Top

Published in:

01-02-2018 | Original Article

Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors

Authors: Emily Chan, E. Gabriela Chiorean, Peter J. O’Dwyer, Nashat Y. Gabrail, Thierry Alcindor, Diane Potvin, Richard Chao, Herbert Hurwitz

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2018

Abstract

Purpose

To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer.

Methods

In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m², day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50–110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR).

Results

Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m². Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated.

Conclusions

Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting.

Society AC (2016) Cancer Facts & Figs. 2016. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2016/cancer-facts-and-figures-2016.pdf. Accessed Oct 2017

Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413. https://doi.org/10.1200/jco.1997.15.6.2403 CrossRefPubMed

Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goere D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T et al. (2015) Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 5(26 Suppl):v56–68. https://doi.org/10.1093/annonc/mdv295 CrossRef

Neureiter D, Jager T, Ocker M, Kiesslich T (2014) Epigenetics and pancreatic cancer: pathophysiology and novel treatment aspects. World J Gastroenterol 20(24):7830–7848. https://doi.org/10.3748/wjg.v20.i24.7830 CrossRefPubMedPubMedCentral

Fritsche P, Seidler B, Schuler S, Schnieke A, Gottlicher M, Schmid RM, Saur D, Schneider G (2009) HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA. Gut 58(10):1399–1409. https://doi.org/10.1136/gut.2009.180711 CrossRefPubMed

Giaginis C, Damaskos C, Koutsounas I, Zizi-Serbetzoglou A, Tsoukalas N, Patsouris E, Kouraklis G, Theocharis S (2015) Histone deacetylase (HDAC)-1, -2, -4 and – 6 expression in human pancreatic adenocarcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients’ survival. BMC Gastroenterol 15:148. https://doi.org/10.1186/s12876-015-0379-y CrossRefPubMedPubMedCentral

Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J et al (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424):399–405. https://doi.org/10.1038/nature11547 CrossRefPubMedPubMedCentral

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897):1801–1806. https://doi.org/10.1126/science.1164368 CrossRefPubMedPubMedCentral

Zeitouni D, Pylayeva-Gupta Y, Der CJ, Bryant KL (2016) KRAS mutant pancreatic cancer: no lone path to an effective treatment. Cancers (Basel) 8(4):45. https://doi.org/10.3390/cancers8040045 CrossRef

10.

Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540):495–501. https://doi.org/10.1038/nature14169 CrossRefPubMedPubMedCentral

11.

Javle M, Li Y, Tan D, Dong X, Chang P, Kar S, Li D (2014) Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PLoS One 9(1):e85942. https://doi.org/10.1371/journal.pone.0085942 CrossRefPubMedPubMedCentral

12.

San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Gunther A, Nakorn TN, Siritanaratkul N et al (2014) Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15(11):1195–1206. https://doi.org/10.1016/S1470-2045(14)70440-1 CrossRefPubMed

13.

Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, Wilhelm M et al (2012) Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30(6):631–636. https://doi.org/10.1200/JCO.2011.37.4223 CrossRefPubMed

14.

Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12(10):1247–1252. https://doi.org/10.1634/theoncologist.12-10-1247 CrossRefPubMed

15.

O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S et al (2015) Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal Phase II BELIEF (CLN-19) study. J Clin Oncol 33(23):2492–2499. https://doi.org/10.1200/JCO.2014.59.2782 CrossRefPubMedPubMedCentral

16.

Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, Liu J, Lu AH, Zhou NZ, Robert MF et al. (2008) MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7 (4):759–768. https://doi.org/10.1158/1535-7163.MCT-07-2026 CrossRefPubMed

17.

Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A et al (2008) Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor. J Med Chem 51(14):4072–4075. https://doi.org/10.1021/jm800251w CrossRefPubMed

18.

Garcia-Manero G, Assouline S, Cortes J, Estrov Z, Kantarjian H, Yang H, Newsome WM, Miller WH Jr, Rousseau C, Kalita A et al (2008) Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 112(4):981–989. https://doi.org/10.1182/blood-2007-10-115873 CrossRefPubMedPubMedCentral

19.

Blum KA, Advani A, Fernandez L, Van Der Jagt R, Brandwein J, Kambhampati S, Kassis J, Davis M, Bonfils C, Dubay M et al (2009) Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia. Br J Haematol 147(4):507–514. https://doi.org/10.1111/j.1365-2141.2009.07881.x CrossRefPubMedPubMedCentral

20.

Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M, Neelapu S, Copeland A, Buglio D, Galal A, Besterman J et al (2011) Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol 12(13):1222–1228CrossRefPubMedPubMedCentral

21.

Batlevi CL, Crump M, Andreadis C, Rizzieri D, Assouline SE, Fox S, van der Jagt RHC, Copeland A, Potvin D, Chao R et al (2017) A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br J Haematol 178(4):434–441. https://doi.org/10.1111/bjh.14698 CrossRefPubMedPubMedCentral

22.

Sung V, Richard N, Brady H, Maier A, Kelter G, Heise C (2011) Histone deacetylase inhibitor MGCD0103 synergizes with gemcitabine in human pancreatic cells. Cancer Sci 102(6):1201–1207. https://doi.org/10.1111/j.1349-7006.2011.01921.x CrossRefPubMed

23.

Wang G, He J, Zhao J, Yun W, Xie C, Taub JW, Azmi A, Mohammad RM, Dong Y, Kong W et al (2012) Class I and class II histone deacetylases are potential therapeutic targets for treating pancreatic cancer. PLoS One 7(12):e52095. https://doi.org/10.1371/journal.pone.0052095 CrossRefPubMedPubMedCentral

24.

