Skip to main content

Advertisement

SpringerLink
Log in

Figitumumab in patients with refractory metastatic colorectal cancer previously treated with standard therapies: a nonrandomized, open-label, phase II trial

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Figitumumab (CP-751,871) is a human IgG2 monoclonal antibody that binds and down-regulates insulin-like growth factor receptor-1 (IGF-1R) and inhibits activation of this receptor by IGF-1 and IGF-2. This nonrandomized, open-label, single-arm, phase II trial evaluated the antitumor activity and safety of figitumumab in patients with metastatic colorectal cancer that was refractory to ≥2 systemic therapies.

Methods

Cohorts A and B received intravenous figitumumab 20 and 30 mg/kg in 3-week cycles, respectively. Both received loading doses (20 or 30 mg/kg) on days 1 and 2 of cycle 1. The primary endpoint was 6-month survival (null hypothesis for each cohort, H0: p6 mo surv = 0.45). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response, safety, and pharmacokinetics.

Results

A total of 168 patients (Cohort A, n = 85; Cohort B, n = 83) received figitumumab. Estimated 6-month survival was 49.4 % (95 % CI 38.8–60.0) in Cohort A and 44.1 % (95 % CI 33.4–54.9) in Cohort B. Median OS was 5.8 and 5.6 months, respectively; median PFS was 1.4 months in both cohorts. No objective partial or complete responses occurred. The respective rates of treatment discontinuation due to treatment-related adverse events (AEs) were 5 and 7 %. The most common grade 3/4 nonhematologic AEs in both cohorts were hyperglycemia and asthenia. No grade 4 hematologic laboratory abnormalities occurred. Most deaths were reported as due to progressive disease; none were due to figitumumab.

Conclusion

Six-month survival data do not support further study of figitumumab 20 or 30 mg/kg in this patient population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

    Article  PubMed  CAS  Google Scholar 

  2. Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2013) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29:2011–2019

    Article  CAS  Google Scholar 

  3. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671

    Article  PubMed  CAS  Google Scholar 

  4. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705

    Article  PubMed  CAS  Google Scholar 

  5. Joulain F, Proskorovsky I, Allegra C, Tabernero J, Hoyle M, Iqbal SU, Van Cutsem E (2013) Mean overall survival gain with aflibercept plus FOLFIRI vs placebo plus FOLFIRI in patients with previously treated metastatic colorectal cancer. Br J Cancer 109:1735–1743

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Shahda S, Saif MW (2013) Regorafenib: from bench to bedside in colorectal cancer. Expert Rev Clin Pharmacol 6:243–248

    Article  PubMed  CAS  Google Scholar 

  7. López-Calderero I, Sánchez Chávez E, García-Carbonero R (2010) The insulin-like growth factor pathway as a target for cancer therapy. Clin Transl Oncol 12:326–338

    Article  PubMed  CAS  Google Scholar 

  8. Donovan EA, Kummar S (2008) Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol Hematol 66:91–98

    Article  PubMed Central  PubMed  Google Scholar 

  9. Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, Tengowski MW, Wang F, Gualberto A, Beebe JS, Moyer JD (2005) Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 11:2063–2073

    Article  PubMed  CAS  Google Scholar 

  10. Haluska P, Shaw HM, Batzel GN, Yin D, Molina JR, Molife LR, Yap TA, Roberts ML, Sharma A, Gualberto A, Adjei AA, de Bono JS (2007) Phase I dose escalation study of the anti insulin-like growth factor-1 receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res 13:5834–5840

    Article  PubMed  CAS  Google Scholar 

  11. Ii M, Li H, Adachi Y, Yamamoto H, Ohashi H, Taniguchi H, Arimura Y, Carbone DP, Imai K, Shinomura Y (2011) The efficacy of IGF-1 receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras status. Clin Cancer Res 17:5048–5049

    Article  PubMed  CAS  Google Scholar 

  12. National Cancer Institute (2012) Common Terminology Criteria for Adverse Events v3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 23 March 2012

  13. 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 92:205–216

    Article  PubMed  CAS  Google Scholar 

  14. Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA (2004) Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 22:3950–3957

    Article  PubMed  CAS  Google Scholar 

  15. Case L, Morgan T (2003) Design of Phase II cancer trials evaluating survival probabilities. BMC Med Res Methodol 3:6

    Article  PubMed Central  PubMed  Google Scholar 

  16. Hart LS, Dolloff NG, Dicker DT, Koumenis C, Christensen JG, Grimberg A, El-Deiry WS (2011) Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab. Cell Cycle 10:2331–2338

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Yin D, Sleight B, Alvey C, Hansson AG, Bello A (2013) Pharmacokinetics and pharmacodynamics of figitumumab, a monoclonal antibody targeting the insulin-like growth factor 1 receptor, in healthy participants. J Clin Pharmacol 53:21–28

