Neoadj ph 2 AI Plus Everolimus in Postmenopausal Women w/ ER Pos/HER2 Neg, Low Risk Score

• Sponsor: Yale University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02236572
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 17
• Location: 1
• Arm: 1
• Actual Duration (Months): 75
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to see whether adding everolimus to hormone treatment before breast surgery will increase the chances of shrinking the breast cancer in those patients with hormone-responsive breast cancer and a lower Oncotype DX® Recurrence Score ( 25 or less), compared to prior experience with hormone therapy alone. Everolimus is a drug currently approved for use by the United States Food and Drug administration (FDA) for the treatment of patients with advanced or metastatic kidney or breast cancer. Everolimus is considered investigational for non-metastatic breast cancer patients.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Everolimus	Phase 2

Detailed Description

This is a single arm open-labeled neoadjuvant phase II clinical trial evaluating everolimus in combination with an aromatase inhibitor in postmenopausal women with hormone receptor positive/HER2 negative breast cancers with low and intermediate risk (< 25) Recurrence Scores by Oncotype Dx.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Neoadjuvant Phase II Trial of Aromatase Inhibitors in Combination With Everolimus in Postmenopausal Women With Hormone Receptor Positive/HER2 Negative Breast Cancers With Low and Intermediate Risk (< 25) Oncotype Dx Recurrence Scores
• Actual Study Start Date: Nov 29, 2014
• Actual Primary Completion Date: Mar 1, 2021
• Actual Study Completion Date: Mar 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aromatase Inhibitor plus Everolimus Aromatase inhibitor plus everolimus by mouth daily for 26 weeks	Drug: Everolimus; Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg

Outcome Measures

Primary Outcome Measures

1. Achievement of a PEPI Score of 0 Following Neoadjuvant Treatment With Everolimus and an Aromatase Inhibitor [up to 26 weeks]

   (PEPI) preoperative endocrine prognostic index. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and estrogen receptor status of the surgical specimen. An HR in the range of 1-2 receives one risk point; a HR in the 2-2.5 range, two risk points; a HR greater than 2.5, three risk points. The total risk point score for each patient is the sum of all the risk points accumulated from the four factors in the model. A lower PEPI score indicates lower risk for recurrence. A score of 0 is lowest risk for recurrence.

Secondary Outcome Measures

1. PEPI Score [up to 26 weeks]

   To obtain the PEPI score, risk points for relapse-free survival (RFS) are assigned depending on the hazard ratio (HR) from the multivariable analysis. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and estrogen receptor status of the surgical specimen. A HR in the range of 1 to 2 receives one risk point; a HR in the 2 to 2.5 range, two risk points; a HR greater than 2.5, three risk points. The total risk point score for each patient is the sum of all the risk points accumulated from the four factors in the model, ranges from 0 (best possible outcome) to 12 (worst possible outcome).

2. Participant Ability to Tolerate Study Treatment With Minimal Side Effects [Up to 26 weeks]

   Adverse events (using CTCAE (4.0)) that begin or worsen after informed consent were recorded. Adverse events are itemized in the adverse events module (in terms of total events and total participants experiencing events). Presented are the total number of participants that experience adverse events. For clarification, counts of participants that experienced serious adverse events and counts of participants that experienced 'other' (not serious) adverse events are presented separately.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a histologically confirmed diagnosis of hormone receptor positive, HER2 negative invasive breast carcinoma.

• Tumors must be estrogen and/or progesterone receptor positive according to ASCO/CAP 2010 guidelines as either ER or PR ≥ 1% positive nuclear staining by immunohistochemistry. Estrogen and/or progesterone receptor results by Oncotype Dx will not be accepted.

• Tumors must be HER2 negative as defined according to ASCO/CAP 2013, as HER2 0 - 1+ by IHC or non-amplified FISH or CISH. If HER2 IHC is 2+, FISH/CISH must be performed and must not be positive (must be a ratio of < 2), but otherwise FISH/CISH is not required if IHC is 0 or 1+ by institutional standards.

• Patients must not have had prior ipsilateral breast-conserving surgery or total mastectomy and be eligible for neoadjuvant treatment.

• Clinical Stage II-IIIC (T2-4 N0-3 M0) by mammogram, ultrasound or MRI

• Baseline Oncotpye Dx recurrence score < 25.

• Staging studies with a CT scan of the chest and abdomen and bone scan, or a PET/CT is required for clinical stage III, and are considered optional for stage II breast cancers.

• Patients with multifocal, multicentric and synchronous bilateral breast cancers are allowed:

• Multifocal disease is defined as more than one invasive cancer < 2 cm from the largest lesion within the same breast quadrant.

• Multicentric disease is defined as more than one invasive cancer ≥ 2 cm from the largest lesion within the same breast quadrant or more than one lesion in different quadrants.

