HOBOE: A Phase 3 Study of Adjuvant Triptorelin and Tamoxifen, Letrozole, or Letrozole and Zoledronic Acid in Premenopausal Patients With Breast Cancer. (HOBOE)

Phase III Randomized Study of the Effects on Bone Mineral Density of Tamoxifen, Letrozole, and Letrozole + Zoledronic Acid as Adjuvant Treatment of Patients With Early Breast Cancer; VERSION 2 AMENDED Phase 3 Study of Triptorelin and Tamoxifen, Letrozole, or Letrozole + Zoledronic Acid in Adjuvant Treatment of Premenopausal Endocrine Responsive Breast Cancer Patients.

The HOBOE study was amended in November 2009, and, after reaching enrollment of the first 500 patients, the study began recruiting premenopausal patients only. The primary objective of the extended study is to compare disease free survival in premenopausal patients with early breast cancer. Patients receive triptorelin and are randomized in a 1:1:1 fashion to receive tamoxifen or letrozole, or letrozole + zoledronic acid.

The purpose of the HOBOE study, Version 1, was to compare the adjuvant hormonal therapy treatments of Tamoxifen, Letrozole and Letrozole + Zoledronate for their effects on bone loss in breast cancer patients. Postmenopausal and premenopausal patients were eligible, the latter also receiving monthly triptorelin. Upon reaching the enrollment of the first 500 patients in March 2010, the study began recruiting premenopausal patients only.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: tamoxifen; Drug: triptorelin; Drug: letrozole; Drug: zoledronic acid

• Study Type: Interventional
• Enrollment (Actual): 1294
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Bagno a Ripoli, Italy
    • OSpedale Santa Maria Annunziata
  • Genova, Italy
    • Istituto nazionale Per la Ricerca sul Cancro
  • Livorno, Italy
    • Ospedale Riuniti
  • Lucca, Italy
    • Ospedale Unico della Versilia
  • Napoli, Italy
    • Seconda Universita di Napoli
  • Napoli, Italy
    • Ospedale Cardarelli
  • Napoli, Italy
    • Istituto Nazionale dei Tumori,
  • Napoli, Italy
    • Università Federico II, Cattedra di Oncologia Medica
  • Palermo, Italy
    • Casa di Cura La Maddalena
  • Perugia, Italy
    • Ospedale Silvestrini
  • Pisa, Italy
    • Ospedale Santa Chiara
  • Sassari, Italy
    • Università di Sassari
  • Trento, Italy
    • Ospedale Santa Chiara
  • Viterbo, Italy
    • ASL Viterbo Ospedale Belcolle
  • AV
    • Avellino, AV, Italy
      • S. Giuseppe Moscati
  • BG
    • Treviglio, BG, Italy
      • Azienda Ospedaliera Treviglio - Caravaggio
  • BN
    • Benevento, BN, Italy
      • Azienda Ospedaliera G. Rummo
  • BR
    • Brindisi, BR, Italy
      • Ospedale Senatore Antonio Perrino
  • FC
    • Meldola, FC, Italy
      • Istituto Romagnolo per lo Studio e la Cura dei Tumori
  • VA
    • Saronno, VA, Italy
      • Presidio Ospedaliero Di Saronno Aziendo Ospedaliera di Busto Arsizio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Histological diagnosis of breast cancer
• Surgical resection of breast cancer (breast conserving surgery or mastectomy)
• No evidence of disease
• Indication for adjuvant hormonal therapy (ER and/or PgR positive with IHC exam in at least 1% of primary tumor cells, according to St. Gallen criteria)
• Patient age at least 18 years
• Written informed consent . Premenopausal status defined as LMP within 12 months of randomization (FSH, LH will not be considered as determinants of menopausal status due the chemotherapy induced reversible ovarian suppression)

Please note that patients who have received neoadjuvant or adjuvant chemotherapy and/or locoregional radiation therapy may be included in the study

Exclusion Criteria:

