Efficacy of Letrozole in Recurrent Ovarian Cancer

NCT04421547 | Terminated Phase 3 DMC

• 1 other identifier: MITO32
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

Randomized phase III multicenter study investigating the role of letrozole in heavily pretreated recurrent ovarian cancer.

Conditions

Epithelial Ovarian Cancer

Keywords

epithelial ovarian cancer; Letrozole

Outcome Measures

Primary Outcomes (1)

• Proportion of patient alive at 12 months

  Evaluate the difference in terms of proportion of survivals at 12 months between the two arms.

  30 months

Secondary Outcomes (7)

• PFS

  30 months

• OS

  30 months

• ORR

  30 months

• TPST

  30 months

• TSST

  30 months

Study Arms (2)

Letrozole

EXPERIMENTAL

Letrozole 1 tablet (2,5 mg) orally once a day

Drug: Letrozole 2.5mg

Standard Chemotherapy

ACTIVE COMPARATOR

Either Paclitaxel 80 mg/m2 as a 1-h infusion, on days 1,8,15,22 every 28 days or Pegylated Liposomal Doxorubicin (PLD) 40 mg/m2 given every 4 weeks or Topotecan 4mg/m2 IV on days 1,8,15 every 4 weeks or Gemcitabine 1000 mg/m2 IV over 30 min on days 1,8,15 every 28 days.

Drug: Standard single agent chemotherapy

Interventions

Letrozole 2.5mg DRUG

This study will investigate the role of Letrozole in patients affected by heavily pretreated platinum resistant ovarian cancer, compared to standard treatment.

Letrozole

Standard single agent chemotherapy DRUG

Either Paclitaxel 80 mg/m2 as a 1-h infusion, on days 1,8,15,22 every 28 days or Pegylated Liposomal Doxorubicin (PLD) 40 mg/m2 given every 4 weeks or Topotecan 4mg/m2 IV on days 1,8,15 every 4 weeks or Gemcitabine 1000 mg/m2 IV over 30 min on days 1,8,15 every 28 days.

Standard Chemotherapy

Eligibility Criteria

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

You may qualify if:

• Female of 18 years of age or older
• Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer
• Platinum resistant or refractory disease (patients who did not respond to last platinumbased therapy or with last relapse occurred \< 6 months from the last dose of platinum) or patients not amenable of platinum treatment
• \>3 previous chemotherapy lines
• ECOG performance status 0 -2
• Measurable and evaluable disease according to RECIST criteria confirmed by radiological imaging: at least one lesion of ≥ 1.0 cm for non-lymph nodes or ≥ 1.5 cm in short-axis diameter for lymph nodes at CT scan (Subjects with isolated rising CA-125 without radiologically visible disease are excluded)
• Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal
• Estimated life expectancy ≥ 16 weeks
• Adequate functions evidenced by:
• Hemoglobin ³10.0 g/dl
• Absolute neutrophil count ³1.5 x 109/L
• White blood cells \>3x109/L
• Platelet \>100 x109/L
• AST and ALT £ 2.5 x Upper limit of normal, unless liver metastasis, in which case AST and ALT \< or = 5 x Upper limit of normal will be accepted
• Bilirubin ≤ 1.5 times the upper limit of normal (ULN)

You may not qualify if:

• Subjects with borderline ovarian cancer
• Subject with low malignant potential tumors
• Less than 3 lines of previous therapies
• Platinum sensitive disease (last relapse occurred \> 6 months from the last dose of platinum)
• Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy
• History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer
• Breastfeeding women
• Pregnant women
• Prior therapy with letrozole.
• Severe osteoporosis documented by BMD (Bone Mineral Density) T-score ≤ -2.5 with existing fragility fracture(s)
• Patients with a known hypersensitivity to Paclitaxel , PLD, Topotecan, Gemcitabine or Letrozole or any case of severe toxicity related to them. Also Patients with a known hypersensitivity to any of the ingredients or excipients of the IMPs (e.g. macrogolglycerol ricinoleate (polyoxyl castor oil), ethanol, anhydrous, citric acid, anhydrous, sodium chloride hydrochloric acid, mannitol, sodium acetate, sodium hydroxide, tartaric acid, lactose monohydrate, maize starch, hypromellose Type 2910, cellulose microcrystalline, sodium starch glycolate type A, colloidal anhydrous silica, magnesium stearate, hypromellose 6 cp E464, titanium dioxide E171, Iron oxide yellow E172, Macrogol 400, talc E553b)
• Prior resistance to Paclitaxel, PLD, Topotecan, Gemcitabine
• Patients with active hepatic disease (HCV or HBV infections), hepatic severe impairment or cirrhosis
• Bowel obstruction, sub-occlusive disease, prior gastrectomy, symptomatic brain metastases.
• Myocardial infarct within six months before enrolment , NYHA Class II or worse heart failure, unstable angina, serious cardiac arrhythmia or cardiac arrhythmia requiring treatment.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

DH Tumori Femminili

Roma, Italy

Location

Related Publications (33)

• Banerjee S, Kaye SB, Ashworth A. Making the best of PARP inhibitors in ovarian cancer. Nat Rev Clin Oncol. 2010 Sep;7(9):508-19. doi: 10.1038/nrclinonc.2010.116. Epub 2010 Aug 10.

