A review of first-in-human small molecule oncology clinical trials

Authors

  • Daniel Greenwood Manchester Pharmacy School, University of Manchester, Manchester,
  • Ian Stratford Manchester Pharmacy School, University of Manchester, Manchester,
  • Steven Booth Early Development Centre, Merck Sharpe & Dohme, Hoddesdon, Hertfordshire,

DOI:

https://doi.org/10.18203/2349-3259.ijct20162790

Keywords:

First-in-human, Oncology, Cancer, Clinical trials, Small molecule

Abstract

First-in-human (FIH) oncology clinical trials are crucial to the development of small-molecule oncology candidates. However, there is a dearth of research investigating how these trials vary from one-another and therefore whether one approach may be better than another. This review aims to investigate variation of FIH trials published over the last decade with respect to four areas: publication particulars; trial design; patient particulars and drug administration and formulation.

Author Biographies

Daniel Greenwood, Manchester Pharmacy School, University of Manchester, Manchester,

Manchester Pharmacy School, Researcher

Ian Stratford, Manchester Pharmacy School, University of Manchester, Manchester,

Manchester Pharmacy School, Professor

References

International Agency for Research on Cancer. Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 10 April 2015.

World Health Organization. Cancer Fact Sheet. Available from: http://www.who.int/mediacentre/ factsheets/fs297/en/. Accessed 16 February 2016.

Hirsch B, Califf M, Cheng S, Tasneem A, Horton J, Chiswell K, et al. Characteristics of oncology clinical trials: Insights from a systematic analysis of clinicaltrials.gov. JAMA Intern Med. 2013;173(11):972-9.

Tourneau C, Lee J, Siu L. Dose Escalation Methods in Phase I Cancer Clinical Trials. JNCI Journal of the National Cancer Institute. J Natl Cancer Inst. 2009;101(10):708-20.

World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Available from: http://www.wma.net/en/30publications/10policies/b3/. Accessed 16 February 2016.

IMS Institute for Healthcare Informatics. Innovation in cancer care and implications for health systems. Availablefrom:http://www.imshealth.com/en/thought-leadership/ims-institute/reports/global-oncology-trend-report-2014#ims-form. Accessed 10 May 2015.

Kummar S, Gutierrez M, Anderson L, Klecker R, Chen A, Murgo A, et al. Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas. Cancer Chemoth Pharm. 2013;72(4):917-23.

Rodon J, Carducci M, Sepulveda-Sanchez J, Azaro A, Calvo E, Seoane J, et al. First-in-Human Dose Study of the Novel Transforming Growth Factor- Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma. Clin Cancer Res. 2015;21(3):553-60.

Shapiro G, Kwak E, Dezube B, Yule M, Ayrton J, Lyons J, et al. First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2015;21(1):87-97.

Sarker B, Ang J, Baird R, Kristeleit R, Shah K, Moreno V et al. First-in-human Phase I study of Pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015;21(1):77-86.

Hong D, Henary H, Falchook G, Naing A, Fu S, Moulder S, et al. First-in-human study of pbi-05204, an oleander-derived inhibitor of akt, fgf-2, nf-B and p70s6k, in patients with advanced solid tumors. Invest New Drugs. 2014;32(6):1204-12.

Blagden S, Olmin A, Josephs D, Stavraka C, Zivi A, Pinato D, et al. First-in-Human study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics and Pharmacodynamics, in Patients with Metastatic Cancer. Clin Cancer Res. 2014;20(23):5908-17.

Shimizu T, LoRusso P, Papadopoulos K, Patnaik A, Beeram M, Smith L, et al. Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors. Clin Cancer Res. 2014;20(19):5032-40.

Isambert N, Delord J, Soria J, Hollebecque A, Gomez-Roca C, Purcea D, et al. Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer - results of a first-in-man dose escalation study with a fixed dose extension phase. Ann Oncol. 2015;26(5):1005-11.

Elez M, Tabernero J, Geary D, Macarulla T, Kang S, Kahatt C, et al. First-In-Human Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2014;20(8):2205-14.