• Performance status (ECOG)>2.
• Previous or concomitant malignancy (with the exception of adequately treated nonmalignant skin cancer and carcinoma in situ of the uterine cervix
• Metastatic breast cancer
• Creatinine > 1.25 times the value of upper normal limit
• Pregnant or lactating females
• Clinical or radiologic evidence of bone fractures
• Treatment with systemic cortisone therapy within 12 months prior to randomization
• Treatment with drugs that could alter bone metabolism (calcitonin, mithramycin, gallium nitrate) within 2 weeks prior to randomization
• Previous treatment with tamoxifen or aromatase inhibitors
• AST and/or ALT > 3 times the value of upper normal limit with clinical and laboratory findings that indicate a grade of hepatic insufficiency that could potentially increase the risk of assuming letrozole
• Any concomitant conditions that would, in the Investigator's opinion, contraindicate the use of any of the drugs used in this study
• Inability to provide informed consent
• Inability to comply with followup
• Patient undergoing invasive dental work at time of baseline evaluation or foreseen during the course of adjuvant therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A; Triptorelin 3.75 mg IM every 4 weeks and Tamoxifen 20 mg daily, for 5 years	Drug: tamoxifen; 20 mg daily for 5 years; Drug: triptorelin; Premenopausal patients will receive triptorelin 3.75 mg IM at the beginning of therapy and every 4 weeks for 5 years or up to age 55
Active Comparator: B; Triptorelin 3.75 mg IM every 4 weeks and Letrozole 2.5 mg daily, for 5 years	Drug: triptorelin; Premenopausal patients will receive triptorelin 3.75 mg IM at the beginning of therapy and every 4 weeks for 5 years or up to age 55; Drug: letrozole; 2.5 mg daily for 5 years
Experimental: C; Triptorelin 3.75 mg IM every 4 weeks and Letrozole 2.5 mg daily for 5 years + zoledronic acid 4 mg every 6 months.	Drug: triptorelin; Premenopausal patients will receive triptorelin 3.75 mg IM at the beginning of therapy and every 4 weeks for 5 years or up to age 55; Drug: letrozole; 2.5 mg daily for 5 years; Drug: zoledronic acid; 4 mg every 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
disease free survival in premenopausal patients	observation period is 10 years from initiation of treatment
bone mineral density	12 months from initiation of therapy

Secondary Outcome Measures

Outcome Measure	Time Frame
Bone mineral density measured	yearly after first year of therapy
disease free survival in postmenopausal patients	observation period is 10 years from initiation of treatment
overall survival	observation period is 10 years from initiation of treatment
toxicity of letrozole + triptorelin and letrozole + zoledronic acid + triptorelin in premenopausal patients	monthly

Collaborators and Investigators

• Sponsor: National Cancer Institute, Naples
• Collaborators: University of Campania "Luigi Vanvitelli"

Publications and helpful links

General Publications

• Rossi E, Morabito A, Di Rella F, Esposito G, Gravina A, Labonia V, Landi G, Nuzzo F, Pacilio C, De Maio E, Di Maio M, Piccirillo MC, De Feo G, D'Aiuto G, Botti G, Chiodini P, Gallo C, Perrone F, de Matteis A. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial. J Clin Oncol. 2009 Jul 1;27(19):3192-7. doi: 10.1200/JCO.2008.18.6213. Epub 2009 Apr 20.
• Rossi E, Morabito A, De Maio E, Di Rella F, Esposito G, Gravina A, Labonia V, Landi G, Nuzzo F, Pacilio C, Piccirillo MC, D'Aiuto G, D'Aiuto M, Rinaldo M, Botti G, Gallo C, Perrone F, de Matteis A. Endocrine effects of adjuvant letrozole + triptorelin compared with tamoxifen + triptorelin in premenopausal patients with early breast cancer. J Clin Oncol. 2008 Jan 10;26(2):264-70. doi: 10.1200/JCO.2007.13.5319. Epub 2007 Dec 17.
• Nuzzo F, Gallo C, Lastoria S, Di Maio M, Piccirillo MC, Gravina A, Landi G, Rossi E, Pacilio C, Labonia V, Di Rella F, Bartiromo A, Buonfanti G, De Feo G, Esposito G, D'Aniello R, Maiolino P, Signoriello S, De Maio E, Tinessa V, Colantuoni G, De Laurentiis M, D'Aiuto M, Di Bonito M, Botti G, Giordano P, Daniele G, Morabito A, Normanno N, de Matteis A, Perrone F. Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study. Ann Oncol. 2012 Aug;23(8):2027-2033. doi: 10.1093/annonc/mdr600. Epub 2012 Mar 12.
• Perrone F, De Laurentiis M, De Placido S, Orditura M, Cinieri S, Riccardi F, Ribecco AS, Putzu C, Del Mastro L, Rossi E, Tinessa V, Mosconi AM, Nuzzo F, Di Rella F, Gravina A, Iodice G, Landi G, Pacilio C, Forestieri V, Lauria R, Fabbri A, Ibrahim T, De Maio E, Barni S, Gori S, Simeon V, Arenare L, Daniele G, Piccirillo MC, Normanno N, de Matteis A, Gallo C. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer. 2019 Sep;118:178-186. doi: 10.1016/j.ejca.2019.05.004. Epub 2019 Jun 1.

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Anticipated): November 1, 2024
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: December 14, 2006
• First Submitted That Met QC Criteria: December 14, 2006
• First Posted (Estimate): December 15, 2006

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: aromatase inhibitors; adjuvant therapy; premenopausal; postmenopause; bone mineral density; letrozole; early breast cancer; disease-free survival; premenopause; menopausal status; hormone sensitive
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Luteolytic Agents; Letrozole; Tamoxifen; Triptorelin Pamoate; Zoledronic Acid
• Other Study ID Numbers: HOBOE