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14-06-2015 | PARP inhibitors | Book chapter | Article

22. Clinical Trials of PARP Inhibitors with Chemotherapy

Authors: Ashley K. Clift, Nicholas Coupe, Mark R. Middleton

Publisher: Springer International Publishing

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Abstract

The first clinical trial of a PARP inhibitor was designed shortly before the concept of synthetic lethality emerged. Single agent activity was not anticipated and, based upon pre-clinical evaluation, PARP inhibition was envisaged as a means to overcome tumour resistance to chemotherapy. The mechanism of action of methylating agents and topoisomerase 1 poisons made these the agents of choice in early combinations, as they were for other DNA repair inhibitors. The pleiotropic effects of PARP inhibition and in vitro evidence supported widening the potential partner drugs to include platinums. The emergence of synthetic lethality brought combinations with drugs used to treat BRCA deficient tumours into play and the clinical trials with these agents are also discussed in this chapter. More recently the interaction between hypoxia, DNA damage processing and PARP sensitivity has suggested new combinations with novel agents, particularly anti-angiogenics, although clinical data are sparse.
Literature
1.
Yung WK et al (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 17(9):2762–2771PubMed
2.
Middleton MR et al (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18(1):158–166PubMed
3.
Danson SJ, Middleton MR (2001) Temozolomide: a novel oral alkylating agent. Expert Rev Anticancer Ther 1(1):13–19PubMedCrossRef
4.
Newlands ES et al (1997) Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23(1):35–61PubMedCrossRef
5.
Fromme JC, Banerjee A, Verdine GL (2004) DNA glycosylase recognition and catalysis. Curr Opin Struct Biol 14(1):43–49PubMedCrossRef
6.
Margison GP, Santibanez Koref MF, Povey AC (2002) Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine. Mutagenesis 17(6):483–487PubMedCrossRef
7.
Ranson M et al (2006) Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 12(5):1577–1584PubMedCrossRef
8.
Ranson M et al (2007) Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma. J Clin Oncol 25(18):2540–2545PubMedCrossRef
9.
Plummer R et al (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(23):7917–7923PubMedCentralPubMedCrossRef
10.
Plummer R et al (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(5):1191–1199PubMedCrossRef
11.
Khan OA et al (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(5):750–755PubMedCentralPubMedCrossRef
12.
Su JM et al (2013) A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: a pediatric brain tumor Consortium report. ASCO meeting abstracts, 2013. 31(15_suppl):2036
13.
Robins HI et al (2012) Phase I results from Rtog 0929, a randomized phase I/Ii Study of Abt-888 (Veliparib) in combination with Temozolomide (Tmz) in recurrent, Tmz-resistant glioblastoma. Neuro Oncol 14:67–67
14.
Kleinberg LR et al (2012) An American Brain tumor consortium (ABTC) phase 1 trial of veliparib (ABT-888), Temozolomide (TMZ), and concurrent radiation therapy (RT) for newly diagnosed glioblastoma multiforme (GBM): need for modification to approach for combining these therapies. Int J Radiat Oncol Biol Phys 84(3):S7–S8CrossRef
15.
Campone M et al (2012) Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single-agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595). ASCO meeting abstracts, 2012. 30(15_suppl):3052
16.
Middleton M, Friedberg EC, Hamid O, Daud A, Plummer R, Schuster R, Qian J, Luo Y, Giranda VL, McArthur G (2011) Veliparib (ABT-888) plus temozolomide versus temozolomide alone: efficacy and safety in patients with metastatic melanoma in a randomized double-blind placebo-controlled trial. Pigment Cell Melanoma Res 24:1022–1023
17.
Kummar S et al (2012) A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res 18(6):1726–1734PubMedCentralPubMedCrossRef
18.
Browder T et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7):1878–1886PubMed
19.
Bocci G et al (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 100(22):12917–12922PubMedCentralPubMedCrossRef
20.
Ghiringhelli F et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56(5):641–648PubMedCrossRef
21.
Kummar S et al (2012) Randomized trial of oral cyclophosphamide (C) with or without veliparib (V), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent BRCA-positive ovarian, or primary peritoneal or high-grade serous ovarian carcinoma. ASCO meeting abstracts, 2012. 30(15_suppl):5020
22.
Tan AR et al (2011) Phase I trial of veliparib, (ABT-888), a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors. ASCO meeting abstracts, 2011. 29(15_suppl):3041
23.
Helleday T et al (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8(3):193–204PubMedCrossRef
24.
Miknyoczki SJ et al (2003) Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol Cancer Ther 2(4):371–382PubMed
25.
Donawho CK et al (2007) ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13(9):2728–2737PubMedCrossRef
26.
Balmana J et al (2012) Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors. ASCO meeting abstracts, 2012. 30(15_suppl):1009
27.
Somlo G et al (2013) Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer. ASCO meeting abstracts, 2013. 31(15_suppl):1024
28.
Lee J et al (2011) Phase I study of the PARP inhibitor olaparib (O) in combination with carboplatin (C) in BRCA1/2 mutation carriers with breast (Br) or ovarian (Ov) cancer (Ca). ASCO meeting abstracts, 2011. 29(15_suppl):2520
