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Open-label phase 1b study of FOLFIRI plus cetuximab plus IMO-2055 in patients with colorectal cancer who have progressed following chemotherapy for advanced or metastatic disease

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Abstract

Purpose

The immune modulatory oligonucleotide IMO-2055 (EMD 1201081) is a phosphorothioate oligodeoxynucleotide agonist of Toll-like receptor 9. In preclinical studies, IMO-2055 was shown to activate natural killer cells and to support the antitumor activity of monoclonal antibodies. This phase 1b, open-label, 3 + 3 dose-escalation trial was performed to determine the recommended phase 2 dose of IMO-2055 combined with FOLFIRI/cetuximab in patients with previously treated, advanced/metastatic colorectal cancer (NCT00719199).

Methods

Patients received 14-day cycles of cetuximab (days 1/8; 400 mg/m2 day 1 cycle 1, 250 mg/m2 for subsequent days/cycles), irinotecan (day 1; 180 mg/m2), folinic acid (day 1; 400 mg/m2 racemic or 200 mg/m2 l-form), 5-fluorouracil (day 1; 400 mg/m2 intravenous bolus, followed by 2,400 mg/m2 as 46-h infusion), and escalating IMO-2055 doses (days 1/8; 0.16, 0.32, 0.48 mg/kg). Fifteen patients received IMO-2055, including six, three, and six patients who were treated at the dose levels 0.16, 0.32, and 0.48 mg/kg, respectively.

Results

One dose-limiting toxicity was observed (grade 3 fatigue; at dose level 0.16 mg/kg). The most common adverse events were injection site reactions, diarrhea, fatigue, hypomagnesemia, and stomatitis. One patient achieved a confirmed partial response; 12 had stable disease, including five with stable disease ≥4.0 months.

Conclusions

IMO-2055 combined with FOLFIRI/cetuximab was well tolerated at all dose levels tested. IMO-2055 0.48 mg/kg was considered as the recommended phase 2 dose.

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Abbreviations

5-FU:

5-Fluorouracil

AE:

Adverse event

ANA:

Antinuclear antibody

CR:

Complete response

CRC:

Colorectal cancer

DLT:

Dose-limiting toxicity

ECOG:

Eastern Cooperative Oncology Group

EGFR:

Epidermal growth factor receptor

FOLFIRI:

Leucovorin, 5-fluorouracil, and irinotecan

IL:

Interleukin

IMO:

Immune modulatory oligonucleotide

IV:

Intravenous

MedDRA:

Medical Dictionary for Regulatory Activities

MTD:

Maximum tolerated dose

NCI-CTCAE:

National Cancer Institute Common Terminology Criteria for Adverse Events

ORR:

Objective response rate

OS:

Overall survival

PD:

Progressive disease

PFS:

Progression-free survival

PR:

Partial response

RECIST:

Response Evaluation Criteria in Solid Tumors

RP2D:

Recommended phase 2 dose

SD:

Stable disease

TEAE:

Treatment-emergent adverse event

Th1:

T helper 1

TLRs:

Toll-like receptors

References

  1. Agrawal S, Kandimalla ER (2007) Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem Soc Trans 35:1461–1467

    Article  CAS  PubMed  Google Scholar 

  2. Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32:305–315

    Article  CAS  PubMed  Google Scholar 

  3. Huang X, Yang Y (2010) Targeting the TLR9-MyD88 pathway in the regulation of adaptive immune responses. Expert Opin Ther Targets 14:787–796

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Krieg AM (2007) Development of TLR9 agonists for cancer therapy. J Clin Invest 117:1184–1194

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Rayburn ER, Wang W, Zhang R, Wang H (2007) Experimental therapy for colon cancer: anti-cancer effects of TLR9 agonism, combination with other therapeutic modalities, and dependence upon p53. Int J Oncol 30:1511–1519

    CAS  PubMed  Google Scholar 

  6. Kandimalla ER, Bhagat L, Li Y, Yu D, Wang D, Cong YP, Song SS, Tang JX, Sullivan T, Agrawal S (2005) Immunomodulatory oligonucleotides containing a cytosine-phosphate-2′-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists. Proc Natl Acad Sci USA 102:6925–6930

