Use of GnRHa During Chemotherapy for Fertility Protection

Official title

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

Overview

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.

Interventions

• Drug Triptorelin Embonate
  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.
• Drug Sodium Chloride solution 0.9%
  One injection compensating for 3 months' effect OR one injection compensating for 1 month' effect to maintain the study blind.

Primary outcome measures

• Anti-Müllerian Hormone (AMH) levels in women with breast cancer [Time frame: 12 months after end of gonadotoxic chemotherapy and study drug treatment]

Secondary outcome measures (12)

• Anti-Müllerian Hormone (AMH) levels in women with acute leukemias, lymphomas and sarcomas. [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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.]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Sweden · 17 centers

• Center for Pediatric Cancer, Queen Silvia Hospital for Children and Youth — Gothenburg
• Center for Pediatric Oncology, Akademiska Hospital — Gothenburg
• Department of Oncology, Sahlgrenska University Hospital — Gothenburg
• Department of Hematology, Skåne University Hospital — Lund
• Department of Oncology, Skåne University Hospital — Lund
• Department of Pediatric Oncology, Skåne University Hospital — Lund
• Department of Oncology, Örebro University Hospital — Örebro
• Karolinska Univeristy Hospital, Breast Centre — Stockholm
• … and 9 more centers

Publications

• Rodriguez-Wallberg KA, Nilsson HP, Bergh J, Malmros J, Ljungman P, Foukakis T, Stragliotto CL, Friman EI, Linderholm B, Valachis A, Andersson A, Harrysson S, Vennstrom L, Frisk P, Morse H, Eloranta S. ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden PMID 38070906

Identifiers

NCT: NCT05328258 · ProFertil

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