Letrozole and Lapatinib Followed by Everolimus in Women With Advanced Breast Cancer

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01499160
• Collaborator: Novartis Pharmaceuticals (Industry), GlaxoSmithKline (Industry)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 55
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

About a third of patients with breast cancer are usually treated by hormone pills called tamoxifen and aromatase inhibitors. Aromatase inhibitors are drugs that stop female hormone production. Female hormone or estrogen is an important hormone for the growth of breast cancer cells. Letrozole is one of the aromatase inhibitors that is approved by the FDA and has been used to treat breast cancer since 1997. However, hormone pills usually work for about 6-10 months in most patients. Later on, breast cancer will start to grow again. This condition when hormone pills or endocrine therapy no longer work is called "endocrine resistant" breast cancer. The scientists here at University of Maryland have discovered how these cancer cells can become resistant to hormone pills. In our laboratory tests, the investigators found that lapatinib and everolimus can reverse this resistance and make letrozole work again. However, it is not known if the drugs can reverse the resistance in humans.

The purpose of this study is to find out whether the combination of letrozole, lapatinib, and everolimus is effective in women with breast cancer when hormone pills no longer work.

Lapatinib is an anti-cancer drug that is already approved by the Food and Drug Administration (FDA). It is the standard of care for the treatment of a particular type of breast cancer called human epithelial growth factor receptor 2 (HER2)-positive breast cancer. HER2 is a protein involved in the growth of some cancer cells. This study will also include patients with HER2-negative breast cancer. This means that the cancer cells in these patients do not depend on the HER2 protein. The use of lapatinib in these patients is considered experimental.

Everolimus is also an anti-cancer drug that is approved by the FDA for kidney cancer. Initial studies in mice and later studies in women with breast cancer have shown that everolimus may also slow the growth of breast cancer. The use of everolimus is experimental in this study.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms; Endocrine Breast Diseases; Neoplasm Metastasis	Drug: letrozole; Drug: lapatinib; Drug: everolimus	Phase 2

Detailed Description

This is a single-institution clinical trial. Patients will be stratified according to the

HER2 status:

Group 1: HER2-positive in the tumor tissue Group 2: HER2 negative in the tumor tissue

In the first part of the study, all of the patients will receive the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day. We do not expect any significant toxicity from this combination since the previous study of lapatinib and letrozole showed that this combination is safe with no grade 3-4 toxicities observed. Restaging scans (CT scan, MRI, or bone scan) will be obtained after every 12 weeks of treatment. In those patients who progress from any group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250 mg/day as per the SWOG phase I study of lapatinib and everolimus. The outcome of each group will continue to be assessed separately. We do not expect to see additional serious toxicity from adding everolimus to the combination of lapatinib and letrozole. All of the treatment will be continued until disease progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: sequential treatment assignment, no masking is donesequential treatment assignment, no masking is done
• Masking: None (Open Label)
• Masking Description: No masking was done
• Primary Purpose: Treatment
• Official Title: GCC 0901- A Phase II Study of Letrozole in Combination With Lapatinib Followed by an Addition of Everolimus in Postmenopausal Women With Advanced Endocrine Resistant Breast Cancer
• Actual Study Start Date: May 1, 2012
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HER2-positive or negative Lapatinib 1,500 mg/day + letrozole 2.5 mg/day until progression followed by everolimus 5 mg/day + letrozole 2.5 mg/day + lapatinib 1,250 mg/day.	Drug: letrozole; Drug is are to be taken orally. 2.5 mg once daily; Other Names: Femara ; Drug: lapatinib; Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression); Other Names: Tykerb ; Drug: everolimus; Drug is to be taken orally. 5 mg once daily.; Other Names: Afinitor

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate of Patients Treated With the Combination of Letrozole and Lapatinib and Then After Progression, Treated With Everolimus, Letrozole and Lapatinib. [From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. Clinical benefit rate is defined as complete response+partial response+ stable disease. All participants will be treated with the combination of letrozole and lapatinib. Once the participant progresses on this regimen, the participant will be treated with everolimus, letrozole and lapatinib until they progress.

Secondary Outcome Measures

1. PROGRESSION FREE SURVIVAL TUMOR ASSESSMENT [From date of study entry until 4 weeks after removal from study or until death (whichever occurs first) up to 24 months.]

