A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer

Deepa S Subramaniam, Stephen V Liu, Jeanette Crawford, Jenna Kramer, Jillian Thompson, Hongkun Wang, Giuseppe Giaccone, Deepa S Subramaniam, Stephen V Liu, Jeanette Crawford, Jenna Kramer, Jillian Thompson, Hongkun Wang, Giuseppe Giaccone

Abstract

Introduction: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin.

Methods: Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0-1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m2 or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m2 on day 1 in 21-day cycles.

Results: Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m2 in combination with doxorubicin at a dose of 50 mg/m2. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days.

Conclusion: Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC.

Clinical trial registration: https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.

Keywords: Hsp90 inhibition; chemotherapy resistance; doxorubicin; ganetespib; small cell lung cancer.

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin (2017) 67:7–30.10.3322/caac.21387
    1. Pietanza C, Byers LA, Minna JD, Rudin CM. Small cell lung cancer: will recent progress lead to improved outcomes? Clin Cancer Res (2015) 21(10):2244–55.10.1158/1078-0432.CCR-14-2958
    1. Giaccone G, Donadio M, Bonardi G, Testore F, Calciati A. Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol (1988) 6(8):1264–70.10.1200/JCO.1988.6.8.1264
    1. Giaccone G, Ferrati P, Donadio M, Testore F, Calciati A. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol (1987) 23(11):1697–9.10.1016/0277-5379(87)90452-4
    1. O’Brien ME, Ciuleanu TE, Tsekov H, Shparyk Y, Cuceviá B, Juhasz G, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol (2006) 24:5441–7.10.1200/JCO.2006.06.5821
    1. Inoue A, Sugawara S, Yamazaki K, Maemondo M, Suzuki T, Gomi K, et al. Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol (2008) 26:5401–6.10.1200/JCO.2008.18.1974
    1. von Pawel J, Jotte R, Spigel DR, O’Brien ME, Socinski MA, Mezger J, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol (2014) 32(35):4012–9.10.1200/JCO.2013.54.5392
    1. Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol (2006) 24(28):4539–44.10.1200/JCO.2005.04.4859
    1. Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol (2017) 18(6):345–60.10.1038/nrm.2017.20
    1. Quadroni M, Potts A, Waridel P. Hsp90 inhibition induces both protein-specific and global changes in the ubiquitinome. J Proteomics (2015) 29(120):215–29.10.1016/j.jprot.2015.02.020
    1. Sharma SV, Fischbach MA, Haber DA, Settleman J. “Oncogenic shock”: explaining oncogene addiction through differential signal attenuation. Clin Cancer Res (2006) 12(14.2):4392s–5s.10.1158/1078-0432.CCR-06-0096
    1. Shimamura T, Perera SA, Foley KP, Sang J, Rodig SJ, Inoue T, et al. Ganetespib (STA-9090), a non-geldanamycin HSP90 inhibitor, has potent antitumor activity in in-vitro and in-vivo models of non-small cell lung cancer. Clin Cancer Res (2012) 18(18):4973–85.10.1158/1078-0432.CCR-11-2967
    1. Sos ML, Michel K, Zander T, Weiss J, Frommolt P, Peifer M, et al. Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. J Clin Invest (2009) 119(6):1727–40.10.1172/JCI37127
    1. Rajkumar T, Yamuna M. Multiple pathways are involved in drug resistance to doxorubicin in an osteosarcoma cell line. Anticancer Drugs (2008) 19:257–65.10.1097/CAD.0b013e3282f435b6
    1. Gangadharan C, Thoh M, Manna SK. Inhibition of constitutive activity of nuclear transcription factor kappaB sensitizes doxorubicin-resistant cells to apoptosis. J Cell Biochem (2009) 107(2):203–13.10.1002/jcb.22115
    1. Jego G, Hazoumé A, Seigneuric R, Garrido C. Targeting heat shock proteins in cancer. Cancer Lett (2013) 332(2):275–85.10.1016/j.canlet.2010.10.014
    1. Cheng JZ, Sharma R, Yang Y, Singhal SS, Sharma A, Saini MK, et al. Accelerated metabolism and exclusion of 4-hydroxy-nonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative-stress. J Biol Chem (2001) 276:41213–23.10.1074/jbc.M106838200
    1. Wang Y, Trepel JB, Neckers LM, Giaccone G. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs (2010) 11(12):1466–76.
    1. Lai CH, Park KS, Lee DH, Alberobello AT, Raffeld M, Pierobon M, et al. HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer. Oncogene (2014) 33(40):4867–76.10.1038/onc.2013.439
    1. Lewis J, Devin A, Miller A, Lin Y, Rodriguez Y, Neckers L, et al. Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation. J Biol Chem (2000) 275(14):10519–26.10.1074/jbc.275.14.10519
    1. Pillai R, Fennell D, Kovcin V, Ciuleanu T, Ramlau R, Kowalski D, et al. Phase 3 study of ganetespib, a heat shock protein 90 inhibitor, with docetaxel versus docetaxel in advanced non-small cell lung cancer (GALAXY-2). J Thorac Oncol (2017) 12(1):S7–S8.10.1016/j.jtho.2016.11.009
    1. Jhaveri K, Modi S. Ganetespib: research and clinical development. Onco Targets Ther (2015) 8:1849–58.10.2147/OTT.S65804
    1. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Lancet (2016) 387(10022):968–77.10.1016/S0140-6736(15)00817-X
    1. Acquaviva J, He S, Sang J, Smith DL, Sequeira M, Zhang C, et al. mTOR inhibition potentiates HSP90 inhibitor activity via cessation of HSP synthesis. Mol Cancer Res (2014) 12(5):703–13.10.1158/1541-7786.MCR-13-0605

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