  PMID: 20700108 BACKGROUND

• Banerjee S, Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res. 2013 Mar 1;19(5):961-8. doi: 10.1158/1078-0432.CCR-12-2243. Epub 2013 Jan 10.

  PMID: 23307860 BACKGROUND

• Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol. 1990 Feb;36(2):207-11. doi: 10.1016/0090-8258(90)90174-j.

  PMID: 2404837 BACKGROUND

• Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, Jones W, Almadrones L, Lewis JL Jr. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991 Mar;9(3):389-93. doi: 10.1200/JCO.1991.9.3.389.

  PMID: 1999708 BACKGROUND

• Buda A, Floriani I, Rossi R, Colombo N, Torri V, Conte PF, Fossati R, Ravaioli A, Mangioni C. Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the Mario Negri Institute, Milan, G.O.N.O. (Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo) group. Br J Cancer. 2004 Jun 1;90(11):2112-7. doi: 10.1038/sj.bjc.6601787.

  PMID: 15150623 BACKGROUND

• Sehouli J, Stengel D, Oskay-Oezcelik G, Zeimet AG, Sommer H, Klare P, Stauch M, Paulenz A, Camara O, Keil E, Lichtenegger W. Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol. 2008 Jul 1;26(19):3176-82. doi: 10.1200/JCO.2007.15.1258.

  PMID: 18591555 BACKGROUND

• ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, Broom C, Scarabelli C, Davidson N, Spanczynski M, Bolis G, Malmstrom H, Coleman R, Fields SC, Heron JF. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997 Jun;15(6):2183-93. doi: 10.1200/JCO.1997.15.6.2183.

  PMID: 9196130 BACKGROUND

• Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001 Jul 15;19(14):3312-22. doi: 10.1200/JCO.2001.19.14.3312.

  PMID: 11454878 BACKGROUND

• Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, Wang Y, Scribner DR Jr, Marciniack M, Naumann RW, Secord AA. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007 Jul 1;25(19):2811-8. doi: 10.1200/JCO.2006.09.6735.

  PMID: 17602086 BACKGROUND

• Vergote I, Finkler NJ, Hall JB, Melnyk O, Edwards RP, Jones M, Keck JG, Meng L, Brown GL, Rankin EM, Burke JJ, Boccia RV, Runowicz CD, Rose PG. Randomized phase III study of canfosfamide in combination with pegylated liposomal doxorubicin compared with pegylated liposomal doxorubicin alone in platinum-resistant ovarian cancer. Int J Gynecol Cancer. 2010 Jul;20(5):772-80. doi: 10.1111/igc.0b013e3181daaf59.

  PMID: 20973267 BACKGROUND

• Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza MR, Follana P, Bollag D, Ray-Coquard I. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014 May 1;32(13):1302-8. doi: 10.1200/JCO.2013.51.4489. Epub 2014 Mar 17.

  PMID: 24637997 BACKGROUND

• Lakusta CM, Atkinson MJ, Robinson JW, Nation J, Taenzer PA, Campo MG. Quality of life in ovarian cancer patients receiving chemotherapy. Gynecol Oncol. 2001 Jun;81(3):490-5. doi: 10.1006/gyno.2001.6199.

  PMID: 11371144 BACKGROUND

• Demers LM, Melby JC, Wilson TE, Lipton A, Harvey HA, Santen RJ. The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis. J Clin Endocrinol Metab. 1990 Apr;70(4):1162-6.

  PMID: 2156889 BACKGROUND

• Lipton A, Demers LM, Harvey HA, Kambic KB, Grossberg H, Brady C, Adlercruetz H, Trunet PF, Santen RJ. Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer. 1995 Apr 15;75(8):2132-8. doi: 10.1002/1097-0142(19950415)75:83.0.co;2-u.

  PMID: 7697604 BACKGROUND

• El Ouagari K, Karnon J, Delea T, Talbot W, Brandman J. Cost-effectiveness of letrozole in the extended adjuvant treatment of women with early breast cancer. Breast Cancer Res Treat. 2007 Jan;101(1):37-49. doi: 10.1007/s10549-006-9262-4. Epub 2006 Jul 4.

  PMID: 16821085 BACKGROUND

• Sioufi A, Gauducheau N, Pineau V, Marfil F, Jaouen A, Cardot JM, Godbillon J, Czendlik C, Howald H, Pfister C, Vreeland F. Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos. 1997 Dec;18(9):779-89. doi: 10.1002/(sici)1099-081x(199712)18:93.0.co;2-5.

  PMID: 9429742 BACKGROUND

• Sioufi A, Sandrenan N, Godbillon J, Trunet P, Czendlik C, Howald H, Pfister C, Ezzet F. Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 2.5 mg single oral administration. Biopharm Drug Dispos. 1997 Aug;18(6):489-97. doi: 10.1002/(sici)1099-081x(199708)18:63.0.co;2-p.

