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A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187

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Background Olaparib is an orally available inhibitor of PARP-1. In pre-clinical studies, olaparib was shown to potentiate anti-tumor effects of irinotecan in colon cancer cell lines. This phase I study was conducted to evaluate the safety and tolerability of olaparib in combination with irinotecan. Patients and Methods Patients with advanced colorectal cancer whose disease progressed after at least one systemic therapy regimen were enrolled. Dose escalation and de-escalation were based on toxicity assessment. Pharmacokinetic samples were collected in Cycle 1 for olaparib, irinotecan and SN-38. Results Twenty-five patients were enrolled, 11 patients on a schedule of continuous olaparib and irinotecan every 3 weeks (Part A) and 14 patients on a schedule of intermittent olaparib and irinotecan every 2 weeks (Part B). Continuous olaparib administration was associated with higher than expected toxicities and was not considered to be tolerable. Intermittent olaparib administration was better tolerated, and the recommended phase 2 doses were olaparib 50 mg p.o twice daily days 1–5 and irinotecan 125 mg/m2 i.v. every 2 weeks. Common toxicities included fatigue, anorexia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia and abdominal pain. Nine patients had stable disease as the best response, 2 from Part A (3 and 9 months respectively), and 7 from Part B (median duration: 7.4 months; range: 4 to 13 months). There was no pharmacokinetic interaction between olaparib and irinotecan. Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353.

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References

  1. Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481:287–294

    Article  CAS  PubMed  Google Scholar 

  2. Benafif S, Hall M (2015) An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther 8:519–528

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134

    Article  CAS  PubMed  Google Scholar 

  4. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, Lubinski J, Shanley S, Messiou C, A'Hern R, Tutt A, Ashworth A, Stone J, Carmichael J, Schellens JH, de Bono JS, Kaye SB (2010) Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28:2512–2519

    Article  CAS  PubMed  Google Scholar 

  5. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861

    Article  CAS  PubMed  Google Scholar 

  6. Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, Colombo N, Spacek J, Vuylsteke P, Hirte H, Mahner S, Plante M, Schmalfeldt B, Mackay H, Rowbottom J, Lowe ES, Dougherty B, Barrett JC, Friedlander M (2015) Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 16:87–97

    Article  CAS  PubMed  Google Scholar 

  7. Tahara M, Inoue T, Sato F, Miyakura Y, Horie H, Yasuda Y, Fujii H, Kotake K, Sugano K (2014) The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks. Mol Cancer Ther 13:1170–1180

    Article  CAS  PubMed  Google Scholar 

  8. Miknyoczki S, Chang H, Grobelny J, Pritchard S, Worrell C, McGann N, Ator M, Husten J, Deibold J, Hudkins R, Zulli A, Parchment R, Ruggeri B (2007) The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther 6:2290–2302

    Article  CAS  PubMed  Google Scholar 

  9. Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf RA, Kyle S, Li J, Maegley K, Newell DR, Notarianni E, Stratford IJ, Skalitzky D, Thomas HD, Wang L-Z, Webber SE, Williams KJ, Curtin NJ (2004) Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 96:56–67

    Article  CAS  PubMed  Google Scholar 

  10. Smith LM, Willmore E, Austin CA, Curtin NJ (2005) The novel poly(ADP-ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res 11:8449–8457

    Article  CAS  PubMed  Google Scholar 

  11. Tentori L, Leonetti C, Scarsella M, Muzi A, Mazzon E, Vergati M, Forini O, Lapidus R, Xu W, Dorio AS, Zhang J, Cuzzocrea S, Graziani G (2006) Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. FASEB J 20:1709–1711

    Article  CAS  PubMed  Google Scholar 

  12. Genther Williams SM, Kuznicki AM, Andrade P, Dolinski BM, Elbi C, O'Hagan RC, Toniatti C (2015) Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status. Cancer Cell Int 15:14

    Article  PubMed  PubMed Central  Google Scholar 

  13. Miura K, K-i S, Someya M, Matsumoto Y, Matsumoto H, Takahashi A, Hareyama M (2012) The combination of olaparib and camptothecin for effective radiosensitization. Radiat Oncol 7:1–9

    Article  Google Scholar 

  14. Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418

    Article  CAS  PubMed  Google Scholar 

  15. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25:4779–4786

    Article  CAS  PubMed  Google Scholar 

  16. Therasse P, Eisenhauer EA, Verweij J (2006) RECIST revisited: a review of validation studies on tumour assessment. Eur J Cancer 42:1031–1039

