First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.
Administration, Oral
Adult
Aged
Azo Compounds
Biomarkers, Tumor
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Isoquinolines
/ administration & dosage
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
/ drug therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Quinazolinones
/ administration & dosage
Survival Analysis
Treatment Outcome
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
27
11
2019
accepted:
14
05
2020
revised:
14
04
2020
pubmed:
12
6
2020
medline:
26
2
2021
entrez:
12
6
2020
Statut:
ppublish
Résumé
This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. www.ClinicalTrials.gov code: NCT01618136.
Sections du résumé
BACKGROUND
This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.
METHODS
E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.
RESULTS
Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing.
CONCLUSION
The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.
CLINICAL TRIAL REGISTRATION
www.ClinicalTrials.gov code: NCT01618136.
Identifiants
pubmed: 32523090
doi: 10.1038/s41416-020-0916-5
pii: 10.1038/s41416-020-0916-5
pmc: PMC7434893
doi:
Substances chimiques
Azo Compounds
0
Biomarkers, Tumor
0
Isoquinolines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Quinazolinones
0
stenoparib
9X5A2QIA7C
Banques de données
ClinicalTrials.gov
['NCT01618136']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
525-533Références
Curtin, N. J. DNA repair dysregulation from cancer driver to therapeutic target. Nat. Rev. Cancer 12, 801–817 (2012).
doi: 10.1038/nrc3399
Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer 10, 293–301 (2010).
doi: 10.1038/nrc2812
Riccio, A. A., Cingolani, G. & Pascal, J. M. PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage. Nucleic Acids Res. 44, 1691–1702 (2016).
doi: 10.1093/nar/gkv1376
Yelamos, J., Farres, J., Llacuna, L., Ampurdanes, C. & Martin-Caballero, J. PARP-1 and PARP-2: New players in tumour development. Am. J. Cancer Res. 1, 328–346 (2011).
pubmed: 21968702
pmcid: 3180065
Davar, D., Beumer, J. H., Hamieh, L. & Tawbi, H. Role of PARP inhibitors in cancer biology and therapy. Curr. Med Chem. 19, 3907–3921 (2012).
doi: 10.2174/092986712802002464
Konecny, G. E. & Kristeleit, R. S. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br. J. Cancer 115, 1157–1173 (2016).
doi: 10.1038/bjc.2016.311
Césaire, M., Thariat, J., Candéias, S. M., Stefan, D., Saintigny, Y. & Chevalier, F. Combining PARP inhibition, radiation, and immunotherapy: a possible strategy to improve the treatment of cancer? Int J. Mol. Sci. 19, E3793 (2018).
doi: 10.3390/ijms19123793
Shen, Y., Aoyagi-Scharber, M. & Wang, B. Trapping poly(ADP-ribose) polymerase. J. Pharm. Exp. Ther. 353, 446–457 (2015).
doi: 10.1124/jpet.114.222448
Chalmers, A. J. The potential role and application of PARP inhibitors in cancer treatment. Br. Med Bull. 89, 23–40 (2009).
doi: 10.1093/bmb/ldp005
Lynparza (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP, 2017.
Rubraca (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology, Inc., 2016.
Kaufman, B., Shapira-Frommer, R., Schmutzler, R. K., Audeh, M. W., Friedlander, M., Balmaña, J. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).
doi: 10.1200/JCO.2014.56.2728
Shapira-Frommer, R., Oza, A. M., Domchek, S. M., Balmaña, J., Patel, M. R., Drew, L. C. et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation [abstract]. J. Clin. Oncol. 33(15 Suppl), 5513 (2015).
doi: 10.1200/jco.2015.33.15_suppl.5513
Zejula (niraparib) [prescribing information]. (Tesaro, Inc., Waltham, MA, 2019).
Mirza, M. R., Monk, B. J., Herrstedt, J., Oza, A. M., Mahner, S., Redondo, A. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).
doi: 10.1056/NEJMoa1611310
Moore, K., Colombo, N., Scambia, G., Kim, B. G., Oaknin, A., Friedlander, M. et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379, 2495–2505 (2018).
doi: 10.1056/NEJMoa1810858
McGonigle, S., Chen, Z., Wu, J., Chang, P., Kolber-Simonds, D., Ackermann, K. et al. E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling. Oncotarget 6, 41307–41323 (2015).
doi: 10.18632/oncotarget.5846
McGonigle, S., Chen, Z., Wu, J., Ackermann, K., Tendyke, K., Moniz, G. et al. E7449: A novel PARP inhibitor enhances the efficacy of radiotherapy and chemotherapy and has potent single agent anticancer activity in BRCA-deficient tumors [abstract]. Cancer Res. 72(8 Suppl), Abstract 4688 (2012).