   Patients treated with the combination of Letrozole and Lapatinib will provide tumor biopsy sample

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Female greater than or equal to 18 years.

• Histologically confirmed breast adenocarcinoma with incurable progressing local-regional or metastatic.

• ER and/or PR positivity of primary and/or secondary tumor.

• Patients must have measurable or evaluable disease.

• Evidence of disease progression or relapse while on or less than 6 months off aromatase inhibitors or tamoxifen either in adjuvant or first line metastatic setting.

• Postmenopausal

• Patients may have received up to one prior chemotherapy regimen for stage IV breast cancer. Prior chemotherapy in the adjuvant and/or neoadjuvant setting is permitted. Chemotherapy must be finished at least 2 weeks prior to enrollment.

• ECOG performance status <2

• Fasting cholesterol ≤300 mg/dL OR ≤7.75 mmol/LAND fasting triglycerides ≤ 2.5 x ULN despite appropriate treatment.

• Patients must have adequate organ function as defined by the protocol.

• Stratification 1:

• HER2 positive in the primary or secondary tumor tissue

• Prior trastuzumab therapy is allowed but NOT required. However, trastuzumab should be discontinued at least 3 weeks prior to enrollment.

• Stratification 2:

• HER2 negative in the primary or secondary tumor tissue

Exclusion Criteria:

• Patients receiving any other investigational agents.

• Prior exposure to lapatinib, everolimus, or other mTOR inhibitors.

• History of allergic reactions or hypersensitivity to compounds similar to everolimus, lapatinib, or letrozole.

• Patients who have any severe and/or uncontrolled medical conditions that could affect their participation such as:

• Left ventricular ejection fraction (LVEF) < 50%

• Unstable angina, symptomatic congestive heart failure, myocardial infarction within 6 months, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.

• Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is ≤ 88% at rest on room air.

• Uncontrolled diabetes

• Active or uncontrolled severe infection

• Patients with QTc interval > 0.47 seconds.

• Significant chronic or acute gastrointestinal disorder with diarrhea as a major symptom.

• Prior exposure to more than 360 mg/m2 doxorubicin, more than 120 mg/m2mitoxantrone, or more than 90 mg/m2idarubicin, or elevated baseline cardiac troponin I.

• Patients with active CNS metastasis and/or carcinomatous meningtitis. However, patients with CNS metastasis who have completed a therapy and are clinically stable for 3 weeks as defined as: (1) no evidence of new or enlarging CNS metastasis and (2) off steroids and/or anticonvulsants.

• Patient is known to be HIV, Hepatitis B, or Hepatitis C-positive (these tests are not required).

• Patients with current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease).

• Patients with INR ≥ 2 or PTT ≥ 2 x upper normal limit.

• Previous or current systemic malignancy other than breast cancer within the past 3 years other than carcinoma in situ of the cervix or basal/squamous carcinoma of the skin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Marlene & Stewart Greenebaum Cancer Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• Novartis Pharmaceuticals
• GlaxoSmithKline

Investigators

• Principal Investigator: Katherine Tkaczuk, MD, University of Maryland Marlene & Stewart Greenebaum Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Katherine Tkaczuk, Professor of Medicine, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT01499160
• Other Study ID Numbers: HP-00040802; GCC 0901; GCC 0901
• First Posted: Dec 26, 2011
• Last Update Posted: Feb 11, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Katherine Tkaczuk, Professor of Medicine, University of Maryland, Baltimore: endocrine resistant; everolimus; lapatinib; letrozole
• Additional relevant MeSH terms: Neoplasms; Neoplasm Metastasis; Breast Neoplasms; Breast Diseases; Everolimus; Letrozole; Lapatinib

Study Results

Participant Flow

Recruitment Details	University Medical Centers and Hospital Based Oncology Programs recruited participants from July 2012 to December 2014.
Pre-assignment Detail	All 7 patients (2 pts were HER2+ and 5 pts were HER2-) started the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day.