Saito K, Nagashima H, Noguchi K, Yoshisue K, Yokogawa T, Matsushima E, et al. First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in healthy male volunteers. Cancer Chemoth Pharm. 2014;73(3):577-83.

Pant S, Burris H, Moore K, Bendell J, Kurkjian C, Jones S, et al. A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2014;32(1):87-93.

Nemunaitis J, Small K, Kirschmeier P, Zhang D, Zhu Y, Jou Y, et al. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11:259.

Brunetto A, Ang J, Lal R, Olmos D, Molife L, Kristeleit R, et al. First-in-human, Pharmacokinetic and Pharmacodynamic Phase I Study of Resminostat, an Oral Histone Deacetylase Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Research. 2013;19(19):5494-504.

Ossenkoppele G, Lowenberg B, Zachee P, Vey N, Breems D, Van de Loosdrecht A, et al. A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies. Brit J Haematol. 2013;162(2):191-201.

Sessa C, Shapiro G, Bhalla K, Britten C, Jacks K, Mita M, et al. First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors. Clin Cancer Res. 2013;19(13):3671-80.

Kummar S, Anderson L, Hill K, Majerova E, Allen D, Horneffer Y, et al. First-in-Human Phase 0 Trial of Oral 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) in Patients with Advanced Malignancies. Clin Cancer Research. 2013;19(7):1852-7.

Goldman J, Raju R, Gordon G, El-Hariry I, Teofilivici F, Vukovic V, et al. A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer. 2013;13:152.

Yap T, Arkenau H, Camidge D, George S, Serkova N, Gwyther S, et al. First-in-Human Phase I Trial of Two Schedules of OSI-930, a Novel Multikinase Inhibitor, Incorporating Translational Proof-of-Mechanism Studies. Clin Cancer Res. 2013;19(4):909-19.

Tibes R, Fine G, Choy G, Redkar S, Taverna P, Oganesian A, et al. A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. Cancer Chemoth Pharm. 2012;71(2):463-71.

Gallerani E, Zucchetti M, Brunelli D, Marangon E, Noberasco C, Hess D, et al. A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma. Eur J Cancer. 2013;49(2):290-6.

Lehmann S, Bykov V, Ali D, Andren O, Cherif H, Tidefelt U, et al. Targeting p53 in Vivo: A First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer. J Clin Oncol. 2012;30(29):3633-9.

Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-Bodere F, et al. First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors. Clin Cancer Res. 2012;18(17):4806-19.

Hong D, Kurzrock R, Supko J, He X, Naing A, Wheler J, et al. A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res. 2012;18(12):3396-406.

'Yap T, Cortes-Funes H, Shaw H, Rodriguez R, Olmos D, Lal R, et al. First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours. Br J Cancer. 2012;106(8):1379-85.

Chung V, Heath E, Schelman W, Johnson B, Kirby L, Lynch K, et al. First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer. Cancer Chemoth and Pharm. 2011;69(3):733-41.

Doi T, Takiuchi H, Ohtsu A, Fuse N, Goto M, Yoshida M, et al. Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients. Br J Cancer. 2012;106(4):666-72.

Yap T, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors. J Clin Onc. 2011;29(35):4688-95.

Tabernero J, Dirix L, Schoffski P, Cervantes A, Lopez-Martin J, Capdevila J, et al. Clin Cancer Res. 2011;17(19):6313-21.

Massard C, Soria J, Anthoney D, Proctor A, Scaburri A, Pacciarini M, et al. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011;10(6):963-70.

Holen K, Belani C, Wilding G, Ramalingam S, Volkman J, Ramanathan R, et al. A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Cancer Chemoth Pharm. 2011;67(2):447-54.

Mita M, Spear M, Yee L, Mita A, Heath E, Papadopoulos K, et al. Phase 1 First-in-Human Trial of the Vascular Disrupting Agent Plinabulin (NPI-2358) in Patients with Solid Tumors or Lymphomas. Clin Cancer Res. 2010;16(23):5892-9.

Kolesar J, Hoel R, Pomplun M, Havighurst T, Stublaski J, Wollmer B, et al. A Pilot, First-in-Human, Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers. Cancer Prev Res. 2010;3(12):1565-70.