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Wang D, Li Y, Yu D, Song SS, Kandimalla ER, Agrawal S (2004) Immunopharmacological and antitumor effects of second-generation immunomodulatory oligonucleotides containing synthetic CpR motifs. Int J Oncol 24:901–908

    CAS  PubMed  Google Scholar 

  8. van Ojik HH, Bevaart L, Dahle CE, Bakker A, Jansen MJ, van Vugt MJ, van de Winkel JG, Weiner GJ (2003) CpG-A and B oligodeoxynucleotides enhance the efficacy of antibody therapy by activating different effector cell populations. Cancer Res 63:5595–5600

    PubMed  Google Scholar 

  9. Damiano V, Caputo R, Bianco R, D’Armiento FP, Leonardi A, De Placido S, Bianco AR, Agrawal S, Ciardiello F, Tortora G (2006) Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Clin Cancer Res 12:577–583

    Article  CAS  PubMed  Google Scholar 

  10. Damiano V, Caputo R, Garofalo S, Bianco R, Rosa R, Merola G, Gelardi T, Racioppi L, Fontanini G, De Placido S, Kandimalla ER, Agrawal S, Ciardiello F, Tortora G (2007) TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts. Proc Natl Acad Sci USA 104:12468–12473

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Rosa R, Melisi D, Damiano V, Bianco R, Garofalo S, Gelardi T, Agrawal S, Di Nicolantonio F, Scarpa A, Bardelli A, Tortora G (2011) Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers. Clin Cancer Res 17:6531–6541

    Article  CAS  PubMed  Google Scholar 

  12. Zent CS, Smith BJ, Ballas ZK, Wooldridge JE, Link BK, Call TG, Shanafelt TD, Bowen DA, Kay NE, Witzig TE, Weiner GJ (2012) Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leuk Lymphoma 53:211–217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Kim YH, Girardi M, Duvic M, Kuzel T, Link BK, Pinter-Brown L, Rook AH (2010) Phase I trial of a Toll-like receptor 9 agonist, PF-3512676 (CPG 7909), in patients with treatment-refractory, cutaneous T-cell lymphoma. J Am Acad Dermatol 63:975–983

    Article  CAS  PubMed  Google Scholar 

  14. Thompson JA, Kuzel T, Drucker BJ, Urba WJ, Bukowski RM (2009) Safety and efficacy of PF-3512676 for the treatment of stage IV renal cell carcinoma: an open-label, multicenter phase I/II study. Clin Genitourin Cancer 7:E58–E65

    Article  CAS  PubMed  Google Scholar 

  15. Kuzel T, Dutcher J, Ebbinghaus S, Gordon M, Grubbs S, Khan K, Lipton A, McDermott D, Millard F, Quinn D, Sullivan T (2009) A phase 2 multicenter, randomized, open-label study of two dose levels of IMO-2055 in patients with metastatic or recurrent renal cell carcinoma. In: Presented at the 8th international kidney cancer symposium; 25–26 Sept, Chicago, IL, USA

  16. Hofmann MA, Kors C, Audring H, Walden P, Sterry W, Trefzer U (2008) Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother 31:520–527

    Article  CAS  PubMed  Google Scholar 

  17. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2011) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417

    Article  Google Scholar 

  18. 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 (2011) 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  PubMed  Google Scholar 

  19. Storer BE (1989) Design and analysis of phase I clinical trials. Biometrics 45:925–937

    Article  CAS  PubMed  Google Scholar 

  20. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:4706–4713

    Article  CAS  PubMed  Google Scholar 

  21. Broering R, Montag M, Jiang M, Lu M, Sowa JP, Kleinehr K, Gerken G, Schlaak JF (2011) Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state. Int Immunol 23:537–544

    Article  CAS  PubMed  Google Scholar 

  22. Zhang C, Kolb A, Mattern J, Gassler N, Wenger T, Herzer K, Debatin KM, Büchler M, Friess H, Rittgen W, Edler L, Herr I (2006) Dexamethasone desensitizes hepatocellular and colorectal tumours toward cytotoxic therapy. Cancer Lett 242:104–111