    Article  PubMed  Google Scholar 

  18. Juergens H, Daw NC, Geoerger B, Ferrari S, Villarroel M, Aerts I, Whelan J, Dirksen U, Hixon ML, Yin D, Wang T, Green S, Paccagnella L, Gualberto A (2011) Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 29:4534–4540

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Retraction (2012) Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab. Br J Cancer 107:2024

    Article  Google Scholar 

  20. Schmitz S, Kaminsky-Forrett MC, Henry S, Zanetta S, Geoffrois L, Bompas E, Moxhon A, Mignion L, Guigay J, Knoops L, Hamoir M, Machiels JP (2012) Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008-02). Ann Oncol 23:2153–2161

    Article  PubMed  CAS  Google Scholar 

  21. Chi KN, Gleave ME, Fazli L, Goldenberg SL, So A, Kollmannsberger C, Murray N, Tinker A, Pollak M (2012) A phase II pharmacodynamic study of preoperative figitumumab in patients with localized prostate cancer. Clin Cancer Res 18:3407–3413

    Article  PubMed  CAS  Google Scholar 

  22. Haluska P, Worden F, Olmos D, Yin D, Schteingart D, Batzel GN, Paccagnella ML, de Bono JS, Gualberto A, Hammer GD (2010) Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 65:765–773

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff. This study was supported by funding from Pfizer Inc. Editorial assistance was provided by Susanne Gilbert at ACUMED® (New York, NY, USA) with funding from Pfizer Inc. Medical writing assistance was provided independently by Ann Morcos, MA, ELS, of US Oncology Research, McKesson Specialty Health (The Woodlands, TX, USA) with funding from the Texas Oncology-Sammons Cancer Center.

Conflict of interest

Carlos R. Becerra has received research funding from Pfizer Inc. Ramon Salazar has no conflicts to disclose. Rocio Garcia-Carbonero has served as an advisor/consultant to Pfizer, Merck, Amgen, and Roche. Anne L. Thomas has no conflicts to disclose. Federico J. Vázquez-Mazón has no conflicts to disclose. James Cassidy has received remuneration from Roche and has served as an advisor/consultant to Roche, Amgen, Sanofi, and GlaxoSmithKline. Tim Maughan has served as an advisor/consultant to Genentech and Sanofi. Manuel Gallén Castillo has no conflicts to disclose. Tim Iveson has no conflicts to disclose. Donghua Yin and Stephanie Green are employees of Pfizer Inc, and Stephanie Green holds stock in Pfizer. Emily K. Bergsland has served as an advisor/consultant to Pfizer (uncompensated).

Author information

Authors and Affiliations

  1. Texas Oncology-Sammons Cancer Center at Baylor, 3410 Worth Street, Dallas, TX, 75246, USA

    Carlos R. Becerra

  2. US Oncology, The Woodlands, TX, USA

    Carlos R. Becerra

  3. Hospital Duran I Reynals, Institut Catalá d’Oncologia, Barcelona, Spain

    Ramon Salazar

  4. Hospital Universitario Virgen del Rocío (HUVR), Instituto de Biomedicina de Sevilla (IBIS), CSIC, Universidad de Sevilla, Seville, Spain

    Rocio Garcia-Carbonero

  5. University of Leicester, Leicester, UK

    Anne L. Thomas

  6. Elche General University Hospital, Elche, Spain

    Federico J. Vázquez-Mazón

  7. The Beatson West of Scotland Cancer Centre, Glasgow, UK

    James Cassidy

  8. University of Oxford, Oxford, UK

    Tim Maughan

  9. Hospital del Mar, Barcelona, Spain

    Manuel Gallén Castillo

  10. University Hospitals Southampton NHS Foundation Trust, Southampton, UK

    Tim Iveson

  11. Pfizer Inc, Groton, CT, USA

    Donghua Yin & Stephanie Green

  12. University of California, San Francisco (UCSF), San Francisco, CA, USA

    Emily K. Bergsland

Authors
  1. Carlos R. Becerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramon Salazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rocio Garcia-Carbonero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne L. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Federico J. Vázquez-Mazón
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James Cassidy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tim Maughan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel Gallén Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tim Iveson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Donghua Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephanie Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Emily K. Bergsland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos R. Becerra.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Becerra, C.R., Salazar, R., Garcia-Carbonero, R. et al. Figitumumab in patients with refractory metastatic colorectal cancer previously treated with standard therapies: a nonrandomized, open-label, phase II trial. Cancer Chemother Pharmacol 73, 695–702 (2014). https://doi.org/10.1007/s00280-014-2391-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-014-2391-2

Keywords

Search

Navigation