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A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

Published:August 10, 2017DOI:https://doi.org/10.1016/j.ygyno.2017.08.001

      Highlights

      • Recurrent EOC patients were treated with GEN-1 and pegylated liposomal doxorubicin.
      • Three had partial responses and five had stable disease of the 16 patients.
      • IL-12 expression and downstream immunological effect were found.
      • Maximum tolerated dose of GEN-1 was not achieved.

      Abstract

      Objective

      The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC).

      Methods

      Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect.

      Results

      Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment.

      Conclusions

      GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1.

      Keywords

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      References

        • Howlader N.
        • Noone A.M.
        • Krapcho M.
        • Garshell J.
        • Miller D.
        • Altekruse S.F.
        • et al.
        SEER Cancer Statistics Review.
        National Cancer Institute, Bethesda, MD1975–2012 (based on November 2014 SEER data submission, posted to the SEER web site, April 2015)
        • Whitworth J.M.
        • Alvarez R.D.
        Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature.
        Expert. Opin. Biol. Ther. 2011; 11: 751-762
        • Duda D.G.
        • Sunamura M.
        • Lozonschi L.
        • Kodoma T.
        • Egawa S.I.
        • Matsumoto G.
        • et al.
        Direct in vitro evidence and in vivo analysis of the anti-angiogenesis effects of interleukin 12.
        Cancer Res. 2000; 60: 111-116
        • Lenzi R.
        • Edwards R.
        • June C.
        • Seiden M.V.
        • Garcia M.E.
        • Rosenblum M.
        • et al.
        Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease <1 cm) associated with ovarian cancer or primary peritoneal carcinoma.
        J. Transl. Med. 2007; 5: 66
        • Fewell J.G.
        • Matar M.
        • Slobodkin G.
        • Han S.O.
        • Rice J.
        • Hovanes B.
        • et al.
        Synthesis and application of biocompatible non-viral gene delivery system for immunogene therapy of cancer.
        J. Control. Release. 2005; 109: 288-298
        • Fewell J.G.
        • Rice J.
        • Matar M.
        • Brunhoeber E.
        • Pence C.
        • Slobodkin G.
        • et al.
        Use of interleukin-12 gene nanocomplexes as a general treatment against disseminated peritoneal malignancies.
        Proc Am Assoc Cancer Res. 2007; 48: 3304
        • Fewell J.G.
        • Matar M.M.
        • Rice J.S.
        • Brunhoeber E.
        • Slobodkin G.
        • Pence C.
        • et al.
        Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally.
        J. Gene Med. 2009; 11: 718-728
        • Anwer K.
        • Barnes M.N.
        • Fewell J.
        • Lewis D.H.
        • Alvarez R.D.
        Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer.
        Gene Ther. 2010; 17: 360-369
        • Anwer K.
        • Kelly F.J.
        • Chu C.
        • Fewell J.G.
        • Lewis D.
        • Chu J.G.
        • et al.
        Phase I trial of a formulated IL-12 plasmid in combination with carboplatin and docetaxel chemotherapy in the treatment of platinum-sensitive recurrent ovarian cancer.
        Gynecol. Oncol. 2013; 131: 169-173
        • Markman M.
        • Gordan A.N.
        • McGuire W.P.
        • Muggia F.M.
        Liposomal anthracycline treatment for ovarian cancer.
        Semin. Oncol. 2004; 31: 91-105
        • Gordon A.N.
        • Granai C.O.
        • Rose P.G.
        • Hainsworth J.
        • Lopez A.
        • Weismann C.
        • et al.
        Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer.
        J. Clin. Oncol. 2000; 18: 3093-3100
        • Colombo N.
        • Kutarska E.
        • Dimopoulos M.
        • Bae D.S.
        • Rzepka-Gorska I.
        • Bidzinski M.
        • et al.
        Randomized, open-label phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer.
        J. Clin. Oncol. 2012; 30: 3841-3847
        • Kepp O.
        • Galluzzi L.
        • Martins I.
        • Schlemmer F.
        • Adjemian S.
        • Michaud M.
        • et al.
        Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy.
        Cancer Metastasis Rev. 2011; 30: 61-69
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur. J. Cancer. 2009; 45: 228-247
        • Le Tourneau C.
        • Lee J.J.
        • Siu L.L.
        Dose escalation methods in phase I cancer clinical trials.
        J. Natl. Cancer Inst. 2009; 101: 708-720
        • Deprimo S.E.
        • Bello C.L.
        • Smeraglia J.
        • Baum C.M.
        • Spinella D.
        • Rini B.I.
        • et al.
        Circulating protein biomarkers of pharmacodynamics activity of sunitinib in patients with metastatic renal carcinoma: modulation of VEGF and VEGF-related proteins.
        J. Transl. Med. 2007; 5: 32-38
        • Alidzanovic L.
        • Starlinger P.
        • Schauer D.
        • Maier T.
        • Feldman A.
        • Buchberger E.
        • et al.
