Evaluation of Triptorelin for Ovarian Reserve Preservation in Young Females Undergoing Chemotherapy for Breast Cancer, Leukemia, Lymphomas, and Sarcomas

The primary objective of this study is to estimate the changes in **ovarian reserve** following chemotherapy for the treatment of cancer, with or without the use of Gonadotropin-Releasing Hormone agonists (**GnRHa**), by determining the levels of Anti-Müllerian Hormone (**AMH**) at 12 months after the end of gonadotoxic treatment in women with breast cancer. This is clinically relevant as it aims to assess the potential protective effects of GnRHa on ovarian function, which is crucial for fertility preservation in young women undergoing chemotherapy.

Secondary objectives include:

• Estimating changes in ovarian reserve following chemotherapy in women with acute leukemias, lymphomas, and sarcomas by determining AMH levels at 12 months after treatment.
• Assessing changes in ovarian reserve by determining antral follicle counts (**AFC**) in women with breast cancer, acute leukemias, lymphomas, and sarcomas, with or without GnRHa.
• Longitudinal observation of AMH levels in women with breast cancer and other cancers to estimate changes in ovarian reserve.
• Comparing the proportion of females developing ovarian insufficiency by measuring follicle-stimulating hormone (**FSH**), inhibin, and estradiol at standardized timepoints.
• Investigating the impact of body mass index (**BMI**), contraceptive use, and endocrine adjuvant therapy on ovarian reserve changes.
• Exploring the effect of GnRHa on ovarian blood supply.
• Estimating the proportion of females developing amenorrhea.
• Investigating fertility and childbirth outcomes post-cancer treatment in women attempting pregnancy.
• Determining health-related quality of life (**QoL**) during and after chemotherapy.
• Studying the development of co-morbidities and bone mineral density post-treatment.
• Estimating disease-specific oncologic outcomes, recurrence rate, overall survival, and disease-free survival.

The clinical trial involves a study population of **female** subjects aged 14 to 42 years, diagnosed with **breast cancer**, acute leukemias, lymphomas (Hodgkin and non-Hodgkin), or sarcomas (osteosarcoma, soft tissue, and Ewing sarcoma). Participants are required to have confirmed menarche and an ECOG performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on the confirmation of these conditions by histology and their assignment for disease-specific chemotherapy. Participants must have adequate bone marrow, renal, hepatic, and cardiac functions, and should not have any uncontrolled medical or psychiatric disorders. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial aims to estimate changes in ovarian reserve following chemotherapy, with or without GnRHa, by measuring the Anti-Müllerian Hormone (AMH) levels 12 months after the end of gonadotoxic treatment.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the use of GnRHa during chemotherapy for fertility protection in young women and teenagers diagnosed with **breast cancer**, acute leukemia, lymphomas (Hodgkin and non-Hodgkin), and sarcomas (osteosarcoma, soft tissue sarcoma, and Ewing sarcoma). The primary objective is to assess changes in ovarian reserve by measuring the Anti-Müllerian Hormone (AMH) levels 12 months after the end of gonadotoxic treatment (EOT) in women with breast cancer. The trial is expected to run from October 2022 to October 2030, with participant involvement lasting up to 12 months post-EOT, followed by additional follow-up visits.

Participants will be randomly assigned to receive either the active treatment, **triptorelin**, or a placebo, both administered as a prolonged-release suspension for injection via the intramuscular route. The study will include several key visits: an initial screening visit to confirm eligibility, baseline assessments, and subsequent follow-up visits at 6 and 12 months after EOT. Continuous follow-up will occur during years 2, 3, 4, and 5 post-EOT to monitor long-term outcomes. The end-of-study visit will conclude the participant's involvement, barring any conditions that necessitate early termination, such as adverse events or withdrawal of consent.

Inclusion criteria require participants to be female, aged 14-42 years at cancer diagnosis, with confirmed menarche and an ECOG performance status of 0-1. Adequate bone marrow, renal, hepatic, and cardiac functions are necessary, along with the absence of uncontrolled medical or psychiatric disorders. The primary endpoint is the difference in AMH recovery at 12 months post-EOT between the GnRHa and placebo groups in women with breast cancer. Secondary endpoints include similar comparisons in women with other cancers, assessments of antral follicle count (AFC), hormone levels, ovarian blood flow, amenorrhea incidence, and health-related quality of life (QoL).

The clinical trial involves the administration of **Pamorelin**, a **prolonged-release suspension for injection** containing the active substance **triptorelin**. This medication is provided in two dosages: 3.75 mg and 11.25 mg. The pharmaceutical form is a powder and liquid for injection, depot suspension. The route of administration is **intramuscular use**. The maximum daily dose for the 3.75 mg formulation is 3.75 mg, and for the 11.25 mg formulation, it is 11.25 mg. The maximum treatment period for both dosages is 12 months. The medication is of chemical origin and is manufactured by Institut Produits Synthèse (IPSEN) AB. The administration schedule and participant compliance are monitored according to the study protocol.

The trial also includes a **placebo** control, which is a 0.9% **sodium chloride solution** containing 9 mg/ml sodium chloride in water for injection. The placebo syringes are covered with aluminum foil by an unblinded research nurse to maintain the study blind. The placebo is administered in the same manner as the experimental medication to ensure consistency in the study's methodology. The placebo serves as a comparator treatment to evaluate the efficacy of the experimental medication in preserving ovarian reserve during chemotherapy in young women and teenagers with cancer.

Efficacy in this clinical trial will be assessed by evaluating the changes in ovarian reserve following chemotherapy for cancer treatment, with or without the use of **GnRHa**. The primary endpoint is the difference in recovery of Anti-Müllerian Hormone (AMH) levels at 12 months after the end of gonadotoxic treatment (EoT), compared between the GnRHa group and the placebo group in women with breast cancer. Secondary endpoints include the difference in recovery of AMH levels at various timepoints, such as 6 months and follow-up years 2, 3, 4, and 5 after EoT, in women with breast cancer and those with acute leukemias, lymphomas, and sarcomas.

Additional secondary endpoints involve the comparison of Antral Follicle Count (AFC) measured by ultrasound at EoT, 6, and 12 months after EoT, and continuously during follow-up years 2, 3, 4, and 5. Other parameters include the comparison of Follicle-Stimulating Hormone (FSH), inhibin, and estradiol levels, as well as blood flow to the ovarian artery, amenorrhea development, and health-related quality of life (QoL). These assessments will be conducted at baseline, EoT, 6, and 12 months after EoT, and continuously during follow-up years 2, 3, 4, and 5. The impact of body mass index (BMI), contraceptive use, and endocrine adjuvant therapy on ovarian reserve changes will also be investigated through longitudinal observation of AMH, FSH, inhibin, and estradiol levels at standardized timepoints.

Furthermore, the trial will compare pregnancy wish, attempts, and outcomes, as well as bone mineral density at baseline, EoT, 12 months after EoT, and follow-up year 5. Recurrence rate, overall survival, and disease-free survival will be evaluated at 12 months after EoT and during follow-up years 2, 3, 4, and 5. These efficacy parameters will be measured and analyzed using validated scales and laboratory tests, ensuring a comprehensive assessment of the trial's objectives.