Use of GnRHa During Chemotherapy for Fertility Protection (ProFertil)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Soft Tissue Sarcoma; Lymphoma; Osteosarcoma; Ewing Sarcoma; Acute Leukemia; Breast Cancer Female
• Intervention / Treatment: Drug: Triptorelin Embonate; Drug: Sodium Chloride solution 0.9%

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kenny Rodriguez Wallberg, MD, PhD; Phone Number: +46 858580000; Email: kenny.rodriguez-wallberg@ki.se
• Study Contact Backup: Name: Hanna Nilsson, PhD; Email: hanna.nilsson@ki.se

Study Locations

• Sweden
  • Göteborg, Sweden
    • Not yet recruiting
    • Center for Pediatric Cancer, Queen Silvia Hospital for Children and Youth
    • Contact: Karin Mellgren
  • Göteborg, Sweden
    • Not yet recruiting
    • Center for Pediatric Oncology, Akademiska Hospital
    • Contact: Per Frisk
  • Göteborg, Sweden
    • Not yet recruiting
    • Department of Oncology, Sahlgrenska University Hospital
    • Contact: Barbro Linderholm
  • Lund, Sweden
    • Not yet recruiting
    • Department of Hematology, Skåne University Hospital
    • Contact: Niklas Loman
  • Lund, Sweden
    • Not yet recruiting
    • Department of Oncology, Skåne University Hospital
    • Contact: Mats Jerkerman
  • Lund, Sweden
    • Not yet recruiting
    • Department of Pediatric Oncology, Skåne University Hospital
    • Contact: Helena Mörse
  • Stockholm, Sweden, 17176
    • Recruiting
    • Karolinska Univeristy Hospital, Breast Centre
    • Contact: Theo Foukakis, MD, PhD; Email: theo.foukakis@ki.se
  • Stockholm, Sweden
    • Not yet recruiting
    • Department of Hematology and Coagulation, Sahlgrenska University Hospital
    • Contact: Lovisa Vennström
  • Stockholm, Sweden
    • Not yet recruiting
    • Department of Hematology, Capio ST. Göran Hospital
    • Contact: Barbro Kedinge
  • Stockholm, Sweden
    • Not yet recruiting
    • Department of Internal Medicine, Södersjukhuset
    • Contact: Annelie Liljegren
  • Stockholm, Sweden
    • Not yet recruiting
    • Department of Oncology, Capio ST. Göran Hospital
    • Contact: Erika Isaksson Friman
  • Stockholm, Sweden
    • Not yet recruiting
    • Department of Oncology, Södersjukhuset
    • Contact: Christina Linder-Stragliotto
  • Stockholm, Sweden
    • Recruiting
    • Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet
    • Contact: Per Ljungman
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital, Hematology
    • Contact: Sara Harrysson, MD, PhD; Email: sara.harrysson@regionstockholm.se
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital, High Specialised Pediatric Medicine
    • Contact: Johan Malmros, MD, PhD; Email: johan.malmros@ki.se
  • Umeå, Sweden
    • Not yet recruiting
    • Department of Oncology, Norrlands University Hospital
    • Contact: Anne Andersson
  • Örebro, Sweden
    • Active, not recruiting
    • Department of Oncology, Örebro University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 42 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Triptorelin; 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; 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.; Other Names: Pamorelin
Placebo Comparator: Arm B: Placebo; 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%; One injection compensating for 3 months' effect OR one injection compensating for 1 month' effect to maintain the study blind.; Other Names: Placebo

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Kenny Rodriguez-Wallberg

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2023
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 31, 2032

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: April 6, 2022
• First Posted (Actual): April 14, 2022

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Fertility protection of young women receiving chemotherapy
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Sarcoma, Ewing; Osteosarcoma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Luteolytic Agents; Triptorelin Pamoate
• Other Study ID Numbers: ProFertil

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

The identity of the individual participants is protected by GDPR through the The Swedish Authority for Privacy Protection as regulated by the informed consent and any data sharing must be in accordance with their regulations. We can thus only share IPD that underlie the results reported in this study (text, tables, figures, and appendices), after full anonymization of the data.

After completion of the study the protocol, informed consent form and statistical analysis plan will be available.

Requests for additional analyses or to access the anonymized datasets should be directed to kenny.rodriguez-wallberg@ki.se. Information will be available upon reasonable request to the sponsor and if in correspondence with the proposed research in the signed informed consent e.g to achieve aims in the approved proposal.

Drug and device information, study documents

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