• Synchronous bilateral disease is defined as invasive breast cancer in both breasts, diagnosed within 30 days of each other.

• In patients with multicentric or bilateral invasive breast cancers, all sampled lesions must be hormone receptor-positive and HER2-negative. Any lesion measuring

1 cm must have an Oncotype Dx and the score must be < 25. Lesions less than 1 cm in size are not required to have an Oncotype Dx. One lesion (typically the largest) should be designated as the target lesion for which clinical and radiographic response to the neoadjuvant therapy will be judged.

• Patients with a hormone receptor-positive, HER2-negative invasive cancer that meets study criteria may have ductal carcinoma in situ in another quadrant of the same breast or in the contralateral breast even if the DCIS is hormone receptor-negative.

• Patients must have adequate bone marrow function, as defined by peripheral granulocyte count of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a platelet count ≥ 100,000/ mL within 28 days prior to registration.

• Patients must have adequate hepatic function obtained within 28 days prior to registration and documented by all of the following:

• Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome)

• ALT and AST ≤ 1.5 x Institutional Upper Limit of Normal (IULN)

• Alkaline phosphatase ≤ 1.5 x IULN

• Patients must have adequate renal function with serum creatinine level ≤ IULN within 28 days prior to registration.

• Patients must have a fasting cholesterol ≤ 300 mg/dl OR ≤7.75 mmol/L and triglycerides ≤ 2.5 x IULN obtained within 28 days prior to registration. Patients may be on lipid lowering agents to reach these values.

• Patients must have a ECOG performance status of 0-2.

• Patients must be able to take oral medications.

• Postmenopausal women (women are considered post-menopausal and not of child-bearing potential if they are > 18 years of age and have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms or biochemically postmenopausal by estradiol and FSH levels) prior to enrollment, or have had surgical bilateral oophorectomy (with or without hysterectomy) prior to registration. Medical ovarian suppression with LHRH agonists to render a patient postmenopausal will not be acceptable.

1. Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent prior to any screening procedures in accordance with institutional and federal guidelines.

Exclusion Criteria:

• Patients must not have inflammatory breast cancer (T4d) and must not have metastatic breast cancer (Stage IV disease).

• Patients must not have prior exposure to mTOR inhibitors (e.g. rapamycin, everolimus, sirolimus, temsirolimus, deforolimus).

• Patients must not have prior treatment with any investigational drug within the preceding 28 days and must not be planning to receive any other investigational drug for the duration of the study.

• Patient may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).

• Uncontrolled diabetes mellitus as defined by HbA1c >8% within 28 days prior to registration despite adequate therapy.

• Patients who have any severe and/or uncontrolled cardiac disease within ≤ 6 months prior to start of everolimus, including: unstable angina pectoris, Symptomatic congestive heart failure of New York heart Association Class III or IV, myocardial infarction, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease

• Patients must not have an organ allograft or other history of immune compromise.

• Patients must not be receiving chronic, systemic treatment with corticosteroids or other immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

• Patients must not have a known history of HIV seropositivity

• Patients must not have a known diagnosis of hepatitis B or C. Patients with the following risk factors must have hepatitis screening pre-treatment:

• Blood transfusions prior to 1990

• Current or prior IV drug users

• Current or prior dialysis

• Household contact with a hepatitis B or C patient

• Current or prior high-risk sexual activity

• History of jaundice.

• Patients must not have any known uncontrolled underlying pulmonary disease or severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air),

• Active (acute or chronic) or uncontrolled severe infection.

• Patients who have received live attenuated vaccines within 1 week of start of Everolimus, or have plans to receive such vaccination while on protocol treatment. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;

• Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing;

• Patients must not have taken within 14 days prior to registration , be taking, nor plan to take while on protocol treatment, strong CYP3A4 inhibitors, and/or CYP3A4 inducers.

• Patients with active bleeding diathesis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University	New Haven	Connecticut	United States	06520

Sponsors and Collaborators

• Yale University
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Lajos Pusztai, MD, Yale University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 16, 2016

More Information

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT02236572
• Other Study ID Numbers: 1405013982
• First Posted: Sep 10, 2014
• Last Update Posted: Feb 1, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Yale University: Postmenopausal; ER-positive, PR-positive, HER2-negative; Low and intermediate risk
• Additional relevant MeSH terms: Breast Neoplasms; Everolimus