29.
Lee J.-m et al (2013) Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062). ASCO meeting abstracts, 2013. 31(15_suppl):2514
30.
Molife LR et al (2013) A phase I study of oral rucaparib in combination with carboplatin. ASCO meeting abstracts, 2013. 31(15_suppl):2586
31.
Bang Y-J et al (2013) Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study. ASCO meeting abstracts, 2013. 31(15_suppl):4013
32.
Dent RA et al (2010) Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the first- or second-line treatment of patients with metastatic triple-negative breast cancer: Results from the safety cohort of a phase I/II multicenter trial. ASCO meeting abstracts, 2010. 28(15_suppl):1018
33.
Appleman LJ et al (2012) A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies. ASCO meeting abstracts, 2012. 30(15_suppl):3049
34.
Avery TP et al (2013) An adaptive randomized phase II trial to determine pathologic complete response with the addition of carboplatin with and without ABT-888 to standard chemotherapy in the neoadjuvant treatment of triple-negative breast cancer. ASCO meeting abstracts, 2013. 31(15_suppl):TPS1135
35.
Swift LP et al (2006) Doxorubicin-DNA adducts induce a non-topoisomerase II-mediated form of cell death. Cancer Res 66(9):4863–4871PubMedCrossRef
36.
Burger A, Adams C, Horiba MN, Robert J, Chen A, LoRusso P (2008) The poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the topoisomerase I poison irinotecan. AACR meeting abstracts, 2008. 1590
37.
Samol J et al (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(4):1493–1500PubMedCrossRef
38.
Kummar S et al (2011) Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res 71(17):5626–5634PubMedCentralPubMedCrossRef
39.
LoRusso P et al (2011) Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888; V) in combination with irinotecan (CPT-11; Ir) in patients (pts) with advanced solid tumors. ASCO meeting abstracts, 2011. 29(15_suppl):3000
40.
Pothuri B et al (2012) Phase I study of the PARP inhibitor ABT-888 (veliparib) and pegylated liposomal doxorubicin (PLD) in recurrent ovarian (ov) and breast (br) cancers. Gynecol Oncol 125:S22–S22CrossRef
41.
Sessa C et al (2011) Phase I safety and tolerability study of olaparib (AZD2281) in combination with liposomal doxorubicin (PLD) in patients with advanced metastatic solid tumours. Eur J Cancer 47:S161–S162CrossRef
42.
Karp JE et al (2010) Phase I trial of the oral poly (ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888, V) combined with topoecan (T) and carboplatin (C) for adults with relapsed and refractory acute leukemias. Blood 116(21):1342–1343
43.
Pratz KW et al (2011) Phase I trial of the oral poly (ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888, V) combined wtih topoecan (T) and carboplatin (C) for adults with relapsed and refractory acute leukemias. Blood 118(21):1552–1552
44.
Tan AR et al (2011) Phase I trial of veliparib, (ABT-888), a poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with doxorubicin and cyclophosphamide in breast cancer and other solid tumors. ASCO meeting abstracts, 2011. 29(15_suppl):3041
45.
Oza AM et al (2012) Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): A randomized, open-label phase II study. ASCO meeting abstracts, 2012. 30(15_suppl):5001
46.
van der Noll R et al (2013) Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors. ASCO meeting abstracts, 2013. 31(15_suppl):2579
47.
Rajan A et al (2012) A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Clin Cancer Res 18(8):2344–2351 (an official journal of the American Association for Cancer Research)PubMedCrossRef
48.
Bell-McGuinn KM et al (2013) Phase I study of ABT-888 in combination with carboplatin and gemcitabine in subjects with advanced solid tumors. ASCO meeting abstracts, 2013. 31(15_suppl):2584
49.
Pishvaian MJ et al (2013) A phase I/II study of ABT-888 in combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with metastatic pancreatic cancer (MPC). ASCO meeting abstracts, 2013. 31(4_suppl):147
50.
Escudier B et al (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–2111PubMedCrossRef
51.
Burger RA et al (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–2483PubMedCrossRef
52.
Perren TJ et al (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–2496PubMedCrossRef
53.
Sandler A et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550PubMedCrossRef
54.
Hurwitz H et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342PubMedCrossRef
55.
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307PubMedCentralPubMedCrossRef
56.
Bindra RS et al (2005) Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res 65(24):11597–11604PubMedCrossRef
57.
Chan N, Bristow RG (2010) “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair. Clin Cancer Res: an official journal of the American Association for Cancer Research 16(18):4553–4560PubMedCrossRef
58.
Bindra RS et al (2004) Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 24(19):8504–8518PubMedCentralPubMedCrossRef
59.
Hegan DC et al (2010) Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A 107(5):2201–2206PubMedCentralPubMedCrossRef
60.
Tentori L et al (2007) Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur J Cancer 43(14):2124–2133PubMedCrossRef
61.
Dean E et al (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(3):468–474PubMedCentralPubMedCrossRef
62.
Liu JF et al (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(14):2972–2978PubMedCentralPubMedCrossRef