Licciardi PV, Karagiannis TC (2012) Regulation of immune responses by histone deacetylase inhibitors. ISRN Hematol 2012:690901. https://doi.org/10.5402/2012/690901 CrossRefPubMedPubMedCentral

25.

Khan AN, Tomasi TB (2008) Histone deacetylase regulation of immune gene expression in tumor cells. Immunol Res 40(2):164–178. https://doi.org/10.1007/s12026-007-0085-0 CrossRefPubMedPubMedCentral

26.

Christiansen AJ, West A, Banks KM, Haynes NM, Teng MW, Smyth MJ, Johnstone RW (2011) Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies. Proc Natl Acad Sci U S A 108(10):4141–4146. https://doi.org/10.1073/pnas.1011037108 CrossRefPubMedPubMedCentral

27.

Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, Sotomayor P, Shrikant P, Fenstermaker R, Pili R (2012) Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One 7(1):e30815. https://doi.org/10.1371/journal.pone.0030815 CrossRefPubMedPubMedCentral

28.

Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3(12):1375–1385. https://doi.org/10.1158/2326-6066.CIR-15-0077-T CrossRefPubMedPubMedCentral

29.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefPubMed

30.

Bonfils C, Kalita A, Dubay M, Siu LL, Carducci MA, Reid G, Martell RE, Besterman JM, Li Z (2008) Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay. Clin Cancer Res 14(11):3441–3449. https://doi.org/10.1158/1078-0432.CCR-07-4427 CrossRefPubMedPubMedCentral

31.

Siu LL, Pili R, Duran I, Messersmith WA, Chen EX, Sullivan R, MacLean M, King S, Brown S, Reid GK et al (2008) Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors. J Clin Oncol 26(12):1940–1947. https://doi.org/10.1200/JCO.2007.14.5730 CrossRefPubMedPubMedCentral

32.

Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. https://doi.org/10.1056/NEJMoa1011923 CrossRefPubMed

33.

Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. https://doi.org/10.1056/NEJMoa1304369 CrossRef

34.

Jones SF, Bendell JC, Infante JR, Spigel DR, Thompson DS, Yardley DA, Greco FA, Murphy PB, Burris HA, 3rd (2011) A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors. Clin Adv Hematol Oncol 9(3):225–230PubMed

35.

Jones SF, Infante JR, Spigel DR, Peacock NW, Thompson DS, Greco FA, McCulloch W, Burris HA, 3rd (2012) Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors. Cancer Invest 30(6):481–486. https://doi.org/10.3109/07357907.2012.675382 CrossRefPubMed

36.

Richards DA, Boehm KA, Waterhouse DM, Wagener DJ, Krishnamurthi SS, Rosemurgy A, Grove W, Macdonald K, Gulyas S, Clark M et al (2006) Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study. Ann Oncol 17(7):1096–1102. https://doi.org/10.1093/annonc/mdl081 CrossRefPubMed

37.

EliLilly (2017) Gemzar prescribing information. http://pi.lilly.com/us/gemzar.pdf. Accessed Oct 2017

38.

MedFacts.com (2017) Study of possible correlation between cystitis and gemcitabine HCl. http://mobile.medsfacts.com/study-GEMCITABINE%20HCL-causing-CYSTITIS.php. Accessed Oct 2017

39.

Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G et al (2010) Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol 28(4):543–548. https://doi.org/10.1200/JCO.2008.20.8199 CrossRefPubMed

40.

Pokuri V, Sule N, Soofi Y, Xu B, Guru K, George S (2013) A case of unusual mast cell response with interstitial cystitis-like symptoms to neoadjuvant chemotherapy for muscle-invasive transitional cell carcinoma of the bladder. J Natl Compr Canc Netw 11(12):1459–1463CrossRefPubMed

41.

Boumber Y, Younes A, Garcia-Manero G (2011) Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor. Expert Opin Investig Drugs 20(6):823–829. https://doi.org/10.1517/13543784.2011.577737 CrossRefPubMedPubMedCentral

42.

Martell RE, Garcia-Manero G, Younes A, Ewer M, Daher IN, Hunt W, Lortie K, Wilhelm J, Besterman JM (2009) Clinical development of MGCD0103, an isotype-selective HDAC inhibitor: pericarditis/pericardial effusion in the context of overall safety and efficacy. Blood 114:4756

43.

Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J, Saletti P, Bauer J, Figer A, Pestalozzi B et al (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25(16):2212–2217. https://doi.org/10.1200/JCO.2006.09.0886 CrossRefPubMed

44.

Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B et al (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24(24):3946–3952. https://doi.org/10.1200/JCO.2005.05.1490 CrossRefPubMed

45.

Chan E, Arlinghaus LR, Cardin DB, Goff L, Berlin JD, Parikh A, Abramson RG, Yankeelov TE, Hiebert S, Merchant N et al (2016) Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Radiother Oncol 119(2):312–318. https://doi.org/10.1016/j.radonc.2016.04.013 CrossRefPubMedPubMedCentral

Title: Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors
Authors: Emily Chan
E. Gabriela Chiorean
Peter J. O’Dwyer
Nashat Y. Gabrail
Thierry Alcindor
Diane Potvin
Richard Chao
Herbert Hurwitz
Publication date: 01-02-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3494-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2018

Metabolomic prediction of treatment outcome in pancreatic ductal adenocarcinoma patients receiving gemcitabine

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study)

B7-H3 in tumors: friend or foe for tumor immunity?

A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin—integration of in vitro results, Phase I and Phase II data and model application for drug–drug interaction potential analysis

Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Keynote webinar | Spotlight on antibody–drug conjugates in cancer