Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer

Angus G Dalgleish, Justin Stebbing, Douglas Ja Adamson, Seema Safia Arif, Paolo Bidoli, David Chang, Sue Cheeseman, Robert Diaz-Beveridge, Carlos Fernandez-Martos, Rob Glynne-Jones, Cristina Granetto, Bartomeu Massuti, Karen McAdam, Raymond McDermott, Andrés J Muñoz Martín, Demetris Papamichael, Roberto Pazo-Cid, Jose M Vieitez, Alberto Zaniboni, Kevin J Carroll, Shama Wagle, Andrew Gaya, Satvinder S Mudan, Angus G Dalgleish, Justin Stebbing, Douglas Ja Adamson, Seema Safia Arif, Paolo Bidoli, David Chang, Sue Cheeseman, Robert Diaz-Beveridge, Carlos Fernandez-Martos, Rob Glynne-Jones, Cristina Granetto, Bartomeu Massuti, Karen McAdam, Raymond McDermott, Andrés J Muñoz Martín, Demetris Papamichael, Roberto Pazo-Cid, Jose M Vieitez, Alberto Zaniboni, Kevin J Carroll, Shama Wagle, Andrew Gaya, Satvinder S Mudan

Abstract

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma.

Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected.

Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01).

Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

Conflict of interest statement

Angus G Dalgleish and Andrew Gaya have received travel grants and conference funding from Immodulon Therapeutics. Satvinder Mudan is an unsalaried director and shareholder of Immodulon Therapeutics, Ltd. Robert Glynne-Jones received honoraria and research funding from Merck KgaA, Roche and Sanofi-Aventis. Shama Wagle and Kevin Carroll, of TranScrip, LLP, provided medical writing and statistical support to Immodulon Therapeutics. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Progression-free survival ITT Analysis Set (A) and ITT Metastatic Subgroup (B). Overall survival Metastatic Subgroup (C). Arrows denote censored events. IMM-101 treated: IMM-101+GEM; Control: GEM alone.

References

    1. Bazzi S, Modjtahedi H, Mudan S, Akle C, Bahr GM (2015) Analysis of the immunomodulatory properties of two heat-killed mycobacterial preparations in a human whole blood model. Immunobiology 220: 1293–1304.
    1. Bilici A (2014) Prognostic factors related with survival in patients with pancreatic adenocarcinoma. World J Gastroenterol 20(31): 10802–10812.
    1. Braiteh F, Patel M, Parisi M, Quanhong N, Park S, Faria C (2016) Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine (nab-P+G) versus FOLFIRINOX (FFX) in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) in a U.S. community oncology setting. J Clin Oncol 2016(4): abstract 433.
    1. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (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.
    1. Carrato A, Falcone A, Ducreux M, Valle JW, Parnaby A, Djazouli K, Alnwick-Allu K, Hutchings A, Palaska C, Parthenaki I (2015) A systematic review of the burden of pancreatic cancer in Europe: real world impact on survival, quality of life and costs. J Gastrointest Cancer 46: 201–211.
    1. Colucci G, Labianca R, Di Costanzo F, Gebbia V, Carteni G, Massidda B, Dapretto E, Manzione L, Piazza E, Sannicolo M, Ciaparrone M, Cavanna L, Giuliani F, Maiello E, Testa A, Pederzoli P, Falconi M, Gallo C, Di Maio M, Perrone F, Gruppo Oncologico Italia M Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato D, Gruppo Oncologico Italiano di Ricerca C (2010) Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28(10): 1645–1651.
    1. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M Groupe Tumeurs Digestives of U, Intergroup P (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19): 1817–1825.
    1. Fowler D, Copier J, Wilson N, Dalgleish AG, Bodman-Smith MD (2011) Mycobacteria activate gamma delta T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy. Cancer Immunol Immunother 61(4): 535–547.
    1. Gunturu KS, Rossi GR, Saif MW (2013) Immunotherapy updates in pancreatic cancer: are we there yet? Therap Adv Med Oncol 5(1): 81–89.
    1. Haas M, Heinemann V, Kullmann F, Laubender RP, Klose C, Bruns CJ, Holdenrieder S, Modest DP, Schulz C, Boeck S (2013) Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol 139(4): 681–689.
    1. Hidalgo M, Cascinu S, Kleeff J, Labianca R, Lohr JM, Neoptolemos J, Real FX, Van Laethem JL, Heinemann V (2015) Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 15(1): 8–18.
    1. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, Onners B, Uram JN, Laheru DA, Lutz ER, Solt S, Murphy AL, Skoble J, Lemmens E, Grous J, Dubensky T Jr, Brockstedt DG, Jaffee EM (2015) Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 33(12): 1325–1333.
    1. Network NCC Pancreatic adenocarcinoma (Version 2.2015).
    1. NICE (2001) Guidance on the use of gemcitabine for the treatment of pancreatic cancer.
    1. NICE (2015) Paclitaxel as albumin-bound nanoparticles in combination with gemcitabine for previously untreated metastatic pancreatic cancer.
    1. Nywening T, Wang-Gillam A, Sanford D, Belt B, Panni R, Cusworth B (2016) Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17(5): 651–662.
    1. Pico de Coana Y, Choudhury A, Kiessling R (2015) Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med 21(8): 482–491.
    1. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd (2009) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27(23): 3778–3785.
    1. Seufferlein T, Bachet JB, Van Cutsem E, Rougier P Group EGW (2012) Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7): vii33–vii40.
    1. Stebbing J, Dalgleish A, Gifford-Moore A, Martin A, Gleeson C, Wilson G, Brunet LR, Grange J, Mudan S (2012) An intra-patient placebo-controlled phase I trial to evaluate the safety and tolerability of intradermal IMM-101 in melanoma. Ann Oncol 23(5): 1314–1319.
    1. Tempero MA, Arnoletti JP, Behrman SW, Ben-Josef E, Benson AB 3rd, Casper ES, Cohen SJ, Czito B, Ellenhorn JD, Hawkins WG, Herman J, Hoffman JP, Ko A, Komanduri S, Koong A, Ma WW, Malafa MP, Merchant NB, Mulvihill SJ, Muscarella P 2nd, Nakakura EK, Obando J, Pitman MB, Sasson AR, Tally A, Thayer SP, Whiting S, Wolff RA, Wolpin BM, Freedman-Cass DA, Shead DA National Comprehensive Cancer N (2012) Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. J Natl Comprehens Cancer Netw 10(6): 703–713.
    1. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18): 1691–1703.
    1. Wang-Gillam A, Li C, Bodoky G, Dean A, Shan Y, Jameson G, Macarulla T, Lee K, Cunningham D, Blanc J, Hubner R, Chiu C, Schwartsmann G, Siveke J, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen L (2016) Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet Oncol 387(10018): 545–547.
    1. Wormann SM, Diakopoulos KN, Lesina M, Algul H (2014) The immune network in pancreatic cancer development and progression. Oncogene 33: 2956–2967.

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