DEPO-Trigger Trial: GnRH Agonist DEPOt TRIGGER for Final Oocyte Maturation (Depo-Trigger)

• ClinicalTrials.gov Identifier: NCT04616729
• Recruitment Status: Not yet recruiting
• First Posted: November 5, 2020
• Last Update Posted: November 5, 2020
• Sponsor: Universitair Ziekenhuis Brussel
• Collaborator: Universitaire Ziekenhuizen Leuven
• Information provided by (Responsible Party): Universitair Ziekenhuis Brussel

Study Description

Brief Summary:

For breast cancer patients who are candidates to receive chemotherapy, concurrent use of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) can be offered as ovarian protection.

Because ovarian stimulation for oocyte cryopreservation is usually performed using a GnRH antagonist protocol and typically involves final oocyte maturation triggering with a GnRH agonist, the investigators designed this study to explore the feasibility of combining the final oocyte maturation trigger and the start of ovarian suppression. Short-term cotreatment with GnRH antagonists is needed to induce rapid luteolysis (in view of prevention of ovarian hyperstimulation).

To demonstrate the safety of GnRH agonist depot triggering followed by daily GnRH antagonist luteolysis, this pilot study is set out to analyse the endocrine profile and ovarian morphology of this novel protocol.

Condition or disease	Intervention/treatment	Phase
Breast Cancer Female	Drug: Triptorelin 3.75 MG Injection; Procedure: Transvaginal oocyte retrieval; Drug: Triptorelin Injection	Phase 1; Phase 2

Detailed Description:

For breast cancer patients who are candidates to receive chemotherapy, concurrent use of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) can be offered as ovarian protection. A recent meta-analysis of individual patient data from the largest randomised clinical trials in women with early breast cancer indicated beneficial effects of GnRHa ovarian suppression in reducing POI risk and increasing post-chemotherapy pregnancy rates with no negative effect on patients' outcomes. However, it should not be considered as an alternative to cryopreservation strategies in fertility preservation.

Because ovarian stimulation for oocyte cryopreservation is usually performed using a GnRH antagonist protocol and typically involves final oocyte maturation triggering with a GnRH agonist, the investigators designed this study to explore the feasibility of combining the final oocyte maturation trigger and the start of ovarian suppression. Replacement of the 0,2mg triptorelin trigger by a GnRH agonist depot has potential to provide this dual action. However, the protracted action of the GnRH agonist depot will result in prolonged stimulation of multiple corpora lutea, which will lead to enhanced production of steroids (estradiol and progesterone) and growth factors such as vascular endothelial growth factor. Consequently, GnRH agonist-induced stimulation of multiple corpora lutea is potentially unsafe in a patient with breast cancer because of the impact of estradiol and progesterone on breast tumour cells. In addition, VEGF may increase the risk of OHSS, which will lead to postponement of cancer treatment. Therefore, short-term cotreatment with GnRH antagonists is needed to induce rapid luteolysis.

To demonstrate the safety of GnRH agonist depot triggering followed by daily GnRH antagonist luteolysis, this pilot study is set out to analyse the endocrine profile and ovarian morphology of this novel protocol.

Patients will be randomized before start of stimulation to either DEPOT group (group A) or control group (group B), only after patient eligibility has been established and patient consent has been obtained.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Patients will be randomized before start of ovarian stimulation to either DEPOT group (group A) or control group (group B), only after patient eligibility has been established and patient consent has been obtained.

Group A will receive the GnRH agonist Depot form for final oocyte maturation followed by daily GnRH antagonist injections for 1 week.

Group B will receive the GnRH agonist daily form for final oocyte maturation. After one week the Depot form combined with daily GnRH antagonist injections for 7 days, will be administered in view of ovarian protection during chemotherapy.