Wang, D. D., Li, C., Sun, W., Zhang, S., Shalinsky, D. R., Kern, K. A. et al. PARP activity in peripheral blood lymphocytes as a predictive biomarker for PARP inhibition in tumor tissues - A population pharmacokinetic/pharmacodynamic analysis of rucaparib. Clin. Pharm. Drug Dev. 4, 89–98 (2015).
doi: 10.1002/cpdd.176
Jusko, W. J. & Ko, H. C. Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clin. Pharm. Ther. 56, 406–419 (1994).
doi: 10.1038/clpt.1994.155
Buhl, A. S. K., Christensen, T. D., Christensen, I. J., Nelausen, K. M., Balslev, E., Knoop, A. S. et al. Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study. Breast Cancer Res. Treat. 172, 391–400 (2018).
doi: 10.1007/s10549-018-4918-4
Buhl, I. K., Santoni-Rugiu, E., Ravn, J., Hansen, A., Christensen, I. J., Jensen, T. et al. Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent cohorts. PLoS ONE 13, e0194609 (2018).
doi: 10.1371/journal.pone.0194609
Karn, T., Pusztai, L., Holtrich, U., Iwamoto, T., Shiang, C. Y., Schmidt, M. et al. Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures. PLoS ONE 6, e28403 (2011).
doi: 10.1371/journal.pone.0028403
Evans, T. & Matulonis, U. PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther. Adv. Med. Oncol. 9, 253–267 (2017).
doi: 10.1177/1758834016687254
Kristeleit, R., Shapiro, G. I., Burris, H. A., Oza, A. M., LoRusso, P., Patel, M. R. et al. A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin. Cancer Res. 23, 4095–4106 (2017).
doi: 10.1158/1078-0432.CCR-16-2796
Dulaney, C., Marcrom, S., Stanley, J. & Yang, E. S. Poly(ADP-ribose) polymerase activity and inhibition in cancer. Semin Cell Dev. Biol. 63, 144–153 (2017).
doi: 10.1016/j.semcdb.2017.01.007
O’Sullivan Coyne, G., Chen, A. P., Meehan, R. & Doroshow, J. H. PARP inhibitors in reproductive system cancers: current use and developments. Drugs 77, 113–130 (2017).
doi: 10.1007/s40265-016-0688-7
Coleman, R. L., Sill, M. W., Bell-McGuinn, K., Aghajanian, C., Gray, H. J., Tewari, K. S. et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 137, 386–391 (2015).
doi: 10.1016/j.ygyno.2015.03.042
Puhalla, S., Beumer, J. H., Pahuja, S., Appleman, L. J., Tawbi, H. A., Stoller, R. G. et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt) [abstract]. J. Clin. Oncol. 32(15 Suppl), 2570 (2014).
doi: 10.1200/jco.2014.32.15_suppl.2570
Murai, J., Huang, S. Y., Renaud, A., Zhang, Y., Ji, J., Takeda, S. et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol. Cancer Ther. 13, 433–443 (2014).
doi: 10.1158/1535-7163.MCT-13-0803
Jones, P., Altamura, S., Boueres, J., Ferrigno, F., Fonsi, M., Giomini, C. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J. Med. Chem. 52, 7170–7185 (2009)..
Menear, K. A., Adcock, C., Boulter, R., Cockcroft, X. L., Copsey, L., Cranston, A. et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin- 1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J. Med. Chem. 51, 6581–6591 (2008)..
Mizutani, A., Yashiroda, Y., Muramatsu, Y., Yoshida, H., Chikada, T., Tsumura, T. et al. RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model. Cancer Sci. 109, 4003–4014 (2018).
doi: 10.1111/cas.13805
Li, C., Zheng, X., Han, Y., Lv, Y., Lan, F. & Zhao, J. XAV939 inhibits the proliferation and migration of lung adenocarcinoma A549 cells through the WNT pathway. Oncol. Lett. 15, 8973–8982 (2018).
pubmed: 29805633
pmcid: 5958670
Tentori, L., Lacal, P. M., Muzi, A., Dorio, A. S., Leonetti, C., Scarsella, M. et al. Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur. J. Cancer 43, 2124–2133 (2007).
doi: 10.1016/j.ejca.2007.07.010
Galbis-Martínez, M., Saenz, L., Ramírez, P., Parrilla, P. & Yélamos, J. Poly(ADP-ribose) polymerase-1 modulates interferon-gamma-inducible protein (IP)-10 expression in murine embryonic fibroblasts by stabilizing IP-10 mRNA. Mol. Immunol. 47, 1492–1499 (2010).
doi: 10.1016/j.molimm.2010.01.022
Cabrera, R., Ararat, M., Eksioglu, E. A., Cao, M., Xu, Y., Wasserfall, C. et al. Influence of serum and soluble CD25 (sCD25) on regulatory and effector T-cell function in hepatocellular carcinoma. Scand. J. Immunol. 72, 293–301 (2010).
doi: 10.1111/j.1365-3083.2010.02427.x
Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).
doi: 10.1016/j.immuni.2013.01.004
Zhang, P., Maruyama, T., Konkel, J. E., Abbatiello, B., Zamarron, B., Wang, Z. Q. et al. PARP-1 controls immunosuppressive function of regulatory T cells by destabilizing Foxp3. PLoS ONE 8, e71590 (2013).
doi: 10.1371/journal.pone.0071590
Luo, X., Nie, J., Wang, S., Chen, Z., Chen, W., Li, D. et al. Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J. Biol. Chem. 290, 28675–28682 (2015).
doi: 10.1074/jbc.M115.661611
Nasta, F., Laudisi, F., Sambucci, M., Rosado, M. M. & Pioli, C. Increased Foxp3+ regulatory T cells in poly(ADP-Ribose) polymerase-1 deficiency. J. Immunol. 184, 3470–3477 (2010).
doi: 10.4049/jimmunol.0901568
Ahmad, S. F., Zoheir, K. M., Bakheet, S. A., Ashour, A. E. & Attia, S. M. Poly(ADP-ribose) polymerase-1 inhibitor modulates T regulatory and IL-17 cells in the prevention of adjuvant induced arthritis in mice model. Cytokine 68, 76–85 (2014).
doi: 10.1016/j.cyto.2014.04.006