Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours

G Del Conte, C Sessa, R von Moos, L Viganò, T Digena, A Locatelli, E Gallerani, A Fasolo, A Tessari, R Cathomas, L Gianni, G Del Conte, C Sessa, R von Moos, L Viganò, T Digena, A Locatelli, E Gallerani, A Fasolo, A Tessari, R Cathomas, L Gianni

Abstract

Background: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221).

Methods: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).

Results: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.

Conclusions: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Figures

Figure 1
Figure 1
Analysis of γH2AX phosphorylation in ovarian cancer patients. Both treatment regimens are shown: continuous olaparib dosing, days 1–28 in platinum-resistant (A) and platinum-sensitive (C) patients, and intermittent olaparib dosing, days 2 8, in platinum-resistant (B) and platinum-sensitive (D) patients. A Wilcoxon signed-rank test was performed (P=0.046; statistical significance was defined as P<0.05). Median values are indicated.

References

    1. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR. OCEANS: a randomized, double-blind, placebo-controlled Phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–2045.
    1. AstraZeneca 2011. Global Policy: Bioethics Available at .
    1. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376:245–251.
    1. Balmaña J, Tung NM, Isakoff SJ, Graña B, Ryan PD, Rafi R, Tracy M, Winer E, Baselga J, Garber JE.2012Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors J Clin Oncol 30(15S): abst1009
    1. Berenson JR, Yellin O, Kazamel T, Hilger JD, Chen CS, Cartmell A, Woliver T, Flam M, Bravin E, Nassir Y, Vescio R, Swift RA. A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma. Leukemia. 2012;26:1675–1680.
    1. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, Pommier Y. GammaH2AX and cancer. Nat Rev Cancer. 2008;8:957–967.
    1. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–917.
    1. Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, Singer CF, Lowe ES, Watkins CL, Carmichael J. 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. 2013;15:R88.
    1. Drew Y, Plummer R. PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications. Drug Resist Updat. 2009;12:153–156.
    1. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–921.
    1. 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 JHM, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–134.
    1. 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 JHM, de Bono JS, Kaye SB. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28:2512–2519.
    1. 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. 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. 2011;12:852–861.
    1. Giaccone G, Rajan A, Kelly RJ, Gutierrez M, Kummar S, Yancey M, Ji JJ, Zhang Y, Parchment RE, Doroshow JH.2010A Phase I combination study of olaparib (AZD2281; KU-0059436) and cisplatin (C) plus gemcitabine (G) in adults with solid tumors J Clin Oncol 28(15S): abst3027
    1. Gibson JM, Alzghari S, Ahn C, Trantham H, La-Beck NM. The role of pegylated liposomal doxorubicin in ovarian cancer: a meta-analysis of randomized clinical trials. Oncologist. 2013;18:1022–1031.
    1. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312–3322.
    1. Julius JM, Tanyi JL, Nogueras-Gonzalez GM, Watkins JL, Coleman RL, Wolf JK, Smith JA. Evaluation of pegylated liposomal doxorubicin dose on the adverse drug event profile and outcomes in treatment of recurrent endometrial cancer. Int J Gynecol Cancer. 2013;23:348–354.
    1. 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. 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. 2012;30:372–379.
    1. 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. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer. 2011;104:750–755.
    1. 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, Tomaszawski JE, Doroshow JH. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 2011;71:5626–5634.
    1. Kummar S, Ji J, Morgan R, Lenz HJ, Puhalla SL, Belani CP, Gandara DR, Allen D, Kiesel B, Beumer JH, Newman EM, Rubinstein L, Chen A, Zhang Y, Wang L, Kinders RJ, Parchment RE, Tomaszawski JE, Doroshow JH. A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012;18:1726–1734.
    1. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira Frommer R, Safra T, Matei D, MacPherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–1392.
    1. Magan N, Isaacs RJ, Stowell KM. Treatment with the PARP-inhibitor PJ34 causes enhanced doxorubicin-mediated cell death in HeLa cells. Anticancer Drugs. 2012;23:627–637.
    1. Mateo J, Friedlander M, Sessa C, Leunen K, Nicum S, Gourley C, Fielding A, Bowen K, Kaye S, Molife LR.2013Administration of continuous/intermittent olaparib in ovarian cancer patients with a germline BRCA1/2 mutation to determine an optimal dosing schedule for the tablet formulation Eur J Cancer 49(2 suppl): abst801
    1. Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Lisyanskaya AS, Makhson AN, Rolski J, Gorbounova VA, Ghatage P, Bidzinski M, Shen K, Ngan HY, Vergote I, Nam JH, Park YC, Lebedinsky CA, Poveda AM. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol. 2010;28:3107–3114.
    1. Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair. Mol Cell. 1999;4:511–518.
    1. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263–272.
    1. Muñoz-Gámez JA, Quiles-Pérez R, Ruiz-Extremera A, Martín-Álvarez AB, Sanjuan-Nuñez L, Carazo A, León J, Oliver FJ, Salmerón J. Inhibition of poly (ADP-ribose) polymerase-1 enhances doxorubicin activity against liver cancer cells. Cancer Lett. 2011;301:47–56.
    1. Numico G, Castiglione F, Granetto C, Garrone O, Mariani G, Costanzo GD, Ciura PL, Gasco M, Ostellino O, Porcile G, Merlano M. Single-agent pegylated liposomal doxorubicin (Caelix) in chemotherapy pretreated non-small cell lung cancer patients: a pilot trial. Lung Cancer. 2002;35:59–64.
    1. Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S, Bologna A, Weber B, Raspagliesi F, Panici PB, Cormio G, Sorio R, Cavazzini MG, Ferrandina G, Breda E, Murgia V, Sacco C, Cinieri S, Salutari V, Ricci C, Pisano C, Greggi S, Lauria R, Lorusso D, Marchetti C, Selvaggi L, Signoriello S, Piccirillo MC, Di Maio M, Perrone F. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2014;15:396–405.
    1. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, Volgger B, Vergote I, Pignata S, Ferrero A, Sehouli J, Lortholary A, Kristensen G, Jackisch C, Joly F, Brown C, Le Fur N, du Bois A. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol. 2010;28:3323–3329.
    1. 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. A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res. 2012;18:2344–2351.
    1. Redon CE, Nakamura AJ, Zhang YW, Ji JJ, Bonner WM, Kinders RJ, Parchment RE, Doroshow JH, Pommier Y. Histone gammaH2AX and poly(ADP-ribose) as clinical pharmacodynamic biomarkers. Clin Cancer Res. 2010;16:4532–4542.
    1. Rose PG. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer. Oncologist. 2005;10:205–214.
    1. Samol J, Ranson M, Scott E, MacPherson E, Carmichael J, Thomas A, Cassidy J. 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. Invest New Drugs. 2012;30:1493–1500.
    1. Sedelnikova OA, Bonner WM. GammaH2AX in cancer cells: a potential biomarker for cancer diagnostics, prediction and recurrence. Cell Cycle. 2006;5:2909–2913.
    1. Sessa C, Cresta S, Cerny T, Baselga J, Rota CE, Malossi A, Hess D, Trigo J, Zucchetti M, D'Incalci M, Zaniboni A, Capri G, Gatti B, Carminati P, Zanna C, Marsoni S, Gianni L. Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. Ann Oncol. 2007;18:561–568.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. 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. 2000;92:205–216.
    1. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235–244.

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