Study Results

Participant Flow

Arm/Group Title	Aromatase Inhibitor Plus Everolimus
Arm/Group Description	Aromatase inhibitor plus everolimus by mouth daily for 26 weeks Everolimus: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg
Period Title: Overall Study
STARTED	17
COMPLETED	14
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Aromatase Inhibitor Plus Everolimus
Arm/Group Description	Aromatase inhibitor plus everolimus by mouth daily for 26 weeks Everolimus: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg
Overall Participants	17
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66
Sex: Female, Male (Count of Participants)
Female	17 100%
Male	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	10 58.8%
Black	3 17.6%
Multiple or unknown	4 23.5%
Region of Enrollment (participants) [Number]
United States	17 100%
Clinical Tumor Size at Presentation - pt no. (Count of Participants)
T1	5 29.4%
T2	12 70.6%
T3	0 0%
Nodal Status at Presentation (Count of Participants)
Positive (biopsy proven)	2 11.8%
Negative	15 88.2%
Tumor Histology (Count of Participants)
Ductal	12 70.6%
Lobular	3 17.6%
Unknown	2 11.8%

Outcome Measures

1. Primary Outcome

Title	Achievement of a PEPI Score of 0 Following Neoadjuvant Treatment With Everolimus and an Aromatase Inhibitor
Description	(PEPI) preoperative endocrine prognostic index. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and estrogen receptor status of the surgical specimen. An HR in the range of 1-2 receives one risk point; a HR in the 2-2.5 range, two risk points; a HR greater than 2.5, three risk points. The total risk point score for each patient is the sum of all the risk points accumulated from the four factors in the model. A lower PEPI score indicates lower risk for recurrence. A score of 0 is lowest risk for recurrence.
Time Frame	up to 26 weeks

Outcome Measure Data

Analysis Population Description

15 patients had surgery.

Arm/Group Title	Aromatase Inhibitor Plus Everolimus
Arm/Group Description	Aromatase inhibitor plus everolimus by mouth daily for 26 weeks Everolimus: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg
Measure Participants	15
PEPI Score = 0	4 23.5%
PEPI Score > 0	11 64.7%

2. Secondary Outcome

Title	PEPI Score
Description	To obtain the PEPI score, risk points for relapse-free survival (RFS) are assigned depending on the hazard ratio (HR) from the multivariable analysis. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and estrogen receptor status of the surgical specimen. A HR in the range of 1 to 2 receives one risk point; a HR in the 2 to 2.5 range, two risk points; a HR greater than 2.5, three risk points. The total risk point score for each patient is the sum of all the risk points accumulated from the four factors in the model, ranges from 0 (best possible outcome) to 12 (worst possible outcome).
Time Frame	up to 26 weeks

Outcome Measure Data

Analysis Population Description

Those that completed surgery

Arm/Group Title	Aromatase Inhibitor Plus Everolimus
Arm/Group Description	Aromatase inhibitor plus everolimus by mouth daily for 26 weeks Everolimus: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg
Measure Participants	15
Median (Full Range) [units on a scale]	3

3. Secondary Outcome

Title	Participant Ability to Tolerate Study Treatment With Minimal Side Effects
Description	Adverse events (using CTCAE (4.0)) that begin or worsen after informed consent were recorded. Adverse events are itemized in the adverse events module (in terms of total events and total participants experiencing events). Presented are the total number of participants that experience adverse events. For clarification, counts of participants that experienced serious adverse events and counts of participants that experienced 'other' (not serious) adverse events are presented separately.
Time Frame	Up to 26 weeks

Outcome Measure Data

Analysis Population Description

All participants that were enrolled in the study.

Arm/Group Title	Aromatase Inhibitor Plus Everolimus
Arm/Group Description	Aromatase inhibitor plus everolimus by mouth daily for 26 weeks Everolimus: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg
Measure Participants	17
Participants with Serious Adverse Events	5 29.4%
Participants with Other (Not Including Serious) Adverse Events	17 100%

