TRIal evalUating the Menstrual and Ovarian Function of Young Breast Cancer Patients Treated With a cycloPHosphamide-free Regimen

Study Overview
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Brief Summary
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Recently, there has been a rising trend of delaying childbearing and hence more women are diagnosed with breast cancer before completing their families. Given the continuous decline in recurrences and death secondary to breast cancer and the reassuring data on the safety of pregnancy following breast cancer more women are inquiring into the possibility of preserving fertility following chemotherapy. The challenge remains in using a regimen that is devoid of cyclophosphamide, but is as effective as the standard regimens that incorporate cyclophosphamide. The combination doxorubicin (50 mg/m2) and paclitaxel (200 mg/m2) (AP) followed by 12 weeks of paclitaxel (80 mg/m2) (P) emerges as a treatment option with convincing results regarding its effectiveness in the early setting, and could be potentially associated with less ovarian toxicity being devoid of cyclophosphamide.

Official Title
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A Phase II TRIal evalUating the Menstrual and Ovarian Function of Young Breast Cancer Patients Treated With a cycloPHosphamide-free Regimen Composed of Doxorubicin and Paclitaxel

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Doxorubicin
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≤ 40 years. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Non-metastatic primary invasive carcinoma of the breast eligible for adjuvant or neoadjuvant chemotherapy. Negative estrogen (ER) and progesterone receptor (PgR) status. Baseline left ventricular ejection fraction (LVEF) ≥50% measured by an echocardiogram or MUGA. Interested in maintaining menstrual and/or ovarian function following completion of chemotherapy. Known HER2/neu status. Negative pregnancy test within 14 days prior to starting chemotherapy. Adequate hematologic, hepatic and renal function. Signed informed consent. Exclusion Criteria: History of prior malignant disease (breast or non-breast) or non-malignant condition which was treated with chemotherapy, pelvic irradiation or any therapy that could potentially affect ovarian function. Previous history of amenorrhea > 3 months within the last 2 years (excluding pregnancy). Ovarian insufficiency defined as serum FSH > 20 IU/L at the local laboratory, anytime during the menstrual cycle. Any ovarian pathology or abnormalities at the screening pelvic ultrasound, except for functional follicular cysts. Pregnant or breastfeeding patients. Inability or unwillingness to use effective contraception during and up to 3 months after the last dose of study medication. Effective methods include the following: non-hormonal intrauterine device, barrier method - condoms, diaphragm - also in conjugation with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed. Concurrent use of any other cytotoxic or hormonal agent, namely GnRH agonists. Prior pre-existing peripheral neuropathy of any cause, including diabetes mellitus, alcohol abuse, HIV infection, autoimmune and hereditary neuropathies, amyloidosis, hypothyroidism, vitamin deficiencies. Serious cardiac illness, uncontrolled hypertension or medical condition that would affect administration of chemotherapy and compliance to study procedures. Known sensitivity to any of the study medications.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: doxorubicin and paclitaxel<br>All patients will receive four cycles of doxorubicin (A) (50 mg/m2) and paclitaxel (P) (200 mg/m2), given on a three-weekly basis for four cycles, followed by weekly paclitaxel (P) (80 mg/m2) for twelve weeks. | Drug: Doxorubicin<br>* All patients will receive four cycles of doxorubicin (A) (50 mg/m2)<br>Drug: paclitaxel<br>* All patients will receive four cycles paclitaxel (P) (200 mg/m2), given on a three-weekly basis for four cycles, followed by weekly paclitaxel (P) (80 mg/m2) for twelve weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in ovarian function | Ovarian function will be evaluated using serum FSH, estradiol and AMH. Ovarian failure is defined as serum FSH >40 IU/L. Ovarian insufficiency is defined as serum FSH level from 20 - 40 IU/L. Ovarian reserve will be evaluated by serum AMH. Adequate ovarian reserve is defined as serum AMH >1 ng/ml. Menstrual function will be evaluated by collecting information of the 1st day of last menstrual cycle, and cycle length (days between two menstruating periods). Ovarian function will be evaluated using serum FSH, estradiol and AMH. Ovarian failure is defined as serum FSH >40 IU/L. Ovarian insufficiency is defined as serum FSH level from 20 - 40 IU/L. Ovarian reserve will be evaluated by serum AMH. Adequate ovarian reserve is defined as serum AMH >1 ng/ml. | At screening, after 4 cycles of chemotherapy, at the end of chemotherapy, at 6, 12, 18 and 24 months following chemotherapy | 
| Change from baseline in menstrual function | Menstrual function will be evaluated by collecting information of the 1st day of last menstrual cycle, and cycle length (days between two menstruating periods). In patients menstruating regularly after 12 months of chemotherapy cessation, information on menstrual cycle will be collected at 6-monthly intervals until developing menopause, disease recurrence, becoming pregnant, whichever occurs earlier, for a maximum period of 5 years after end of chemotherapy. | At screening, after 4 cycles of chemotherapy, at the end of chemotherapy, at 6, 12, 18 and 24 months following chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ovarian reserve | A serum AMH determination will be performed at 12 months after the end of chemotherapy. An adequate ovarian reserve is defined as serum AMH >1 ng/ml at that timepoint. | At 12 months following the end of chemotherapy. | 
| Occurence of Adverse Events | This study will use the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, for adverse event reporting. | From the signature of informed consent until until the end of study treatment/treatment discontinuation visit 30 days after the last dose of study medication | 
| Impact of treatment on the behavior of menstruation after menses resumption | In patients menstruating regularly after 12 months of chemotherapy cessation, information on menstrual cycles will be collected at 18, 24 and up to 60 months after end of chemotherapy, until developing menopause, disease recurrence or becoming pregnant, whichever occurs earlier. This information will include the date of last menstrual period, menstruation duration and if 2 or more consecutive menstrual cycles were missed, allowing to assess irregularity and possible cessation of menses. | At 18, 24 and 60 months after end of chemotherapy. | 
| Evaluate the impact of a cyclophosphamide-free regimen on sexual function | Patient will complete two validated health-related quality of life questionnaires, one on menopausal symptoms (FACT-ES version 4) and the other on sexual functioning (FSAQ). | At baseline, after 4 cycles, end of chemotherapy, 6, 12 and 24 months following the end of chemotherapy. | 
| Evaluate the impact of the regimen on peripheral neurotoxicity | Patient will complete one validated health-related quality of life questionnaire on peripheral neurotoxicity (FACT-Taxane version 4). | At baseline, after 4 cycles, end of chemotherapy, 6, 12 and 24 months following the end of chemotherapy. | 
| Pregnancy rate after cessation of chemotherapy | Number of pregnancies among participants. | From end of chemotherapy up until 60 months after. | 
| Event-free survival | Event-free survival will be calculated from the date of registration to the study to developing local, loco-regional or distant metastasis, secondary malignancies or death. All patients will be considered for the primary efficacy analysis (ITT analysis). | From the date of registration up until 60 months after the end of chemotherapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary breast cancer, Young women, Ovarian function, Sexual function, Eligible for adjuvant or neoadjuvant chemotherapy, Negative hormone-receptor status