Breast Neoplasms
Conditions
Keywords
Aromatase Inhibitors
Brief summary
The purpose of this study is to examine how key patient factors, including body size affect how well letrozole suppresses circulating estrogen levels. This study has two components: (1) Part A - an observational phase to evaluate the impact of vitamin D and obesity on estrogen suppression in post-menopausal women already receiving letrozole treatment, and (2) Part B - an interventional phase for women with body mass index (BMI) \> 25 kg/m2 to assess the effect of double AI dose on estrogen levels. If BMI or other patient factors reduce the effectiveness of letrozole, modifications to treatment recommendations and studies to test higher dosing of letrozole may be needed to maximize the benefit of this treatment and minimize the risk of the breast cancer coming back.
Detailed description
The available evidence suggests that circulating estradiol levels play a critical role in determining effectiveness of aromatase inhibitor therapy, and that maximal suppression of aromatase activity and estrogen production is essential for optimal disease control. Host factors such as high 25-Hydroxy Vitamin D (25-OH D) levels and obesity, which might increase residual estrogen levels, could adversely impact outcome and lead to an increased risk of recurrence or death. The primary objective of Part A (which includes women regardless of BMI) is to directly evaluate the relationship between (i) 25-OH D levels and serum estrogen levels and (ii) BMI and serum estrogen levels in a cohort of postmenopausal women on standard dose letrozole therapy (2.5 mg/day). Part B (which includes only women with BMI \> 25 kg/m2) will determine whether an increased dose of letrozole (5 mg/day), which had no dose limiting side effects in a Phase I study improves suppression of estrogen in overweight/obese women.
Interventions
DRUGLetrozole
Part A Monitor standard of care letrozole use for 28 days; measure blood levels of estrogens and vitamin D at start and end of period. Part B In overweight/obese participants who completed Part A, provide a double dose of letrozole and monitor use for 28 days; measure blood levels of estrogens and vitamin D at start and end of period.
Sponsors
Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
* Postmenopausal female patients * histological confirmed diagnosis of estrogen receptor and/or progesterone receptor positive breast cancer (Stage I-III) who have completed local therapy * Currently prescribed and taking letrozole 2.5 mg daily for a minimum of 3 months * Willing to provide written informed consent to participate * for the experimental arm: all of the above and body mass index (BMI) \> 25 kg/m2
Exclusion criteria
* Known abnormal liver or renal function defined by: 1. Serum Creatinine \> 1.25 times institutional upper limit of normal (ULN) or Calculated Creatinine Clearance \< 40 mL/min 2. Serum Bilirubin, Aspartate transaminase (AST) or alanine transaminase (ALT) \> 1.5 times ULN * Presence of persistent local or known metastatic cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part B Change in Estradiol Level After Double Dose of Letrozole | Day 29 to Day 58 | In overweight/obese patients enrolled in part B, determine if blood levels of estradiol levels changed from before to after the double dose of letrozole |
| Part A Correlation of Day 29 Estradiol With BMI | Day 29 | Determine if estradiol levels vary with BMI levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estradiol and log-transformed BMI |
| Part A Correlation of Day 29 Estrone With BMI | Day 29 | Determine if estrone levels vary with BMI levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estrone and log-transformed BMI |
| Part A Correlation of Day 29 Estradiol With Vitamin D | Day 29 | Determine if estradiol levels vary with Vitamin D levels levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estradiol and log-transformed Vitamin D level |
| Part A Correlation of Day 29 Estrone With Vitamin D | Day 29 | Determine if estrone levels vary with Vitamin D levels levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estrone and log-transformed Vitamin D level |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Letrozole | Day 29 and day 58 | — |
| Endocrine Symptoms During Part A of Study | baseline, day 29 (end of part A) | Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) consists of 19 questions answered of a Likert scale. The sub-scale score ranges from 0 to 76 and the higher the score the better the quality of life |
| Endocrine Symptoms During Part B of the Study | day 29 (end of part A) and day 58 (end of part B) | Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) consists of 19 questions answered of a Likert scale. The sub-scale score ranges from 0 to 76 and the higher the score the better the quality of life |
Other
| Measure | Time frame |
|---|---|