Blood analysis and ultrasounds will be organised on day 3, 5 and 7 after oocyte pick-up in both groups.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: DEPO-Trigger Trial: GnRH Agonist DEPOt TRIGGER for Final Oocyte Maturation in Breast Cancer Patients Undergoing Fertility Preservation: a Pilot Study
• Estimated Study Start Date: November 1, 2020
• Estimated Primary Completion Date: November 30, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: GnRH agonist Depot form; Ovarian stimulation will be performed using a fixed antagonist protocol with Follitropin Alfa (daily in the evening) and Ganirelix or Cetrorelix (daily in the morning). Selection of the daily gonadotropin dose will be based on ovarian reserve parameters (AMH and AFC) and BMI. Co-administration of 5 mg of letrozole daily (in the morning) commencing on the first day of gonadotropin administration and continuing throughout the ovarian stimulation will be performed as this reduces oestradiol concentrations. GnRH agonist Triptorelin 3.75 mg Depot form will be used for final oocyte maturation. Ganirelix/Cetrorelix 0.25mg daily (in the morning) will resume for 7 days from the evening of the day of oocyte retrieval onwards. Hormone analysis, analysis of haematology and biochemistry and a pelvic ultrasound scan will be done on days 3, 5 and 7 after oocyte retrieval.	Drug: Triptorelin 3.75 MG Injection; Depot Group (Group A) will receive Triptorelin 3.75mg Depot form for final oocyte maturation.; Other Names: Gonapeptyl; Decapeptyl; Procedure: Transvaginal oocyte retrieval; Patients in both groups will undergo a transvaginal oocyte retrieval after ovarian stimulation.
Active Comparator: GnRH agonist Daily form; Ovarian stimulation will be performed using a fixed antagonist protocol with Follitropin Alfa (daily in the evening) and Ganirelix/Cetrorelix (daily in the morning). Selection of the daily gonadotropin dose will be based on ovarian reserve parameters (AMH and AFC) and BMI. Co-administration of 5 mg of letrozole daily (in the morning) commencing on the first day of gonadotropin administration and continuing throughout the ovarian stimulation will be performed as this reduces oestradiol concentrations. GnRH agonist Triptorelin 0.2 mg Daily form will be used for final oocyte maturation. Hormone analysis, analysis of haematology and biochemistry and a pelvic ultrasound scan will be done on days 3, 5 and 7 after oocyte retrieval. The first administration of Triptorelin 3.75mg depot will be scheduled on the first day of the menstrual cycle after oocyte retrieval. To prevent the flare-up produced by the GnRH agonist, daily doses of 0.25mg of Ganirelix/Cetrorelix will be given for seven days.	Procedure: Transvaginal oocyte retrieval; Patients in both groups will undergo a transvaginal oocyte retrieval after ovarian stimulation.; Drug: Triptorelin Injection; Daily Group (Group B) will receive Triptorelin 0.2mg Daily form for final oocyte maturation.; Other Names: Gonapeptyl; Decapeptyl

Outcome Measures

Primary Outcome Measures :

1. Safety profile with regard to the risk of OHSS: assessment of change in ovarian volume [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]

   A transvaginal ultrasound will be performed to measure the ovarian volume according to the formula 'length x width x height x 0.523' mm³.

   In the assumption of safety ovarian volume should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.

2. Safety profile with regard to the risk of OHSS: assessment of change in hematocrit [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate hematocrit (%). In the assumption of safety hematocrit levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
3. Safety profile with regard to the risk of OHSS: assessment of change in hemoglobine [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate hemoglobine (g/dL). In the assumption of safety hemoglobine levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
4. Safety profile with regard to the risk of OHSS: assessment of change in White Blood cell Count [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate White Blood cell Count (X10³/mm³). In the assumption of safety White Blood cell Count should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
5. Safety profile with regard to the risk of OHSS: assessment of change in Platelet Count [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate Platelet Count (X10³/mm³). In the assumption of safety Platelet Count should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
6. Safety profile with regard to the risk of OHSS: assessment of change in estimated glomerular filtration rate (eGFR) [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate eGFR (mL/min/1.73m²). In the assumption of safety eGFR levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
7. Safety profile with regard to the risk of OHSS: assessment of change in Creatinine [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate Creatinine (mg/dL). In the assumption of safety creatinine levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
8. Safety profile with regard to the risk of OHSS: assessment of change in Albumin [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
   A blood sample will be taken to evaluate Albumin (g/L). In the assumption of safety Albumin levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
9. Safety profile with regard to the risk of OHSS: assessment of change in liver function (AST, ALT, Gamma-GT, bilirubine, LDH) [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]

   A blood sample will be taken to evaluate liver function (AST U/L, ALT U/L, Gamma-GT U/L, bilirubine mg/dL, LDH U/L).

   In the assumption of safety liver function levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.

