PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial
Condition: Fertility Preservation; Cancer
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to determine whether gonadotropin releasing hormone agonists
      (medical therapy) will protect against ovarian failure in reproductive aged women undergoing
      sterilizing chemotherapy.
    

Detailed description: 
      Fertility preservation is defined as the maintenance of one's ability to reproduce.

      The hypothesis for this study is that medical treatment (GnRHa) will help female cancer
      patients, receiving sterilizing chemotherapy, preserve their ovarian function and therefore
      fertility. This study is a feasibility trial of the drug (GnRHa)vs placebo in female cancer
      patients receiving gonadotoxic chemotherapy between the ages of 18 and 38 who wish to
      participate.

      The objective of the feasibility trial is to determine the feasibility of a definitive study
      to answer this question and also to define the required parameters needed to design the
      definitive study such as the observable difference in ovarian failure between the drug and
      placebo groups. The same protocol will be followed as proposed for the definitive trial but
      with a smaller sample size.

      This pilot study will be conducted at the Ottawa Hospital Regional Cancer Centre/Division of
      Reproductive Medicine of Department of Obstetrics and Gynecology, University of Ottawa and
      the Cancer Centre of Southeastern Ontario/Division of Reproductive Medicine of Department of
      Obstetrics and Gynecology, University of Ottawa.

      The planned trial intervention is trimonthly (every 3 months) administration of depot GnRHa
      (Leuprolide acetate (LA) 11.25 mg intramuscularly) or placebo. Injections would start prior
      to initiation of chemotherapy, in the luteal phase of the menstrual cycle preceding
      chemotherapy, and will continue until cessation of chemotherapy (maximum of 6 months or 2
      injections). Since only adjuvant/curative chemotherapy patients will be enrolled,
      chemotherapy will last a maximum of six months.

      Subjects will be randomized, with concealed allocation, to either GnRHa or placebo. Subjects
      and investigators will be blinded to the intervention administered.

      Inclusion criteria: Women who are

        1. between ages 18 to 38;

        2. who will be undergoing gonadotoxic (sterilizing) curative/ adjuvant chemotherapy for
           early stage disease; and

        3. have provided informed consent. All subjects will be enrolled from the Ottawa Hospital
           Regional Cancer Institute (OHRCC) and the Cancer Center of South Eastern Ontario at
           Kingston General Hospital (CCSEO). Gonadotoxic chemotherapy includes alkylating /
           anthracycline agents eg. cyclophosphamide.

      Exclusion criteria: Women who;

        1. have advanced stage disease and/or whose median survival is expected to be less than 6
           months

        2. have cancer of the ovaries, uterus, or fallopian tubes;

        3. have clinical or biochemical evidence of diminished ovarian reserve (recent shortening
           of cycles &lt; 24 days between menses, age &gt; 38, elevated serum FSH (follicular
           stimulating hormone)&gt; 15 IU/L, or low antral follicle count (AFC- number of follicles
           less than 10 mm on day 2 or 3 of natural menses) on baseline pelvic ultrasound (&lt;5)
           or elevated day 2 or 3 estradiol (&gt; 280 pmol/ml);

        4. have previously received chemotherapy or abdominal/pelvic radiation or have planned to
           receive abdomino/pelvic radiation;

        5. are pregnant;

        6. have contraindications to intramuscular injections; or 7) have a history of fractures
           secondary to/or documented osteoporosis.

      Outcomes: Subjects will be assessed at baseline, monthly (for adverse effects only) during
      active intervention, and at 0, 3, 6, 9, and 12 months post cessation of chemotherapy and
      treatment (GnRHa/ placebo) for predictors of ovarian reserve.

      The primary outcome is protection against ovarian failure at 12 months post chemotherapy.
      This is measured by resumption of regular menstrual cycles (every 24 -35 days) with
      documentation of ovulation by biochemistry (progesterone levels) over a minimum of three
      months.

      Secondary outcomes will include sonographic (biophysical) and biochemical markers of ovarian
      reserve.
    

Intervention name(s): Leuprolide acetate
Intervention type(s): Drug
Intervention MeSH terms: Leuprolide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Gonadotropin releasing hormone agonist; GnRH; Fertility; Fertility preservation; Oncology; Cancer; Chemotherapy