Unger C, Berdel W, Hanauske A, Sindermann H, Engel J, Mross K. First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours. Eur J Cancer. 2010;46(5):920-5.

Goss G, Siu L, Gauthier I, Chen E, A Oza, R Goel, et al. A phase I, first in man study of OSI-7836 in patients with advanced refractory solid tumors: IND.147, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. Cancer Chemoth Pharm. 2006;58(5):703-10.

Tsimberidou A, Rudek M, Hong D, Ng C, Blair J, Goldsweig H, et al. Phase 1 first-in-human clinical study of S-trans, trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors. Cancer Chemoth Pharm. 2009;65(2):235-41.

Reid A, Protheroe A, Attard G, Hayward N, Vidal L, Spicer J, et al. A First-in-Man Phase I and Pharmacokinetic Study on CHR-2797 (Tosedostat), an Inhibitor of M1 Aminopeptidases, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2009;15(15):4978-85.

Dudek A, Yunis C, Harrison L, Kumar S, Hawkinson R, Cooley S, et al. First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer. Clin Cancer Res. 2007;13(23):7119-25.

Camidge D, Smethurst D, Growcott J, Barrass N, Foster J, Febbraro S, et al. A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers. Cancer Chemoth Pharm. 2006;60(3):391-8.

Ando Y, Inada-Inoue M, Mitsuma A, Yoshino T, Ohtsu A, Suenaga N, et al. Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105(3):347-53.

Hurwitz H, Smith D, Pitot H, Brill J, Chugh R, Rouits E, et al. Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Cancer Chemoth Pharm. 2015;75(4):851-9.

LoRusso P, Goncalves P, Casetta L, Carter J, Litwiler K, Roseberry D, et al. First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2015;33(2):440-9.

Schoffski P, Jones S, Dumez H, Infante J, Van Mieghem E, Fowst C, et al. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer. 2011;47(15):2256-64.

Schmid P, Kiewe P, Possinger K, Korfel A, Lindemann S, Giurescu M, et al. Phase I study of the novel, fully synthetic epothilone sagopilone (ZK-EPO) in patients with solid tumors. Ann Oncol. 2010;21(3):633-9.

Hollebecque A, Deutsch E, Massard C, Gomez-Roca C, Bahleda R, Ribrag V, et al. A phase I, dose-escalation study of the Eg5-inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma. Invest New Drugs. 2013;31(6):1530-8.

Lam E, Goel S, Schaaf L, Cropp G, Hannah A, Zhou Y, et al. Phase I dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors. Cancer Chemoth Pharm. 2012;69(2):523-31.

Infante J, Dees E, Olszanski A, Dhuria S, Sen S, Cameron S, et al. Phase I Dose-Escalation Study of LCL161, an Oral Inhibitor of Apoptosis Proteins Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2014;32(28):3103-10.

Infante J, Weiss G, Jones S, Tibes R, Bauer T, Bendell J, et al. Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours. Eur J Cancer. 2014;50(17):2897-904.

Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 2014;15(9):975-85.

Bendell J, Hong D, Burris H, Naing A, Jones S, Falchook G, et al. Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors. Cancer Chemoth Pharm. 2014;74(1):125-30.

Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, Hirata T, et al. Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors. Clin Cancer Res. 2011;17(8):2528-37.

Ghamande S, Lin C, Cho D, Shapiro G, Kwak E, Silverman M, et al. A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors. Invest New Drugs. 2013;32(3):445-51.

Saif M, Takimoto C, Mita M, Banerji U, Lamanna N, Castro J, et al. A Phase 1, Dose-Escalation, Pharmacokinetic and Pharmacodynamic Study of BIIB021 Administered Orally in Patients with Advanced Solid Tumors. Clin Cancer Res. 2014;20(2):445-55.

Patnaik A, Papadopoulos K, Tolcher A, Beeram M, Urien S, Schaaf L, et al. Phase I Dose-Escalation Study of EZN-2208 (PEG-SN38), a Novel Conjugate of Poly(ethylene) Glycol and SN38, Administered Weekly in Patients With Advanced Cancer. Cancer Chemoth Pharm. 2013;71(6):1499-506.