10. Safety profile with regard to the risk of OHSS: assessment of change in Oestradiol (E2) [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
    A blood sample will be taken to evaluate Oestradiol (ng/L). In the assumption of safety Oestradiol levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
11. Safety profile with regard to the risk of OHSS: assessment of change in Progesteron [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
    A blood sample will be taken to evaluate Progesteron (mcg/L). In the assumption of safety Progesteron levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
12. Safety profile with regard to the risk of OHSS: assessment of change in Follicle Stimulating Hormone (FSH) [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
    A blood sample will be taken to evaluate FSH (IU/L). In the assumption of safety FSH levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.
13. Safety profile with regard to the risk of OHSS: assessment of change in Luteinizing Hormone (LH) [ Time Frame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7) ]
    A blood sample will be taken to evaluate LH (IU/L). In the assumption of safety LH levels should be similar to that in the control group and there should be no events of ovarian hyperstimulation syndrome.

Secondary Outcome Measures :

1. Number of cumulus-oocyte complexes [ Time Frame: During the procedure of the transvaginal oocyte retrieval ]
   Evaluation of the number of cumulus-oocyte complexes between the Depot Group and Daily Group
2. Number of Metaphase II oocytes [ Time Frame: Immediately after the procedure of the transvaginal oocyte retrieval ]
   Evaluation of the number of Metaphase II oocytes between the Depot group and Daily group
3. Evaluation of climacteric symptoms [ Time Frame: One week after the transvaginal oocyte retrieval (on day 7) ]
   Assessment of MENQOL (The Menopause-Specific Quality of Life) Questionnaire

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age <36y
• BMI ≥ 18 and ≤ 35 kg/m²
• Early stage breast cancer
• Any hormone receptor status
• Any HER status
• Cryopreservation of oocytes and/or embryos
• Oncologist's approval to participate to the DEPO-trigger trial
• Signed informed consent form

Exclusion Criteria:

• Contra-indications for controlled ovarian stimulation or oocyte retrieval
• Necessity of neo-adjuvant chemotherapy

Contacts and Locations

Contacts

Contact: Sien Delattre, MD; 0473272422 ext 0032; sien.delattre@uzbrussel.be

Contact: Elsie Nulens; 024776648 ext 0032; Elsie.Nulens@uzbrussel.be

Locations

Belgium

Universitaire Ziekenhuizen Leuven

Leuven, Vlaams-Brabant, Belgium, 3000

Contact: Sharon Lie Fong, MD PhD 016343650 ext 0032

Universitair Ziekenhuis Brussel

Brussels, Belgium, 1090

Sponsors and Collaborators

Universitair Ziekenhuis Brussel

Universitaire Ziekenhuizen Leuven

Investigators

• Principal Investigator: Michel De Vos, MD PhD; Universitair Ziekenhuis Brussel

More Information

Publications:

Lambertini M, Cinquini M, Moschetti I, Peccatori FA, Anserini P, Valenzano Menada M, Tomirotti M, Del Mastro L. Temporary ovarian suppression during chemotherapy to preserve ovarian function and fertility in breast cancer patients: A GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology. Eur J Cancer. 2017 Jan;71:25-33. doi: 10.1016/j.ejca.2016.10.034. Epub 2016 Dec 9. Review.

Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient-Level Data. J Clin Oncol. 2018 Jul 1;36(19):1981-1990. doi: 10.1200/JCO.2018.78.0858. Epub 2018 May 2.

• Responsible Party: Universitair Ziekenhuis Brussel
• ClinicalTrials.gov Identifier: NCT04616729
• Other Study ID Numbers: 2019DEPO-TRIGGER001
• First Posted: November 5, 2020
• Last Update Posted: November 5, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: As this is a multicenter study, we plan to share IPD between the study sites. An electronically case report form (eCRF) will be set up and completed in all sites. Data will be handled in accordance with the general data protection regulation (GDPR).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: The data will become available over the course of the study until 6 months after ending this study. This will give us the time to analyse the data of the different sites.
• Access Criteria: eCRF

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Universitair Ziekenhuis Brussel:

Fertility preservation; Reproductive Techniques, assisted; Ovulation Induction; Oocyte Retrieval; Cryopreservation

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Triptorelin Pamoate; Luteolytic Agents; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Antineoplastic Agents, Hormonal; Antineoplastic Agents