Clinical trial NCT04616729: DEPO-Trigger Trial: GnRH Agonist DEPOt TRIGGER for Final Oocyte Maturation
Official title: DEPO-Trigger Trial: GnRH Agonist DEPOt TRIGGER for Final Oocyte Maturation in Breast Cancer Patients Undergoing Fertility Preservation: a Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Breast Cancer Female
Keywords: Fertility preservation
Reproductive Techniques, assisted
Ovulation Induction
Oocyte Retrieval
Cryopreservation
Lead sponsor: Universitair Ziekenhuis Brussel
Sponsor class: OTHER
Collaborators: name: Universitaire Ziekenhuizen KU Leuven
First posted: 2020-11-05
Enrollment: 30
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Safety profile with regard to the risk of OHSS: assessment of change in ovarian volume
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in hematocrit
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in hemoglobine
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in White Blood cell Count
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Platelet Count
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in estimated glomerular filtration rate (eGFR)
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Creatinine
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Albumin
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in liver function (AST, ALT, Gamma-GT, bilirubine, LDH)
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Oestradiol (E2)
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Progesteron
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Follicle Stimulating Hormone (FSH)
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
measure: Safety profile with regard to the risk of OHSS: assessment of change in Luteinizing Hormone (LH)
timeFrame: During one week after the transvaginal oocyte retrieval (on day 3, 5 and 7)
Secondary outcomes:
measure: Number of cumulus-oocyte complexes
timeFrame: During the procedure of the transvaginal oocyte retrieval
measure: Number of Metaphase II oocytes
timeFrame: Immediately after the procedure of the transvaginal oocyte retrieval
measure: Evaluation of climacteric symptoms
timeFrame: One week after the transvaginal oocyte retrieval (on day 7)
Other outcomes:
Locations:
city: Boortmeerbeek
country: Belgium
facility: Universitair Ziekenhuis Brussel
state: Brussels
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
state: Vlaams-Brabant
Study officials:
affiliation: Universitair Ziekenhuis Brussel
name: Michel De Vos, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.