  PMID: 9267682 BACKGROUND

• Dave N, Gudelsky GA, Desai PB. The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis. Cancer Chemother Pharmacol. 2013 Aug;72(2):349-57. doi: 10.1007/s00280-013-2205-y. Epub 2013 Jun 9.

  PMID: 23748921 BACKGROUND

• Lamb HM, Adkins JC. Letrozole. A review of its use in postmenopausal women with advanced breast cancer. Drugs. 1998 Dec;56(6):1125-40. doi: 10.2165/00003495-199856060-00020.

  PMID: 9878997 BACKGROUND

• Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. doi: 10.1056/NEJMoa032312. Epub 2003 Oct 9.

  PMID: 14551341 BACKGROUND

• Batra S, Iosif CS. Elevated concentrations of antiestrogen binding sites in membrane fractions of human ovarian tumors. Gynecol Oncol. 1996 Feb;60(2):228-32. doi: 10.1006/gyno.1996.0030.

  PMID: 8631543 BACKGROUND

• Langdon SP, Gourley C, Gabra H, Stanley B. Endocrine therapy in epithelial ovarian cancer. Expert Rev Anticancer Ther. 2017 Feb;17(2):109-117. doi: 10.1080/14737140.2017.1272414. Epub 2016 Dec 24.

  PMID: 27967255 BACKGROUND

• Slotman BJ, Rao BR. Ovarian cancer (review). Etiology, diagnosis, prognosis, surgery, radiotherapy, chemotherapy and endocrine therapy. Anticancer Res. 1988 May-Jun;8(3):417-34.

  PMID: 3291746 BACKGROUND

• Langdon SP, Hawkes MM, Lawrie SS, Hawkins RA, Tesdale AL, Crew AJ, Miller WR, Smyth JF. Oestrogen receptor expression and the effects of oestrogen and tamoxifen on the growth of human ovarian carcinoma cell lines. Br J Cancer. 1990 Aug;62(2):213-6. doi: 10.1038/bjc.1990.263.

  PMID: 2386737 BACKGROUND

• Langdon SP, Crew AJ, Ritchie AA, Muir M, Wakeling A, Smyth JF, Miller WR. Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model. Eur J Cancer. 1994;30A(5):682-6. doi: 10.1016/0959-8049(94)90545-2.

  PMID: 8080688 BACKGROUND

• O'Donnell AJ, Macleod KG, Burns DJ, Smyth JF, Langdon SP. Estrogen receptor-alpha mediates gene expression changes and growth response in ovarian cancer cells exposed to estrogen. Endocr Relat Cancer. 2005 Dec;12(4):851-66. doi: 10.1677/erc.1.01039.

  PMID: 16322326 BACKGROUND

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.

  PMID: 2702835 BACKGROUND

• Papadimitriou CA, Markaki S, Siapkaras J, Vlachos G, Efstathiou E, Grimani I, Hamilos G, Zorzou M, Dimopoulos MA. Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study. Oncology. 2004;66(2):112-7. doi: 10.1159/000077436.

  PMID: 15138362 BACKGROUND

• Bowman A, Gabra H, Langdon SP, Lessells A, Stewart M, Young A, Smyth JF. CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup. Clin Cancer Res. 2002 Jul;8(7):2233-9.

  PMID: 12114425 BACKGROUND

• Markman M, Iseminger KA, Hatch KD, Creasman WT, Barnes W, Dubeshter B. Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group Ancillary Report. Gynecol Oncol. 1996 Jul;62(1):4-6. doi: 10.1006/gyno.1996.0181.

  PMID: 8690289 BACKGROUND

• Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, Savarese A, Del Medico P, Scaltriti L, Katsaros D, Priolo D, Scambia G. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008 Feb 20;26(6):890-6. doi: 10.1200/JCO.2007.13.6606.

  PMID: 18281662 BACKGROUND

• Le T, Leis A, Pahwa P, Wright K, Ali K, Reeder B, Kinderchuck M, Ward K. Quality of life evaluations of caregivers of ovarian cancer patients during chemotherapy treatment. J Obstet Gynaecol Can. 2004 Jul;26(7):627-31. doi: 10.1016/s1701-2163(16)30609-0.

  PMID: 15248931 BACKGROUND

• Stiggelbout AM, de Haes JC. Patient preference for cancer therapy: an overview of measurement approaches. J Clin Oncol. 2001 Jan 1;19(1):220-30. doi: 10.1200/JCO.2001.19.1.220.

  PMID: 11134216 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Ovarian Epithelial

Interventions

Letrozole

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Claudia Marchetti

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a two arms, prospective, open-label multi center randomized phase III study.

Study Record Dates

• First Submitted: May 15, 2020
• First Posted: June 9, 2020
• Study Start: June 22, 2020
• Primary Completion: November 1, 2024
• Study Completion: November 4, 2024
• Last Updated: March 7, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

IT (1)