, Yamamoto N, Shimoyama T, Murakami H, Horiike A, Fujisaka Y, Shinkai T, Tahara M, Kawada K, Ebi H, Sasaki Y, Jiang H, Saijo N (2006) A Phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thorac Oncol 1(9):1002–1009

    Article  PubMed  Google Scholar 

  13. Rinaldi DA, Kuhn JG, Burris HA, Dorr FA, Rodriguez G, Eckhardt SG, Jones S, Woodworth JR, Baker S, Langley C, Mascorro D, Abrahams T, Von Hoff DD (1999) A Phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 44(5):372–380

    Article  PubMed  CAS  Google Scholar 

  14. Von Hoff DD, Turner J (1991) Response rates, duration of response, and dose response effects in Phase I studies of antineoplastics. Invest New Drugs 9(1):115–122

    Article  Google Scholar 

  15. Sherman RE, Li J, Shapley S, Robb M, Woodcock J (2013) Expediting drug development–the FDA’s new “breakthrough therapy” designation. N Engl J Med 369(20):1877–1880. doi:10.1056/NEJMp1311439

    Article  PubMed  CAS  Google Scholar 

  16. Suspension of Marketing and Sales: Iclusig (ponatinib) (2014) US Food and Drug Administration website. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm373072.htm. Accessed March 2014

  17. Food and Drug Administration. Mylotarg (gemtuzumab ozogamicin): market withdrawal (2010) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm216458.htm. Accessed March 2014

  18. Djulbegovic B, Hozo I, Ioannidis JP (2014) Improving the drug development process: more not less randomized trials. JAMA 311(4):355–356. doi:10.1001/jama.2013.283742

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to express their deep appreciation to Dr. Daniel Von Hoff for reviewing the manuscript and providing very valuable comments.

Conflict of interest

None.

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Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Laeeq Malik, Alex Mejia, Devalingam Mahalingam, Andrew Brenner, John Sarantopoulos & Steven Weitman

  2. Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Helen Parsons & Benjamin Ehler

Authors
  1. Laeeq Malik
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  2. Alex Mejia
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  3. Helen Parsons
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  4. Benjamin Ehler
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  5. Devalingam Mahalingam
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  6. Andrew Brenner
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  7. John Sarantopoulos
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  8. Steven Weitman
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Corresponding author

Correspondence to Laeeq Malik.

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Malik, L., Mejia, A., Parsons, H. et al. Predicting success in regulatory approval from Phase I results. Cancer Chemother Pharmacol 74, 1099–1103 (2014). https://doi.org/10.1007/s00280-014-2596-4

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  • DOI: https://doi.org/10.1007/s00280-014-2596-4

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