        The VEGF rise in blood of bevacizumab patients is not based on tumor escape but a host-blockade of VEGF clearance.
        Oncotarget. 2016; 7: 57197-57212
        • Keunen O.
        • Johansson M.
        • Oudin A.
        • Snazey M.
        • Rahim S.A.
        • Fack F.
        • et al.
        Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma.
        Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 3749-3754
        • Stefnani M.O.
        • Wu F.T.
        • mac Gabhann F.
        • Popel A.S.
        Increase of plasma VEGF after intravenous administration of bevacizumab is predicted by a pharmacokinetic model.
        Cancer Res. 2010; 70: 9886-9894
        • Alvarez R.D.
        • Sill M.W.
        • Davidson S.A.
        • Muller C.Y.
        • Bender D.P.
        • Sill M.W.
        • et al.
        A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: a Gynecologic Oncology Group study.
        Gynecol. Oncol. 2014; 133: 433-438
        • Zhu S.
        • Waguespack M.
        • Barker S.A.
        • Li S.
        Doxorubicin directs the accumulation of interleukin-12 induced IFN gamma into tumors for enhancing STAT1 dependent anti-tumor effect.
        Clin. Cancer Res. 2007; 13: 4252-4260
        • Zagozdon R.
        • Golab J.
        • Stoklosa T.
        • Giermasz A.
        • Nowicka D.
        • Feleszko W.
        • et al.
        Effective chemo-immunomodulatory of L1210 leukemia in vivo using interleukin-12 combined with doxorubicin but not with cyclophosphamide, paclitaxel or cisplatin.
        Int. J. Cancer. 1998; 77: 720-727
        • Alagkiozidis I.
        • Facciabene A.
        • Carpenito C.
        • Benecia F.
        • Jonak Z.
        • Adams S.
        • et al.
        Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18.
        J. Transl. Med. 2009; 7: 104
        • Teicher B.A.
        • Ara G.
        • Buxton D.
        • Leonard J.
        • Schaub R.G.
        Optimal scheduling of interleukin 12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma.
        Clin. Cancer Res. 1997; 3: 1661-1667
        • Torrerro M.N.
        • Xia X.
        • Henk W.
        • Yu S.
        • Li S.
        Stat1 deficiency in the host enhances interleukin-12-mediated tumor regression.
        Cancer Res. 2006; 66: 4461-4467
        • Ujhazy P.
        • Zaleskis G.
        • Mihich E.
        Doxorubicin induces specific immune functions and cytokine expression in the peritoneal cells.
        Cancer Immunol. Immunother. 2003; 52: 463-472
        • Orsini F.
        • Pavelic Z.
        • Mihich E.
        Increased primary cell mediated immunity in culture subsequent to Adriamycin or daunorubicin treatment of spleen donor mice.
        Cancer Res. 1997; 37: 1719-1726
        • Maccubbin D.L.
        • Wing K.R.
        • Mace K.F.
        • Ho R.L.X.
        • Ehrke M.J.
        • Mihich E.
        Adriamycin-induced modulation of host defenses in tumor-bearing mice.
        Cancer Res. 1992; 52: 3572-3576
        • Mace K.
        • Mayhew E.
        • Mihich E.
        • Ehrke M.J.
        Alterations in murine host defense functions by Adriamycin or liposome-encapsulated Adriamycin.
        Cancer Res. 1988; 48: 130-136
        • Alizadeh D.
        • Trad M.
        • Hanke N.T.
        • Larmonier C.B.
        • Janikashvili N.
        • Bonnotte B.
        • et al.
        Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer.
        Cancer Res. 2014; : 74104-74118
        • Mutch D.G.
        • Orlando M.
        • Goss T.
        • Teneriello M.G.
        • Gordon A.N.
        • McMeekin S.D.
        • et al.
        Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer.
        J. Clin. Oncol. 2007; 25: 2811-2818
        • Gordon A.N.
        • Fleagle J.T.
        • Guthrie D.
        • Parkin D.E.
        • Gore M.E.
        • Lacave A.J.
        Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan.
        J. Clin. Oncol. 2001; 19: 3312-3322
        • Gollob J.A.
        • Mier J.W.
        • Veenstra K.
        • McDermott D.F.
        • Clancy D.
        • Clancy M.
        • et al.
        Phase I trial of twice-weekly intravenous IL-12 in patients with metastatic renal cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response.
        Clin. Cancer Res. 2000; 6: 1678-1692
        • Gollob J.A.
        • Veenstra K.G.
        • Jyonouchi H.
        • Kelly A.M.
        • Ferrieri P.
        • Panka D.J.
        • et al.
        Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections.
        J. Immunol. 2000; 65: 4120-4126
        • Lippitz B.E.
        Cytokine patterns in patients with cancer: a systematic review.
        Lancet Oncol. 2013; 14: e218-228
        • Yuzhalin A.E.
        • Kutikhin A.G.
        Interleukin-12: clinical usage and molecular markers of cancer susceptibility.
        Growth Factors. 2012; 30: 176-191
        • Thaker P.H.
        • Leath C.A.
        • Bradley W.H.
        • Moore K.N.
        • Borys N.
        • Anwer K.
        • et al.
        Phase I study of the safety and biological activity of intraperitoneal IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer administered in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed ovarian cancer.
        J. Clin. Oncol. 2016; 34TPS5605