Efficacy and Tolerance of an Ovarian Stimulation Protocol Combining Follicle Stimulating Hormone (FSH) and Degarelix Acetate in Female Candidates for Fertility Preservation Before Chemotherapy for Breast Cancer (DEGASTIM)

Efficacy and Tolerance of an Ovarian Stimulation Protocol Combining FSH and Degarelix Acetate in Female Candidates for Fertility Preservation Before Chemotherapy for Breast Cancer

The present investigation aims to evaluate the efficacy of an innovative protocol of controlled ovarian stimulation for breast cancer patients, who are candidates for fertility preservation.

Currently, vitrification of oocytes and/or embryos after controlled ovarian stimulation is the most established method for female fertility preservation. However, this stimulation induces an increase in serum estrogen levels, which is theoretically problematic in case of hormone-sensitive tumors such as breast cancer. The majority of oncology teams accept, in very specific situations (particularly when the tumor has been surgically removed), this ovarian stimulation, because the expected benefits of fertility preservation far outweigh the risks. However, everyone agrees that it would be more comfortable to be able to offer vitrification of oocytes and/or embryos using ovarian stimulation without increasing estrogen levels.

In this research, investigators will evaluate the efficacy of degarelix (Firmagon®), currently indicated for the treatment of prostate cancer, as an innovative ovarian stimulation procedure. Administered at the beginning of ovarian stimulation, they believe it should maintain serum estradiol levels at physiological values at the end of stimulation.

Study Overview

• Status: Completed
• Conditions: Invasive Ductal Breast Carcinoma
• Intervention / Treatment: Drug: Degarelix injection(s)

Detailed Description

Recent improvements in freezing techniques have led to the development of fertility preservation techniques for young women diagnosed with cancer. Currently, vitrification of oocytes or embryos after controlled ovarian stimulation (COS) represents the only established method. This COS is based on the daily administration of exogenous Follicle Stimulating Hormone (FSH) and an ovulation blockage using Gonadotropin Releasing Hormone (GnRH) antagonists (0.25 mg/d) initiated after approximately 6 days of stimulation and continued until ovulation is triggered.

In addition to requiring 15 days, COS induces supraphysiological hyperestradiolaemia (5-10 times normal) which can be problematic in case of hormone-sensitive tumors such as breast cancer. The majority of oncology teams accept, in very specific situations (particularly when the tumor has been surgically removed), this ovarian stimulation, because the expected benefits of fertility preservation far outweigh the risks. However, everyone agrees that it would be more comfortable to be able to offer vitrification of oocytes and/or embryos using ovarian stimulation without increasing estrogen levels.

Therefore, the limitation of serum estradiol concentrations during stimulation represents an important issue. To this end, stimulation protocols combining aromatase inhibitors have been proposed. Inhibition of the P450 aromatase enzyme in the granulosa cells of stimulated follicles prevents the conversion of androgens to estrogens. However, the teratogenic risk of these molecules, although discussed, limits their use in the indication of COS. Recently, a new "natos" protocol was proposed to stimulate the ovaries while maintaining physiological estradiolaemia, without using aromatase inhibitors. Thus, the administration of high doses of Gonadotropin Releasing Hormone (GnRH) antagonists (3 to 6 injections of 0.25 mg/day) from the beginning of COS, would allow a strong Luteinizing Hormone (LH) deprivation, thus limiting the production of androgens according to the 2 cells - 2 gonadotropins theory. In the absence of a precursor, estradiolemia remains at physiological ranges during the total duration of COS. However, the relative heaviness of a protocol combining up to 8 daily injections limits its use in young women who are candidates for fertility preservation.

Investigators therefore propose to evaluate the efficacy and tolerance of a new natos-like COS protocol based on the administration of a long-acting GnRH antagonist, degarelix. This drug is currently off-label for women.

The expected duration of the research is 14 months and participation will be 2 months.

After signature of the consent, during the first visit (oncofertility counseling), the the research (consultations and examinations) will be carried out within the Antoine Béclère hospital. All visits and examinations performed are part of routine care, except for the injection(s) of degarelix which belongs to the research.

Inclusion visit During the oncofertility consultation, the physician will make sure that the patient can be included in the research. Once the consent has been signed, the doctor will schedule the following visits based on the biological results obtained as part of the usual care.

Research follow-up visits

Stimulation: between the day of oncofertility counseling and the following 7 days, the doctor will check that patients are in the early follicular phase of the cycle, Degarelix injection: 1 injection, under the skin (possibly renewable after 5-7 days if the serum LH is ≥2 IU / L and / or the estradiol is ≥400 pg / mL), Concomitant initiation of ovarian stimulation by administration of recombinant FSH - Follitropin alfa (usual care). The injections will be given by the patient or a nurse at home, between 7pm and 10pm.

Stimulation follow-up visit #1 :

After 5 days of ovarian stimulation, transvaginal pelvic ultrasound (counting of ovarian follicles and measurement of their diameters) and blood sampling for serum hormone assays (estradiol, LH, progesterone) will be performed as part of the usual care.

Stimulation follow-up visits #2 and #3 Visits #2 and #3: transvaginal pelvic ultrasound (counting of ovarian follicles and measurement of their diameters) and a blood test for serum hormone assays (estradiol, LH, progesterone) will be required to monitor the response to stimulation, as part of routine care.

Visits are repeated until 4 follicles 16 to 20 mm in diameter are obtained, which is the criterion for ovulation trigger using 1 injection of Human Chorionic Gonadotropin (hCG) (Ovitrelle 250 mcg, SC) (usual care). Thus visits #2 and #3 are systematic. One or two additional visits with the same examinations may sometimes be necessary if the trigger criteria are not met.

Thirty-six hours after Human Chorionic Gonadotropin (hCG) , oocyte retrieval will be performed.

Visit on the day of the oocyte retrieval:

Patients will have a venous blood sample for serum hormone assays (estradiol, LH, progesterone) as part of the usual care.

Oocyte collection will be scheduled, and those which are mature will then be frozen (by vitrification) or fertilized in vitro in case of embryo freezing.

Visit following egg retrieval:

A blood test for serum hormone assays (estradiol, LH, progesterone) will be performed 3-4 days after oocyte retrieval.

End of research visit Participants will be contacted by phone 2 months after the injection of degarelix (Firmagon®) to make sure they are fine.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clamart, France, 92140
    • Hôpital Antoine Béclère

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients with invasive ductal carcinoma breast cancer, whatever the hormonal receptor expression profile
• Age : 18 - 40 years
• Presence of 2 ovaries
• Antral follicular count between 12 and 30 on both ovaries and/or recent measurement of serum anti-Müllerian hormone between 1.5 and 4 ng / mL (between Day-25 and Day0)
• Indication of chemotherapy
• Indication of preservation of fertility according to an oocyte vitrification technique after controlled ovarian stimulation (COS)
• Patient in the early follicular phase of the cycle at the start of the controlled ovarian stimulation (COS) (absence of follicle> 10 mm in ultrasound and estradiolemia <50 pg / mL)
• Oncology team agreement for the controlled ovarian stimulation (COS)
• Social insured patient
• Patient who gave her consent to participate by signing the consent of the study

Exclusion Criteria:

• Patient in late follicular phase or luteal phase
• Known hypersensitivity to one of the constituents of Firmagon®

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: one arm	Drug: Degarelix injection(s); 1 or 2 degarelix injection(s); Other Names: Firmagon®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of follicles 16 to 20 mm in diameter obtained with estradiolemia <500 pg /mL	Success of the procedure if at least 4 follicles 16 to 20 mm in diameter are obtained on the day of ovulation trigger (36 hours before oocyte collection) with estradiolemia <500 pg / mL	Day of ovulation trigger

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum estradiol levels		Day of ovulation trigger
Percentage of women with hyperestradiolemia	Percentage of women with hyperestradiolemia during controlled ovarian stimulation (COS)	from the beginning of the controlled ovarian stimulation until Month 2
Duration of the increase in serum estradiol levels		from the beginning of the controlled ovarian stimulation until Month 2
Number of oocytes collected	Outcome of ovarian stimulation evaluated by the number of oocytes collected, and the number of mature oocytes vitrified	through oocyte collection, an average of Day 20
Number of mature oocytes vitrified	Outcome of ovarian stimulation evaluated by the number of oocytes collected, and the number of mature oocytes vitrified	through oocyte collection, an average of Day 20
Nature of serious side effects	Description : Serious side effects associated with treatment with degarelix (MedDRA coding)	2 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Michaël GRYNBERG, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2019
• Primary Completion (Actual): March 31, 2022
• Study Completion (Actual): August 30, 2022

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: May 10, 2019
• First Posted (Actual): May 13, 2019

Study Record Updates

• Last Update Posted (Actual): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Fertility preservation; Controlled ovarian stimulation; GnRH antagonist protocol; Oocyte vitrification
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Neoplasms, Ductal, Lobular, and Medullary; Carcinoma, Ductal; Breast Neoplasms; Carcinoma, Ductal, Breast
• Other Study ID Numbers: P170407J; 2018-000049-38 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No