    Article  CAS  PubMed  Google Scholar 

  17. Rivory LP, Haaz MC, Canal P, Lokiec F, Armand JP, Robert J (1997) Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. Clin Cancer Res 3:1261–1266

    CAS  PubMed  Google Scholar 

  18. Choy E, Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, D'Adamo D, Cote GM, Flamand Y, Benes CH, Haber DA, Baselga JM, Demetri GD (2014) Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 14:813

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bundred N, Gardovskis J, Jaskiewicz J, Eglitis J, Paramonov V, McCormack P, Swaisland H, Cavallin M, Parry T, Carmichael J, Dixon JM (2013) Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery. Investig New Drugs 31(949–958):20

    Google Scholar 

  20. Yamamoto N, Nokihara H, Yamada Y, Goto Y, Tanioka M, Shibata T, Yamada K, Asahina H, Kawata T, Shi X, Tamura T (2012) A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors. Cancer Sci 103:504–509

    Article  CAS  PubMed  Google Scholar 

  21. Dean E, Middleton MR, Pwint T, Swaisland H, Carmichael J, Goodege-Kunwar P, Ranson M (2012) Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer 106:468–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel B, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA (2014) Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15:1207–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, Lee H, Whalen C, Tyburski K, Winer E, Ivy P, Matulonis UA (2013) A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 49:2972–2978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372–379

    Article  CAS  PubMed  Google Scholar 

  25. Del Conte G, Sessa C, von Moos R, Vigano L, Digena T, Locatelli A, Gallerani E, Fasolo A, Tessari A, Cathomas R, Gianni L (2014) Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br J Cancer 111:651–659

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, Singer CF, Lowe ES, Watkins CL, Carmichael J (2013) Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 15(R88):27

    Google Scholar 

  27. Balmana J, Tung NM, Isakoff SJ, Grana B, Ryan PD, Saura C, Lowe ES, Frewer P, Winer E, Baselga J, Garber JE (2014) Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 25:1656–1663

    Article  CAS  PubMed  Google Scholar 

  28. Bendell J, O'Reilly EM, Middleton MR, Chau I, Hochster H, Fielding A, Burke W, Burris H 3rd (2015) Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer. Ann Oncol 26:804–811

    Article  CAS  PubMed  Google Scholar 

  29. Khan OA, Gore M, Lorigan P, Stone J, Greystoke A, Burke W, Carmichael J, Watson AJ, McGown G, Thorncroft M, Margison GP, Califano R, Larkin J, Wellman S, Middleton MR (2011) A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer 104:750–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee JM, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, Yu M, Gordon N, Ji J, Sissung TM, Figg WD, Azad N, Wood BJ, Doroshow J, Kohn EC (2014) Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 106:dju089

    Article  PubMed  PubMed Central  Google Scholar 

  31. Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, Cassidy J (2012) Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Investig New Drugs 30:1493–1500

    Article  CAS  Google Scholar 

  32. Rajan A, Carter CA, Kelly RJ, Gutierrez M, Kummar S, Szabo E, Yancey MA, Ji J, Mannargudi B, Woo S, Spencer S, Figg WD, Giaccone G (2012) A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res 18:2344–2351

    Article  CAS  PubMed  Google Scholar 

  33. Kummar S, Chen A, Ji J, Zhang Y, Reid JM, Ames M, Jia L, Weil M, Speranza G, Murgo AJ, Kinders R, Wang L, Parchment RE, Carter J, Stotler H, Rubinstein L, Hollingshead M, Melillo G, Pommier Y, Bonner W, Tomaszewski JE, Doroshow JH (2011) Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res 71:5626–5634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hussain M, Carducci MA, Slovin S, Cetnar J, Qian J, McKeegan EM, Refici-Buhr M, Chyla B, Shepherd SP, Giranda VL, Alumkal JJ (2014) Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Investig New Drugs 32:904–912

    Article  CAS  Google Scholar 

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Correspondence to Eric X. Chen.

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Dr. Siu received research funding (clinical trials support) from AstraZeneca / Medimmune. No other authors declared any conflicts of interest. Olaparib was provided by AstraZeneca.

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Chen, E.X., Jonker, D.J., Siu, L.L. et al. A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187. Invest New Drugs 34, 450–457 (2016). https://doi.org/10.1007/s10637-016-0351-x

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