Aromatase Inhibitor Host Factors Study

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01669343
• Collaborator: (none)
• Enrollment: 121
• Locations: 3
• Arm: 1
• Actual Duration (Months): 50
• Patients Per Site: 40.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Letrozole	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Patient-related Predictors of Estrogen Suppression in Postmenopausal Women Using Adjuvant Letrozole
• Actual Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: Post-menopausal Women Using Adjuvant Letrozole Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants	Drug: Letrozole; 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.; Other Names: Femara

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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

Secondary Outcome Measures

1. Plasma Letrozole [Day 29 and day 58]

2. 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

3. 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 Outcome Measures

1. Musculoskeletal Symptoms [baseline (day 1), day 29 (end of part A) and day 58 (end of part B)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 1M9
2	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
3	Women's College Hospital	Toronto	Ontario	Canada	M5S 1B1

Sponsors and Collaborators

• Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Investigators

• Principal Investigator: Srikala Sridhar, M.D., Princess Margaret Hospital, Canada

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
• ClinicalTrials.gov Identifier: NCT01669343
• Other Study ID Numbers: AI Host Factors
• First Posted: Aug 21, 2012
• Last Update Posted: May 13, 2021
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Samuel Lunenfeld Research Institute, Mount Sinai Hospital: Aromatase Inhibitors
• Additional relevant MeSH terms: Breast Neoplasms; Letrozole

Study Results

Participant Flow

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	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
Period Title: Part A: All Patients
STARTED	121
COMPLETED	112
NOT COMPLETED	9
Period Title: Part A: All Patients
STARTED	48
COMPLETED	31
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	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
Overall Participants	112
Age (years) [Mean (Standard Deviation) ]
Part A	61.7 (7.6)
Part B	61.0 (66)
Sex: Female, Male (Count of Participants)
Female	112 100%
Male	0 0%
Female	31 27.7%
Male	0 0%
Age at menopause (years) [Mean (Standard Deviation) ]
Part A	49.2 (4.7)
Part B	48.4 (5.2)
Vitamin D supplementation (Count of Participants)
Part A	109 97.3%
Part B	31 27.7%
Letrozole use prior to study (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	18.1 (17.6)

Outcome Measures

1. Primary Outcome

Title	Part A Correlation of Day 29 Estradiol With BMI
Description	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

Outcome Measure Data

Analysis Population Description

Part A

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants Letrozole: 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.
Measure Participants	112
Number (95% Confidence Interval) [correlation coefficient]	0.06

2. Primary Outcome

Title	Part A Correlation of Day 29 Estrone With BMI
Description	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

Outcome Measure Data

Analysis Population Description

Part A

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants Letrozole: 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.
Measure Participants	112
Number (95% Confidence Interval) [correlation coefficient]	0.07

3. Primary Outcome

Title	Part A Correlation of Day 29 Estradiol With Vitamin D
Description	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

Outcome Measure Data

Analysis Population Description

Part A

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants Letrozole: 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.
Measure Participants	112
Number (95% Confidence Interval) [correlation coefficient]	-0.04

4. Primary Outcome

Title	Part A Correlation of Day 29 Estrone With Vitamin D
Description	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

Outcome Measure Data

Analysis Population Description

Part A

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants Letrozole: 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.
Measure Participants	112
Number (95% Confidence Interval) [correlation coefficient]	0.04

5. Primary Outcome

Title	Part B Change in Estradiol Level After Double Dose of Letrozole
Description	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

Outcome Measure Data

Analysis Population Description

Part B participants

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part A Routine Care Letrozole; Part B Double Dose Letrozole in overweight/obese participants Letrozole: 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.
Measure Participants	31
Mean (95% Confidence Interval) [pmol/L]	0.1

6. Secondary Outcome

Title	Plasma Letrozole
Time Frame	Day 29 and day 58

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part B Double Dose Letrozole in overweight/obese participants 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.
Measure Participants	0

7. Secondary Outcome

Title	Endocrine Symptoms During Part A of Study
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Post-menopausal Women Using Adjuvant Letrozole
Arm/Group Description	Part A: All patients enrolled, on standard of care letrozole
Measure Participants	112
Day 1	62.4 (9.6)
Day 29	62.9 (10.4)

8. Other Pre-specified Outcome

Title	Musculoskeletal Symptoms
Time Frame	baseline (day 1), day 29 (end of part A) and day 58 (end of part B)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Endocrine Symptoms During Part B of the Study
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part B
Arm/Group Description	Part B: Patients With BMI>=25, on double dose of letrozole
Measure Participants	31
Day 29	61.7 (11.1)
Day 58	61.2 (11.5)

Adverse Events

Time Frame	Adverse events were collected over the duration of the study: 29 days for patients taking part in Part A only, 58 days for patients that took part in Parts A and B
Adverse Event Reporting Description	National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.01
Arm/Group Title	Full Study
Arm/Group Description	Adverse events collected during part A, 29 days of monitored adherence to standard of care letrozole and Part B .
All Cause Mortality
	Full Study
	Affected / at Risk (%)	# Events
Total	0/121 (0%)
Serious Adverse Events
	Full Study
	Affected / at Risk (%)	# Events
Total	2/121 (1.7%)
Renal and urinary disorders
Renal Colic/Constipation	1/121 (0.8%)	1
Vascular disorders
Stroke	1/121 (0.8%)	1
Other (Not Including Serious) Adverse Events
	Full Study
	Affected / at Risk (%)	# Events
Total	8/121 (6.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/121 (6.6%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.