| Musculoskeletal Symptoms | baseline (day 1), day 29 (end of part A) and day 58 (end of part B) |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Post-menopausal Women Using Adjuvant Letrozole Part A: All patients enrolled, on standard of care letrozole; Part B: All patients with BMI\>=25 who completed Part A, on a double dose of letrozole | 112 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part A: All Patients | Ineligibility discovered after enrollment | 2 |
| Part A: All Patients | Withdrawal by Subject | 7 |
| Part B: Patients With BMI>=25 | Ineligibility discovered after enrollment | 1 |
| Part B: Patients With BMI>=25 | Recruited during interim analysis | 3 |
| Part B: Patients With BMI>=25 | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | Post-menopausal Women Using Adjuvant Letrozole |
|---|---|
| Age at menopause Part A | 49.2 years STANDARD_DEVIATION 4.7 |
| Age at menopause Part B | 48.4 years STANDARD_DEVIATION 5.2 |
| Age, Continuous Part A | 61.7 years STANDARD_DEVIATION 7.6 |
| Age, Continuous Part B | 61.0 years STANDARD_DEVIATION 66 |
| Letrozole use prior to study | 18.1 months STANDARD_DEVIATION 17.6 |
| Sex: Female, Male Part A Female | 112 Participants |
| Sex: Female, Male Part A Male | 0 Participants |
| Sex: Female, Male Part B Female | 31 Participants |
| Sex: Female, Male Part B Male | 0 Participants |
| Vitamin D supplementation Part A | 109 Participants |
| Vitamin D supplementation Part B | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 121 |
| other Total, other adverse events | 8 / 121 |
| serious Total, serious adverse events | 2 / 121 |
Outcome results
Primary
Part A Correlation of Day 29 Estradiol With BMI
Determine if estradiol levels vary with BMI levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estradiol and log-transformed BMI
Time frame: Day 29
Population: Part A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Part A Correlation of Day 29 Estradiol With BMI | 0.06 correlation coefficient |
Primary
Part A Correlation of Day 29 Estradiol With Vitamin D
Determine if estradiol levels vary with Vitamin D levels levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estradiol and log-transformed Vitamin D level
Time frame: Day 29
Population: Part A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Part A Correlation of Day 29 Estradiol With Vitamin D | -0.04 correlation coefficient |
Primary
Part A Correlation of Day 29 Estrone With BMI
Determine if estrone levels vary with BMI levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estrone and log-transformed BMI
Time frame: Day 29
Population: Part A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Part A Correlation of Day 29 Estrone With BMI | 0.07 correlation coefficient |
Primary
Part A Correlation of Day 29 Estrone With Vitamin D
Determine if estrone levels vary with Vitamin D levels levels after 28 days of monitored adherence to standard dose letrozole, by calculating the Pearson correlation between estrone and log-transformed Vitamin D level
Time frame: Day 29
Population: Part A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Part A Correlation of Day 29 Estrone With Vitamin D | 0.04 correlation coefficient |
Primary
Part B Change in Estradiol Level After Double Dose of Letrozole
In overweight/obese patients enrolled in part B, determine if blood levels of estradiol levels changed from before to after the double dose of letrozole
Time frame: Day 29 to Day 58
Population: Part B participants
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Part B Change in Estradiol Level After Double Dose of Letrozole | 0.1 pmol/L |
Secondary
Endocrine Symptoms During Part A of Study
Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) consists of 19 questions answered of a Likert scale. The sub-scale score ranges from 0 to 76 and the higher the score the better the quality of life
Time frame: baseline, day 29 (end of part A)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Endocrine Symptoms During Part A of Study | Day 1 | 62.4 score on a scale | Standard Deviation 9.6 |
| Post-menopausal Women Using Adjuvant Letrozole | Endocrine Symptoms During Part A of Study | Day 29 | 62.9 score on a scale | Standard Deviation 10.4 |
Secondary
Endocrine Symptoms During Part B of the Study
Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) consists of 19 questions answered of a Likert scale. The sub-scale score ranges from 0 to 76 and the higher the score the better the quality of life
Time frame: day 29 (end of part A) and day 58 (end of part B)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Post-menopausal Women Using Adjuvant Letrozole | Endocrine Symptoms During Part B of the Study | Day 29 | 61.7 score on a scale | Standard Deviation 11.1 |
| Post-menopausal Women Using Adjuvant Letrozole | Endocrine Symptoms During Part B of the Study | Day 58 | 61.2 score on a scale | Standard Deviation 11.5 |
Secondary
Plasma Letrozole
Time frame: Day 29 and day 58
Population: Data were not collected
Other Pre-specified
Musculoskeletal Symptoms
Time frame: baseline (day 1), day 29 (end of part A) and day 58 (end of part B)