    Article  CAS  PubMed  Google Scholar 

  23. Gassler N, Zhang C, Wenger T, Schnabel PA, Dienemann H, Debatin KM, Mattern J, Herr I (2005) Dexamethasone-induced cisplatin and gemcitabine resistance in lung carcinoma samples treated ex vivo. Br J Cancer 92:1084–1088

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Machiels JP, Kaminsky MC, Keller U, Brümmendorf TH, Goddemeier T, Forssmann U, Delord JP (2013) Phase Ib trial of the Toll-like receptor 9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and cetuximab as first-line palliative treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 31:1207–1216

    Article  CAS  PubMed  Google Scholar 

  25. Manegold C, van Zandwijk N, Szczesna A, Zatloukal P, Au JS, Blasinska-Morawiec M, Serwatowski P, Krzakowski M, Jassem J, Tan EH, Benner RJ, Ingrosso A, Meech SJ, Readett D, Thatcher N (2012) A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR agonist) as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol 23:72–77

    Article  CAS  PubMed  Google Scholar 

  26. Hirsh V, Paz-Ares L, Boyer M, Rosell R, Middleton G, Eberhardt WE, Szczesna A, Reiterer P, Saleh M, Arrieta O, Bajetta E, Webb RT, Raats J, Benner RJ, Fowst C, Meech SJ, Readett D, Schiller JH (2011) Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 29:2667–2674

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Alice S. Bexon, MBChB, Bexon Clinical Consulting, Montclair, NJ, USA, for her input provided for the study design and her contribution to the initiation of this trial. Editorial and medical writing support in the preparation of this manuscript was provided by Marianne Jenal-Eyholzer, PhD CMPP, TRM Oncology, The Hague, The Netherlands, funded by Merck KGaA, Darmstadt, Germany. The clinical trial was sponsored by EMD Serono Inc., the US Affiliate of Merck KGaA, Darmstadt, Germany. At Vanderbilt, this study was also supported by the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflict of interest

EC: Research funding from Idera/Merck KGaA to institution for conducting this study; research funding to institution for conduct of clinical trials from Genentech, Pfizer, Bristol-Myers Squibb, and Amgen; Advisory Boards (<$10,000/year) for Amgen, Bristol-Myers Squibb, ImClone, Genentech, Lilly, Bayer, Merrimack, and Castle Biosciences. ELK: Research funding from Idera/Merck KGaA to institution for conducting this study. MH: Former employee of Merck KGaA (2010–2013). GdLB: Former employee of Merck KGaA (2008–2012). JH and MM: no competing interests.

Author information

Author notes

  1. Guillaume de La Bourdonnaye

    Present address: Philip Morris International, Neuchâtel, Switzerland

  2. Monica Mita

    Present address: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Authors and Affiliations

  1. Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232-6307, USA

    Emily Chan

  2. Massachusetts General Hospital, Boston, MA, USA

    Eunice L. Kwak

  3. Georgetown University Hospital, Washington, DC, USA

    Jimmy Hwang

  4. Merck KGaA, Darmstadt, Germany

    Marja Heiskala & Guillaume de La Bourdonnaye

  5. Institute for Drug Development, Cancer Therapy and Research Center UTHSCSA, San Antonio, TX, USA

    Monica Mita

Authors
  1. Emily Chan
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  2. Eunice L. Kwak
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  4. Marja Heiskala
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  5. Guillaume de La Bourdonnaye
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  6. Monica Mita
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Corresponding author

Correspondence to Emily Chan.

Additional information

Trial registration: ClinicalTrials.gov NCT00719199.

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Chan, E., Kwak, E.L., Hwang, J. et al. Open-label phase 1b study of FOLFIRI plus cetuximab plus IMO-2055 in patients with colorectal cancer who have progressed following chemotherapy for advanced or metastatic disease. Cancer Chemother Pharmacol 75, 701–709 (2015). https://doi.org/10.1007/s00280-015-2682-2

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  • DOI: https://doi.org/10.1007/s00280-015-2682-2

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