A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours

K P Papadopoulos, B F El-Rayes, A W Tolcher, A Patnaik, D W Rasco, R D Harvey, P M LoRusso, J C Sachdev, G Abbadessa, R E Savage, T Hall, B Schwartz, Y Wang, J Kazakin, W L Shaib, K P Papadopoulos, B F El-Rayes, A W Tolcher, A Patnaik, D W Rasco, R D Harvey, P M LoRusso, J C Sachdev, G Abbadessa, R E Savage, T Hall, B Schwartz, Y Wang, J Kazakin, W L Shaib

Abstract

Background: ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D).

Methods: Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement.

Results: 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value<0.05) suggest phosphate and FGF19 levels as markers of target engagement. In 18 evaluable patients with FGFR genetic alterations, 3 confirmed partial responses (two intrahepatic cholangiocarcinomas (iCCA) with FGFR2 fusions and one urothelial cancer with FGFR2 and FGF19 amplification) and two durable stable disease at ⩾16 weeks with tumour reduction (FGFR2 fusion-positive iCCA and adrenocortical carcinoma with FGFR1 amplification) were observed.

Conclusions: ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.

Conflict of interest statement

GA, RES, TH, BS, YW, and JK are employees and/or stockholders of ArQule, Inc. KPP and AWT have received funding from ArQule Inc to START for the conduct of clinical trials. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pharmacokinetics of ARQ 087. Mean (+s.d.) plasma concentrations of ARQ 087 vs. time after (A) a single oral dose (day 1) and (B) multiple doses (day 22) of ARQ 087 (semi-log scales).
Figure 2
Figure 2
Serum phosphate per cent change in concentration from baseline in patients doses at 250 mg QD and 300 mg QD.
Figure 3
Figure 3
Relative change from baseline in target lesion size (at best tumour response). Shown is the per cent change of the lowest sum of the target lesions from baseline for patients who were on treatment for ⩾16 weeks. Seven patients had documented FGFR genetic alterations.

References

    1. Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, Turner N, Rugo H, Smith JW, Deudon S, Shi M, Zhang Y, Kay A, Porta DG, Yovine A, Baselga J (2013. a) Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res 19: 3693–3702.
    1. Andre F, Ranson M, Dean E, Varga A, Noll RVD, Stockman PK, Ghiorghiu D, Kilgour E, Smith PD, Macpherson M, Lawrence P, Hastie A, Schellens JH (2013. b) Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors. Cancer Res 73: abstr LB-145.
    1. Cheng CY, Kuro-O M, Razzaque MS (2011) Molecular regulation of phosphate metabolism by fibroblast growth factor-23-klotho system. Adv Chronic Kidney Dis 18: 91–97.
    1. Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, Felip E, Cortes J, Iafrate AJ, Nuciforo P, Tabernero J (2014) Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann Oncol 25: 552–563.
    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. Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G (2016) Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS One 11: e0162594.
    1. Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R (2016) The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 22: 259–267.
    1. Helsten T, Schwaederle M, Kurzrock R (2015) Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Rev 34: 479–496.
    1. Katoh M (2016) FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med 38: 3–15.
    1. Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, Lorusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J (2017) Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol 35: 157–165.
    1. Saka H, Kitagawa C, Kogure Y, Takahashi Y, Fujikawa K, Sagawa T, Iwasa S, Takahashi N, Fukao T, Tchinou C, Landers D, Yamada Y (2017) Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study. Invest New Drugs 35: 451–462.
    1. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19: 429–435.
    1. Soria JC, Debraud F, Bahleda R, Adamo B, Andre F, Dienstmann R, Delmonte A, Cereda R, Isaacson J, Litten J, Allen A, Dubois F, Saba C, Robert R, D'incalci M, Zucchetti M, Camboni MG, Tabernero J (2014) Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors. Ann Oncol 25: 2244–2251.
    1. Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC (2015) Phase I dose-escalation study of jnj-42756493, an oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol 33: 3401–3408.
    1. Wesche J, Haglund K, Haugsten EM (2011) Fibroblast growth factors and their receptors in cancer. Biochem J 437: 199–213.
    1. Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Chinnaiyan AM (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3: 636–647.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa