Use of GnRHa During Chemotherapy for Fertility Protection

Study Overview
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Brief Summary
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Many cytotoxic drugs may harm the fertility of young women treated for cancer. The aim of the study is to investigate if the Gonadotropin-Releasing Hormone agonist (GnRHa) during cancer treatment can preserve the fertility of young female cancer subjects. Approximately 300 women with newly diagnosed breast cancer and up to 200 women with newly diagnosed lymphoma, acute leukemias or sarcomas will be recruited before start of cancer treatment. The patients will be randomised in between treatment with triptorelin (experimental) or placebo (control) intramuscularly a 1:1 ratio during chemotherapy. The injections may be given once monthly or once three months depending on type of chemotherapy given. Randomisation and study drug is blinded, neither investigator, research nurse nor patient will know if it is active drug or placebo. The only person who knows is the nurse preparing the injection. Patients will be followed up to 5 years after end of treatment with physical examinations, vital signs, biochemical markers, bone mineral density exams, ultrasound for antral follicle counts and ovarian doppler flow, concomitant medications, adverse events and quality of life questionnaires.

Official Title
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A Phase 3 Randomised Double-Blinded Placebo-Controlled Study of Use of GnRHa During Chemotherapy for Fertility Protection of Young Women and Teenagers With Cancer

Conditions
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Breast Cancer Female, Acute Leukemia, Lymphoma, Osteosarcoma, Soft Tissue Sarcoma, Ewing Sarcoma

Intervention / Treatment
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* Drug: Triptorelin Embonate
* Drug: Sodium Chloride solution 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Breast cancer or acute leukemias, lymphomas (Hodgkin and non-Hodgkin) or sarcomas (osteo, soft tissue and Ewing) confirmed by histology and assigned for diseace-specific chemotheraphy Confirmed menarche ECOG performance status 0-1 Adequate bone marrow, renal, hepatic and cardiac functions and absence of other uncontrolled medical or psychiatric disorders Exclusion Criteria: Demonstrated premature ovarian failure at time of randomization according to clinical or biochemical data Previous or planned bilateral oophorectomy Pregnancy or breastfeeding at time of start of chemotherapy Other malignancy diagnosed within the last five years Uncontrolled hypertension, heart, liver, kidney related or other uncontrolled medical or psychiatric disorders including previous or current diagnosis of anorexia Known osteoporosis Known low platelet count with increased bleeding risk or refractory thrombocytopenia in subjects with acute leukemias Known or suspected allergy against triptorelin Direct radiation of the gonads previous or planned (TBI allowed) Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomised, double-blinded, placebo-controlled, phase 3 study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Triptorelin<br>Triptorelin given intramuscularly once every month or every third month during gonadotoxic chemotherapy treatment. The dose is ether 11.25 mg triptorelin given for subjects having at least 3 months gonadotoxic treatment, OR 3.75 mg for subjects during one-month of gonadotoxic treatment | Drug: Triptorelin Embonate<br>* 11.25 mg will be given for subjects having at least 3 months gonadotoxic treatment, one injection of 11.25 mg will compensate for 3 months' effect of the study drug. 3.75 mg will be given for subjects during one-month of gonadotoxic treatment, one injection of 3.75 mg will compensate for 1 month' effect of the study drug.<br>* Other names: Pamorelin;|
| Placebo Comparator: Arm B: Placebo<br>Placebo, 0.9% sodium chloride, given intramuscularly once every month or every third month during gonadotoxic chemotherapy treatment. The dose will be provided both as one injection compensating for 3 months' effect and one injection compensating for 1 month' effect to maintain the study blind. | Drug: Sodium Chloride solution 0.9%<br>* One injection compensating for 3 months' effect OR one injection compensating for 1 month' effect to maintain the study blind.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Müllerian Hormone (AMH) levels in women with breast cancer | To estimate the changes in ovarian reserve following chemotherapy for treatment of cancer with or without GnRHa by determination of the AMH relative to AMH levels at EoT in women with breast cancer. | 12 months after end of gonadotoxic chemotherapy and study drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Müllerian Hormone (AMH) levels in women with acute leukemias, lymphomas and sarcomas. | To estimate the changes in ovarian reserve following chemotherapy for treatment of cancer with or without GnRHa by determination of the AMH relative to AMH levels at EoT in women with acute leukemias, lymphomas and sarcomas. | 12 months after end of gonadotoxic chemotherapy and study drug treatment | 
| Changes in ovarian reserve with or without Gonadotropin-Releasing Hormone agonist (GnRHa) by determination of the antral follicle counts (AFC) | Changes in AFC in women with breast cancer and with acute leukemia, lymphoma and sarcoma respectively | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months) and at 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT | 
| Changes in ovarian reserve with or without GnRHa by longitudinal observation of AMH levels | The difference in recovery of AMH levels between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively | At 6 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| The proportion of females with or without GnRHa that develop ovarian insufficiency by determination of follicle stimulating hormone (FSH), inhibin and estradiol | Comparison of FSH, inhibin and estradiol between the GnRHa group and the placebo group | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Impact of body mass index (BMI) (Kg/m2) on changes in ovarian reserve with or without GnRHa | longitudinal observation of AMH levels, FSH, inhibin and estradiol | At Baseline, during treatment, at end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Impact of use of contraceptives (yes/no) in changes of ovarian reserve with or without GnRHa | longitudinal observation of AMH levels, FSH, inhibin and estradiol | At Baseline, during treatment visits (every 1-3 months of gonadotoxic treatment), at end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Impact of endocrine adjuvant therapy (yes/no) in changes of ovarian reserve with or without GnRHa | longitudinal observation of AMH levels, FSH, inhibin and estradiol | At Baseline, during treatment visits (every 1-3 months of gonadotoxic treatment), at end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| The effect of GnRHa with or without GnRHa on ovarian blood supply | Comparison of blood flow to the ovarian artery (right and left Doppler flow) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| The proportion of females with or without GnRHa that develop amenorrhea (no menstruations) | Comparison of the proportion that develop amenorrhea (no menstruations) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Pregnacy wish after cancer treatment in women with or without GnRHa who attempt pregnancy during follow-up | Comparison of of pregnancy wish (Study specific questionaire) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Fertility and childbirth after cancer treatment in women with or without GnRHa who attempt pregnancy during follow-up | Comparison of pregnancy attempts (Study specific questionaire) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At end of chemotherapy (corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Fertility and childbirth after cancer treatment in women with or without GnRHa who attempt pregnancy during follow-up | Comparison of pregnancy outcome between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Health-related quality of life (EORTC QLQ C30) | Comparison of validated outcome on health-related QoL (EORTC QLQ C30) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Health-related quality of life (FSFI) | Comparison of validated outcome of sexuality and reproductive health (Female Sexual Function Index (FSFI)) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Health-related quality of life (HAD) | Comparison of validated outcome on health-related QoL (Hospital Anxiety and Depression Scale (HAD)) between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months), and 6 months, 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| The development of co-morbidities during follow-up and bone mineral density | Comparison of bone mineral density between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At baseline, at end of gonadotoxic chemotherapy (EoT; corresponding to Baseline+2-11 months) and 12 months and 5 years after EoT | 
| Disease-specific oncologic outcomes: disease-free survival | Investigation of disease-free survival between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Disease-specific oncologic outcomes: Recurrence rate | Investigation of recurrence rate between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 
| Disease-specific oncologic outcomes: overall survival | Investigation of overall survival between the GnRHa group and the placebo group in women with breast cancer and in women with acute leukemia, lymphoma and sarcoma respectively. | At 12 months, 2 years, 3 years, 4 years and 5 years after EoT. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fertility protection of young women receiving chemotherapy