A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

Richard H Wilson, Tr Jeffry Evans, Mark R Middleton, L Rhoda Molife, James Spicer, Veronique Dieras, Patricia Roxburgh, Heidi Giordano, Sarah Jaw-Tsai, Sandra Goble, Ruth Plummer, Richard H Wilson, Tr Jeffry Evans, Mark R Middleton, L Rhoda Molife, James Spicer, Veronique Dieras, Patricia Roxburgh, Heidi Giordano, Sarah Jaw-Tsai, Sandra Goble, Ruth Plummer

Abstract

Background: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.

Methods: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.

Results: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml-1 min-1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.

Conclusions: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).

Conflict of interest statement

RHW has received an honorarium from Clovis Oncology for attending an advisory board relating to rucaparib. The institution of TRJE has received reimbursement of study costs for this clinical trial and an honorarium from Clovis Oncology for his participation in an advisory board for another compound. MRM, LRM, JS, VD, and PR have no conflict of interest to declare. HG is an employee of Clovis Oncology. SJ-T was an employee of Clovis Oncology at the time of the study. SG is an employee of Clovis Oncology. RP has received honoraria for attending advisory boards relating to rucaparib, is named on a patent of use for rucaparib for which her institution will receive milestone payments, and has received research funding relating to this agent.

Figures

Figure 1
Figure 1
Study treatment arms.
Figure 2
Figure 2
Plasma rucaparib concentration–time profile following i.v. or oral administration. Graph shows the geometric mean plasma concentration of rucaparib in patients in arm A (oral rucaparib) (n=4) who received i.v. and oral doses on days −10 and −5, respectively.

References

    1. Ashworth A (2008) A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26: 3785–3790.
    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 (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376: 245–251.
    1. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434: 913–917.
    1. 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 LZ, 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.
    1. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O'Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D'Andrea AD (2015) Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature 518: 258–262.
    1. Clark CC, Weitzel JN, O'Connor TR (2012) Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models. Mol Cancer Ther 11: 1948–1958.
    1. 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.
    1. Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ (2007) ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13: 2728–2737.
    1. Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley MS, Jayson GC, Sludden J, Murray J, Jamieson D, Halford S, Acton G, Backholer Z, Mangano R, Boddy A, Curtin N, Plummer E (2016) Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer 114: 723–730.
    1. Drew Y, Mulligan EA, Vong WT, Thomas HD, Kahn S, Kyle S, Mukhopadhyay A, Los G, Hostomsky Z, Plummer ER, Edmondson RJ, Curtin NJ (2011) Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J Natl Cancer Inst 103: 334–346.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 228–247.
    1. Evers B, Drost R, Schut E, de Bruin M, van der Burg E, Derksen PWB, Holstege H, Liu X, van Drunen E, Beverloo HB, Smith GCM, Martin NMB, Lau A, O'Connor MJ, Jonkers J (2008) Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res 14: 3916–3925.
    1. Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NMB, Jackson SP, Smith GCM, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434: 917–921.
    1. Fast DM, Kelley M, Viswanathan CT, O'Shaughnessy J, King SP, Chaudhary A, Weiner R, DeStefano AJ, Tang D (2009) Workshop report and follow-up—AAPS workshop on current topics in GLP bioanalysis: assay reproducibility for incurred samples—implications of Crystal City recommendations. AAPS J 11: 238–241.
    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 (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361: 123–134.
    1. Helleday T (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 5: 387–393.
    1. Helleday T, Lo J, van Gent DC, Engelward BP (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair 6: 923–935.
    1. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8: 193–204.
    1. Ihnen M, zu Eulenburg C, Kolarova T, Qi JW, Manivong K, Chalukya M, Dering J, Anderson L, Ginther C, Meuter A, Winterhoff B, Jones S, Velculescu VE, Venkatesan N, Rong H-M, Dandekar S, Udar N, Jänicke F, Los G, Slamon DJ, Konecny GE (2013) Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer. Mol Cancer Ther 12: 1002–1015.
    1. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM (2015) Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33: 244–250.
    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 (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.
    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 (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.
    1. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD (2015) Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 5: 1137–1154.
    1. Kristeleit RS, Burris HA, LoRusso P, Patel MR, Asghar US, El-Khouly F, Calvert AH, Infante JR, Hilton JF, Tolaney SM, Kittaneh M, Giordano H, Borrow J, Jaw-Tsai SS, Shapiro G (2014) Phase 1/2 study of oral rucaparib: final phase 1 results. J Clin Oncol 32: 2573.
    1. 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. a) 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.
    1. Lee JM, Ledermann JA, Kohn EC (2014. b) PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 25: 32–40.
    1. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A (2015) Mammalian polymerase [THGR] promotes alternative NHEJ and suppresses recombination. Nature 518: 254–257.
    1. Moynahan ME, Chiu JW, Koller BH, Jasin M (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4: 511–518.
    1. Moynahan ME, Pierce AJ, Jasin M (2001) BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7: 263–272.
    1. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 72: 5588–5599.
    1. O'Connor MJ (2015) Targeting the DNA damage response in cancer. Mol Cell 60: 547–560.
    1. Pedersen B, Konstantinopoulos PA, Spillman MA, De S (2013) Copy neutral loss of heterozygosity is more frequent in older ovarian cancer patients. Genes Chromosomes Cancer 52: 794–801.
    1. Plummer R, Jones C, Middleton M, Wilson R, Evans J, Olsen A, Curtin N, Boddy A, McHugh P, Newell D, Harris A, Johnson P, Steinfeldt H, Dewji R, Wang D, Robson L, Calvert H (2008) Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 14: 7917–7923.
    1. Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson RH, Mulligan E, Curtin N, Wang D, Dewji R, Abbattista A, Gallo J, Calvert H (2013) A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol 71: 1191–1199.
    1. Plummer R, Stephens P, Aissat-Daudigny L, Cambois A, Moachon G, Brown PD, Campone M (2014) Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors. Cancer Chemother Pharmacol 74: 257–265.
    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 (2012) A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res 18: 2344–2351.
    1. 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. Invest New Drugs 30: 1493–1500.
    1. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, Hylands L, Riisnaes R, Forster M, Omlin A, Kreischer N, Thway K, Gevensleben H, Sun L, Loughney J, Chatterjee M, Toniatti C, Carpenter CL, Iannone R, Kaye SB, de Bono JS, Wenham RM (2013) The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 14: 882–892.
    1. Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7: 517–528.
    1. Shapira-Frommer R, Oza AM, Domchek SM, Balmana J, Patel MR, Chen L-M, Drew Y, Burris HA, Korach J, Flynn M, Bowering VL, Morgan MA, Watkins SP, Simpson D, Goble S, Maloney L, Kristeleit RS (2015) A phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol 33: 5513.
    1. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O'Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA (2017) Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 18: 75–87.
    1. Thomas HD, Calabrese CR, Batey MA, Canan S, Hostomsky Z, Kyle S, Maegley KA, Newell DR, Skalitzky D, Wang LZ, Webber SE, Curtin NJ (2007) Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol Cancer Ther 6: 945–956.
    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 (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376: 235–244.
    1. US Food and Drug Administration (2001) Bioanalytical Method Validation (May 2001). Available from .
    1. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108: 171–182.
    1. Viswanathan CT, Bansal S, Booth B, DeStefano AJ, Rose MJ, Sailstad J, Shah VP, Skelly JP, Swann PG, Weiner R (2007) Workshop/conference report—quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. AAPS J 9: E30–E42.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir