Study on Decitabine Plus Carboplatin Versus Physician's Choice Chemotherapy in Recurrent, Platinum-resistant Ovarian Cancer.

NCT03467178 | Unknown Phase 2 DMC

• 1 other identifier: INT 189-17
• Study Type: interventional
• Target: 119
• Locations: 1 country
• Sites: 1

Brief Summary

Multicenter Phase II study on Decitabine-Carboplatin combination in platinum resistant ovarian cancer patients. Patients will receive study treatment until disease progression is documented, extraordinary medical circumstances occur, intolerable toxicities occur, or the patient withdraws consent.

Conditions

Recurrent, Platinum-resistant Ovarian Cancer

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS)

  The primary objective is to compare Decitabine plus Carboplatin combination versus physician' choice chemotherapy in terms of progression free survival

  from randomization to the date of radiological/clinical progression of disease or death, assessed up to 3 years

Secondary Outcomes (9)

• Overall survival (OS)

  from randomization to the date of death, assessed up to 3 years

• Radiological response rate (in patients with measurable disease)

  3 years

• Duration of response

  3 years

• Cancer-Antigen 125 (CA-125) response rate per GCIG (Gynaecologic Cancer Intergroup) and change in CA-125

  3 years

• Toxicity profile

  3 years

Study Arms (2)

Decitabine plus Carboplatin

EXPERIMENTAL

Carboplatin AUC 5 d 8 q 28 plus Decitabine 10 mg/mq iv d1-5 q 28

Drug: Decitabine; Drug: Carboplatin

Standard Treatment

OTHER

Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 or Weekly Paclitaxel 80 mg/ m2 dd 1, 8, 15 q 28

Drug: Pegylated Liposomal Doxorubicin; Drug: Gemcitabine; Drug: Paclitaxel

Interventions

Decitabine DRUG

Nucleic Acid Synthesis Inhibitor

Decitabine plus Carboplatin

Carboplatin DRUG

Chemotherapy medication

Decitabine plus Carboplatin

Pegylated Liposomal Doxorubicin DRUG

Chemotherapy medication

Standard Treatment

Gemcitabine DRUG

Chemotherapy medication

Standard Treatment

Paclitaxel DRUG

Chemotherapy medication

Standard Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cytologic / histologic diagnosis of stage 1°C-4° epithelial , fallopian tube and primary peritoneal cancer (carcinosarcomas are included)
• Patient who received 1-2 prior lines of treatments
• Patient relapsed within 6 months after platinum containing regimen
• Disease measurable or evaluable by RECIST version 1.1 or Ca 125 GCIG criteria (Gynaecologic Cancer Intergroup).
• No residual peripheral neurotoxicity \> Grade 1 from previous chemotherapy treatment
• Performance Status (PS) 0-1
• Age 18 years.
• Life expectancy of at least 3 months
• Written informed consent prior to performance of study specific procedures or assessments
• Ability and willingness to comply with treatment and follow up assessments and procedures
• Adequate organ functions:
• Hematopoietic: Leukocytes \> 2,500/mm3; Absolute neutrophil count \>1,500/mm3; Platelets count \>100,000/mm3; Hemoglobin \>9 g/dL
• Hepatic: AST (aspartate transaminase ) and ALT (alanine transaminase) \<3 times upper limit of normal (ULN)\*; Alkaline phosphatase \<3 times ULN\*; Bilirubin \<1.5 times ULN
• \*: \<5 times ULN if liver metastases are present
• Renal: Creatinine clearance \>45 mL/min

You may not qualify if:

• Pregnant (potentially fertile patients must use contraceptive measures to avoid pregnancy during and for at least 3 months after study participation and must have a negative serum pregnancy test at baseline).
• Patients should not be breast-feeding during treatment and for 2 months following the end of treatment.
• Serious heart disease, including heart failure, atrio-ventricular block of any degree, serious arrhythmia or history of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, symptomatic peripheral vascular disease, coronary artery by-pass graft surgery, class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
• Active infection requiring antibiotics.
• History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months
• History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
• Patients who had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with \< Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
• Patients with evidence of interstitial lung disease.
• Major surgical procedure, open biopsy, or significant traumatic injury within 3 weeks prior to beginning therapy, or anticipation of the need for a major surgical procedure during the course of the study; minor surgical procedures such as fine needle aspiration or core biopsy within 1 week prior to beginning therapy are also excluded.
• Known hypersensitivity to the study drugs or to drugs with similar chemical structures.
• Concurrent treatment with other experimental drugs.
• Participation in another clinical trial with any investigational drug within 30 days prior to study screening.

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

RECRUITING

Related Publications (33)

• Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007 Jan 1;109(1):52-7. doi: 10.1182/blood-2006-05-021162. Epub 2006 Aug 1.

  PMID: 16882708 BACKGROUND

• Matei DE, Nephew KP. Epigenetic therapies for chemoresensitization of epithelial ovarian cancer. Gynecol Oncol. 2010 Feb;116(2):195-201. doi: 10.1016/j.ygyno.2009.09.043. Epub 2009 Oct 24.

  PMID: 19854495 BACKGROUND

• Bukowski RM, Ozols RF, Markman M. The management of recurrent ovarian cancer. Semin Oncol. 2007 Apr;34(2 Suppl 2):S1-15. doi: 10.1053/j.seminoncol.2007.03.012. No abstract available.

  PMID: 17512352 RESULT

• Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011 Sep 23;11(10):719-25. doi: 10.1038/nrc3144.

  PMID: 21941283 RESULT

• Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005 Jan;205(2):275-92. doi: 10.1002/path.1706.

  PMID: 15641020 RESULT

• Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010 Jan;31(1):27-36. doi: 10.1093/carcin/bgp220. Epub 2009 Sep 13.

  PMID: 19752007 RESULT

• Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004 Nov 15;22(22):4632-42. doi: 10.1200/JCO.2004.07.151.

  PMID: 15542813 RESULT

• Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics. 2009 Dec;1(2):239-59. doi: 10.2217/epi.09.33.

  PMID: 20495664 RESULT

• Taby R, Issa JP. Cancer epigenetics. CA Cancer J Clin. 2010 Nov-Dec;60(6):376-92. doi: 10.3322/caac.20085. Epub 2010 Oct 19.

  PMID: 20959400 RESULT

• Peedicayil J. The role of DNA methylation in the pathogenesis and treatment of cancer. Curr Clin Pharmacol. 2012 Nov;7(4):333-40. doi: 10.2174/157488412803305858.

  PMID: 22794162 RESULT

• Sang M, Wu X, Fan X, Sang M, Zhou X, Zhou N. Multiple MAGE-A genes as surveillance marker for the detection of circulating tumor cells in patients with ovarian cancer. Biomarkers. 2014 Feb;19(1):34-42. doi: 10.3109/1354750X.2013.865275. Epub 2013 Dec 10.

  PMID: 24320162 RESULT

• Gurion R, Vidal L, Gafter-Gvili A, Belnik Y, Yeshurun M, Raanani P, Shpilberg O. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome--a systematic review and meta-analysis. Haematologica. 2010 Feb;95(2):303-10. doi: 10.3324/haematol.2009.010611. Epub 2009 Sep 22.

  PMID: 19773261 RESULT

• Balch C, Huang TH, Brown R, Nephew KP. The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol. 2004 Nov;191(5):1552-72. doi: 10.1016/j.ajog.2004.05.025.

  PMID: 15547525 RESULT

• Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol. 2010 Oct;28(10):1069-78. doi: 10.1038/nbt.1678.

  PMID: 20944599 RESULT

• Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007 Sep 1;25(25):3884-91. doi: 10.1200/JCO.2006.09.4169. Epub 2007 Aug 6.

  PMID: 17679729 RESULT

• Wang LX, Mei ZY, Zhou JH, Yao YS, Li YH, Xu YH, Li JX, Gao XN, Zhou MH, Jiang MM, Gao L, Ding Y, Lu XC, Shi JL, Luo XF, Wang J, Wang LL, Qu C, Bai XF, Yu L. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS One. 2013 May 9;8(5):e62924. doi: 10.1371/journal.pone.0062924. Print 2013.

  PMID: 23671644 RESULT

• Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A. Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000 Mar;18(5):956-62. doi: 10.1200/JCO.2000.18.5.956.

  PMID: 10694544 RESULT

• Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000 Nov 1;60(21):6039-44.

  PMID: 11085525 RESULT

• Watts GS, Futscher BW, Holtan N, Degeest K, Domann FE, Rose SL. DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage. BMC Med Genomics. 2008 Sep 30;1:47. doi: 10.1186/1755-8794-1-47.

  PMID: 18826610 RESULT

• Barton CA, Hacker NF, Clark SJ, O'Brien PM. DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol. 2008 Apr;109(1):129-39. doi: 10.1016/j.ygyno.2007.12.017. Epub 2008 Jan 29.

  PMID: 18234305 RESULT

• Ibanez de Caceres I, Battagli C, Esteller M, Herman JG, Dulaimi E, Edelson MI, Bergman C, Ehya H, Eisenberg BL, Cairns P. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 2004 Sep 15;64(18):6476-81. doi: 10.1158/0008-5472.CAN-04-1529.

  PMID: 15374957 RESULT

• Li Y, Hu W, Shen DY, Kavanagh JJ, Fu S. Azacitidine enhances sensitivity of platinum-resistant ovarian cancer cells to carboplatin through induction of apoptosis. Am J Obstet Gynecol. 2009 Feb;200(2):177.e1-9. doi: 10.1016/j.ajog.2008.08.030. Epub 2008 Dec 25.

  PMID: 19110234 RESULT

• Frost P, Abbruzzese JL, Hunt B, Lee D, Ellis M. Synergistic cytotoxicity using 2'-deoxy-5-azacytidine and cisplatin or 4-hydroperoxycyclophosphamide with human tumor cells. Cancer Res. 1990 Aug 1;50(15):4572-7.

  PMID: 1695122 RESULT

• Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007 Feb 23;128(4):683-92. doi: 10.1016/j.cell.2007.01.029.

  PMID: 17320506 RESULT

• Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 2007 Jul;63(1):12-31. doi: 10.1016/j.critrevonc.2007.02.001. Epub 2007 Mar 1.

  PMID: 17336087 RESULT

• Gomyo Y, Sasaki J, Branch C, Roth JA, Mukhopadhyay T. 5-aza-2'-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells. Oncogene. 2004 Sep 2;23(40):6779-87. doi: 10.1038/sj.onc.1207381.

  PMID: 15273730 RESULT

• Schwartsmann G, Schunemann H, Gorini CN, Filho AF, Garbino C, Sabini G, Muse I, DiLeone L, Mans DR. A phase I trial of cisplatin plus decitabine, a new DNA-hypomethylating agent, in patients with advanced solid tumors and a follow-up early phase II evaluation in patients with inoperable non-small cell lung cancer. Invest New Drugs. 2000 Feb;18(1):83-91. doi: 10.1023/a:1006388031954.

  PMID: 10830142 RESULT

• Pohlmann P, DiLeone LP, Cancella AI, Caldas AP, Dal Lago L, Campos O Jr, Monego E, Rivoire W, Schwartsmann G. Phase II trial of cisplatin plus decitabine, a new DNA hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix. Am J Clin Oncol. 2002 Oct;25(5):496-501. doi: 10.1097/00000421-200210000-00015.

  PMID: 12393992 RESULT

• Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R. Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. doi: 10.1200/JCO.2007.10.8688.

  PMID: 17925555 RESULT

• Fang F, Balch C, Schilder J, Breen T, Zhang S, Shen C, Li L, Kulesavage C, Snyder AJ, Nephew KP, Matei DE. A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. Cancer. 2010 Sep 1;116(17):4043-53. doi: 10.1002/cncr.25204.

  PMID: 20564122 RESULT

• Glasspool RM, Brown R, Gore ME, Rustin GJ, McNeish IA, Wilson RH, Pledge S, Paul J, Mackean M, Hall GD, Gabra H, Halford SE, Walker J, Appleton K, Ullah R, Kaye S; Scottish Gynaecological Trials Group. A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer. Br J Cancer. 2014 Apr 15;110(8):1923-9. doi: 10.1038/bjc.2014.116. Epub 2014 Mar 18.

  PMID: 24642620 RESULT

• Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. 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. 2000 Feb 2;92(3):205-16. doi: 10.1093/jnci/92.3.205.

  PMID: 10655437 RESULT

• Pignata S, Lorusso D, Scambia G, Sambataro D, Tamberi S, Cinieri S, Mosconi AM, Orditura M, Brandes AA, Arcangeli V, Panici PB, Pisano C, Cecere SC, Di Napoli M, Raspagliesi F, Maltese G, Salutari V, Ricci C, Daniele G, Piccirillo MC, Di Maio M, Gallo C, Perrone F; MITO 11 investigators. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial. Lancet Oncol. 2015 May;16(5):561-8. doi: 10.1016/S1470-2045(15)70115-4. Epub 2015 Apr 14.

  PMID: 25882986 RESULT

MeSH Terms

Conditions

Recurrence

Interventions

Decitabine; Carboplatin; liposomal doxorubicin; Gemcitabine; Paclitaxel

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Coordination Complexes; Deoxycytidine; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Officials

• Domenica Lorusso, MD

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

• Domenica Lorusso, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Domenica Lorusso, MD

CONTACT

+390223903697; domenica.lorusso@istitutotumori.mi.it

Serena Giolitto, MSc

CONTACT

+390223903882; serena.giolitto@istitutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: March 15, 2018
• Study Start: July 30, 2018
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: September 5, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)