Adverse Events

Time Frame	Up to 26 weeks
Arm/Group Title	Aromatase Inhibitor Plus Everolimus
Arm/Group Description	Aromatase inhibitor plus everolimus by mouth daily for 26 weeks Everolimus: Aromatase inhibitor plus everolimus by mouth daily for 26 weeks. All patients will begin treatment on Cycle 1 Day 1 with both the standard dose of one of the following 3 aromatase inhibitors ( physician's choice) plus everolimus 10 mg by mouth daily: Anastrozole 1 mg Letrozole 2.5 mg Exemestane 25 mg
All Cause Mortality
	Aromatase Inhibitor Plus Everolimus
	Affected / at Risk (%)	# Events
Total	0/17 (0%)
Serious Adverse Events
	Aromatase Inhibitor Plus Everolimus
	Affected / at Risk (%)	# Events
Total	5/17 (29.4%)
Cardiac disorders
Atrial Flutter	1/17 (5.9%)	1
General disorders
Fever	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	2/17 (11.8%)	2
Pneumothorax	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Aromatase Inhibitor Plus Everolimus
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Anemia	9/17 (52.9%)	13
Lymph node pain	1/17 (5.9%)	1
Cardiac disorders
Atrial fibrillation	1/17 (5.9%)	1
Atrial flutter	1/17 (5.9%)	1
Cardiac disorders - Other	1/17 (5.9%)	2
Ear and labyrinth disorders
Vertigo	1/17 (5.9%)	1
Vestibular disorder	1/17 (5.9%)	1
Gastrointestinal disorders
Mucositis oral	12/17 (70.6%)	22
Nausea	6/17 (35.3%)	7
Diarrhea	5/17 (29.4%)	9
Constipation	4/17 (23.5%)	4
Abdominal pain	2/17 (11.8%)	2
Dry mouth	2/17 (11.8%)	2
Gastroesophageal reflux disease	2/17 (11.8%)	2
Vomiting	2/17 (11.8%)	2
Abdominal distension	1/17 (5.9%)	1
Flatulence	1/17 (5.9%)	1
Oral dysesthesia	1/17 (5.9%)	1
Oral pain	1/17 (5.9%)	1
Toothache	1/17 (5.9%)	1
General disorders
Fatigue	10/17 (58.8%)	16
Edema limbs	7/17 (41.2%)	8
Pain	6/17 (35.3%)	9
Edema face	2/17 (11.8%)	2
Fever	2/17 (11.8%)	2
Non-cardiac chest pain	2/17 (11.8%)	2
General disorders and administration site conditions - Other	1/17 (5.9%)	2
Malaise	1/17 (5.9%)	1
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/17 (5.9%)	1
Immune system disorders
Allergic reaction	1/17 (5.9%)	1
Infections and infestations
Urinary tract infection	2/17 (11.8%)	2
Bronchial infection	1/17 (5.9%)	1
Mucosal infection	1/17 (5.9%)	1
Papulopustular rash	1/17 (5.9%)	1
Sinusitis	1/17 (5.9%)	1
Skin infection	1/17 (5.9%)	1
Injury, poisoning and procedural complications
Bruising	1/17 (5.9%)	1
Spinal fracture	1/17 (5.9%)	1
Blurred vision	1/17 (5.9%)	1
Eye disorders - Other	1/17 (5.9%)	1
Investigations
Aspartate aminotransferase increased	7/17 (41.2%)	10
Cholesterol high	7/17 (41.2%)	11
Alanine aminotransferase increased	6/17 (35.3%)	8
Platelet count decreased	3/17 (17.6%)	4
Weight loss	3/17 (17.6%)	5
Investigations - Other	2/17 (11.8%)	2
Alkaline phosphatase increased	1/17 (5.9%)	1
INR increased	1/17 (5.9%)	5
Neutrophil count decreased	1/17 (5.9%)	1
White blood cell decreased	1/17 (5.9%)	1
Metabolism and nutrition disorders
Hyperglycemia	9/17 (52.9%)	20
Anorexia	5/17 (29.4%)	10
Hypertriglyceridemia	5/17 (29.4%)	5
Hypokalemia	5/17 (29.4%)	6
Hyponatremia	3/17 (17.6%)	4
Hypophosphatemia	3/17 (17.6%)	3
Hypoalbuminemia	2/17 (11.8%)	3
Hypocalcemia	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/17 (11.8%)	2
Bone pain	2/17 (11.8%)	2
Pain in extremity	1/17 (5.9%)	1
Nervous system disorders
Dysgeusia	7/17 (41.2%)	7
Headache	6/17 (35.3%)	6
Dizziness	4/17 (23.5%)	4
Paresthesia	1/17 (5.9%)	1
Psychiatric disorders
Insomnia	4/17 (23.5%)	4
Anxiety	2/17 (11.8%)	2
Depression	1/17 (5.9%)	1
Renal and urinary disorders
Urinary frequency	1/17 (5.9%)	1
Reproductive system and breast disorders
Vaginal hemorrhage	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	7/17 (41.2%)	12
Cough	6/17 (35.3%)	10
Dyspnea	4/17 (23.5%)	9
Nasal congestion	3/17 (17.6%)	3
Epistaxis	2/17 (11.8%)	3
Sore throat	2/17 (11.8%)	2
Allergic rhinitis	1/17 (5.9%)	1
Laryngeal inflammation	1/17 (5.9%)	1
Pneumothorax	1/17 (5.9%)	1
Sneezing	1/17 (5.9%)	1
Wheezing	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	10/17 (58.8%)	13
Alopecia	3/17 (17.6%)	3
Skin and subcutaneous tissue disorders - Other	3/17 (17.6%)	3
Pruritus	2/17 (11.8%)	3
Hyperhidrosis	1/17 (5.9%)	1
Vascular disorders
Hypertension	5/17 (29.4%)	26
Hot flashes	4/17 (23.5%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.