Eder J, Shapiro G, Appleman L, Zhu A, Miles D, Keer H, et al. A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2. Clin Cancer Res. 2010;16(13):3507-16.

Lee L, Niu H, Rueger R, Igawa Y, Deutsch J, Ishii N, et al. The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of CH4987655 in Healthy Volunteers: Target Suppression Using a Biomarker. Clin Cancer Res. 2009;15(23):7368-74.

Infante J, Camidge D, Mileshkin L, Chen E, Hicks R, Rischin D, et al. Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors. J Clin Oncol. 2012;30(13):1527-33.

Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, et al. A Phase I Dose-scalation Study of Regorafenib (BAY 73GÇô4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2012;18(9):2658-67.

Wong K, Fracasso P, Bukowski R, Lynch T, Munster P, Shapiro G, et al. A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors. Clin Cancer Res. 2009;5(7):2552-8.

Rosen L, Senzer N, Mekhail T, Ganapathi R, Chai F, Savage R, et al. A Phase I Dose-Escalation Study of Tivantinib (ARQ 197) in Adult Patients with Metastatic Solid Tumors. Clin Cancer Res. 2011;17(24):7754-64.

Schwartz G, LoRusso P, Dickson M, Randolph S, Shaik M, Wilner K, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 2011;104(12):1862-8.

Spicer J, Baird R, Suder A, Cresti N, Corbacho J, Hogarth L, et al. Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours. Eur J Cancer. 2015;51(2):137-45.

Schoffski P, Awada A, Dumez H, Gil T, Bartholomeus S, Wolter P, et al. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer. 2012;48(2):179-86.

Isambert N, Campone M, Bourbouloux E, Drouin M, Major A, Yin W, et al. Evaluation of the safety of C-1311 (SYMADEX) administered in a phase 1 dose escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumours. Eur J Cancer. 2010;46(4):729-34.

Scott E, Thomas A, Molife L, Ahmed S, Blagden S, Fong P, et al. A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI™), in patients with advanced solid tumours. Cancer Chemoth Pharm. 2009;64(2):425-9.

Kitzen J, de Jonge M, Lamers C, Eskens F, van der Biessen D, van Doorn L, et al. Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. Eur J Cancer. 2009;45(10):1764-72.

Strumberg D, Schultheis B, Adamietz I, Christensen O, Buechert M, Kraetzschmar J, et al. Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours. Br J Cancer. 2008;99(10):1579-85.

Eskens F, Mom C, Planting A, Gietema J, Amelsberg A, Huisman H, et al. A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer. 2008;98(1):80-5.

Corcoran M, Hovens C, Michael M, Rosenthal M, Costello A. Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer. Br J Cancer. 2010;103(4):462-8.

Rodon J, Tawbi H, Thomas A, Stoller R, Turtschi C, Baselga J, et al. A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2014;20(7):1900-9.

Cancer Research UK. Worldwide cancer

incidence statistics, 2014. Available from: http://www.cancerresearchuk.org/health-professi-onal/cancer-statistics/worldwide-cancer/incidence #heading-Zero. Accessed 20 April 2015.

Cancer Research UK. Worldwide cancer

mortality statistics, 2014. Available from: http://www.cancerresearchuk.org/health-professi-onal/cancer-statistics/worldwide-cancer/mortality #heading-Zero. Accessed 20 April 2015.

Eckhouse S, Lewison G, Sullivan R. Trends in the global funding and activity of cancer research. Mol Oncol. 2008;2(1):20-32.

Oken M, Creech R, Tormey D, Horton J, Davis T, McFadden E, et al. Toxicitiy and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.

Voskoboynik M, Arkenau H. Challenges of Patient Selection for Phase I Oncology Trials. In: Vallisuta O, Olimat S, eds. Drug Discovery and Development. Croatia: InTech; 2015: 65-82.

Downloads

Published

2016-08-06

Issue

Section

Review Articles