Arm/Group Title	Letrozole in Combination With Lapatinib Followed by Everolimus
Arm/Group Description	Group 1: HER2-positive in the tumor tissue Group 2: HER2 negative in the tumor tissue In the first part of the study, all of the patients will receive the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day. Restaging scans (CT scan, MRI, or bone scan) will be obtained after every 12 weeks of treatment. In those patients who progress from any group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250 mg/day as per the SWOG phase I study of lapatinib and everolimus. letrozole: Drug is are to be taken orally. 2.5 mg once daily lapatinib: Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression) everolimus: Drug is to be taken orally. 5 mg once daily.
Period Title: Overall Study
STARTED	7
COMPLETED	5
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Letrozole in Combination With Lapatinib Followed by Everolimus
Arm/Group Description	Group 1: HER2-positive in the tumor tissue Group 2: HER2 negative in the tumor tissue In the first part of the study, all of the patients will receive the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day. Restaging scans (CT scan, MRI, or bone scan) will be obtained after every 12 weeks of treatment. In those patients who progress from any group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250 mg/day as per the SWOG phase I study of lapatinib and everolimus. letrozole: Drug is are to be taken orally. 2.5 mg once daily lapatinib: Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression) everolimus: Drug is to be taken orally. 5 mg once daily.
Overall Participants	7
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	7 100%
Male	0 0%
Region of Enrollment (Count of Participants)
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate of Patients Treated With the Combination of Letrozole and Lapatinib and Then After Progression, Treated With Everolimus, Letrozole and Lapatinib.
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. Clinical benefit rate is defined as complete response+partial response+ stable disease. All participants will be treated with the combination of letrozole and lapatinib. Once the participant progresses on this regimen, the participant will be treated with everolimus, letrozole and lapatinib until they progress.
Time Frame	From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months

Outcome Measure Data

Analysis Population Description

1 patient withdrew during cycle 1

Arm/Group Title	Letrozole in Combination With Lapatinib Followed by Everolimus
Arm/Group Description	Group 1: HER2-positive in the tumor tissue-2 subjects Group 2: HER2 negative in the tumor tissue-5 subjects In the first part of the study, all of the patients will receive the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day. Restaging scans (CT scan, MRI, or bone scan) will be obtained after every 12 weeks of treatment. In those patients who progress from any group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250 mg/day as per the SWOG phase I study of lapatinib and everolimus. letrozole: Drug is are to be taken orally. 2.5 mg once daily lapatinib: Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression) everolimus: Drug is to be taken orally. 5 mg once daily.
Measure Participants	6
Count of Participants [Participants]	6 85.7%

2. Secondary Outcome

Title	PROGRESSION FREE SURVIVAL TUMOR ASSESSMENT
Description	Patients treated with the combination of Letrozole and Lapatinib will provide tumor biopsy sample
Time Frame	From date of study entry until 4 weeks after removal from study or until death (whichever occurs first) up to 24 months.

Outcome Measure Data

Analysis Population Description

data analysis was not conducted due to low sample (low accrual) and study closure

Arm/Group Title	Letrozole in Combination With Lapatinib Followed by Everolimus
Arm/Group Description	Group 1: HER2-positive in the tumor tissue Group 2: HER2 negative in the tumor tissue In the first part of the study, all of the patients will receive the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day. Restaging scans (CT scan, MRI, or bone scan) will be obtained after every 12 weeks of treatment. In those patients who progress from any group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250 mg/day as per the SWOG phase I study of lapatinib and everolimus. letrozole: Drug is are to be taken orally. 2.5 mg once daily lapatinib: Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression) everolimus: Drug is to be taken orally. 5 mg once daily.
Measure Participants	6
Count of Participants [Participants]	6 85.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole in Combination With Lapatinib Followed by Everolimus
	Comments	Not done due to low accrual
	Type of Statistical Test	Other
	Comments	Not done due to low accrual
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Not done due to low accrual

Adverse Events

Time Frame	Adverse events including serious adverse events (SAEs) were collected from the start of study until 30 days after completion of last study drug dose on all study patients (7), but only 4 severe adverse events were noted as reported previously.
Arm/Group Title	Letrozole in Combination With Lapatinib Followed by Everolimus
Arm/Group Description	Group 1: HER2-positive in the tumor tissue Group 2: HER2 negative in the tumor tissue In the first part of the study, all of the patients will receive the combination of lapatinib 1,500 mg/day and letrozole 2.5 mg/day. Restaging scans (CT scan, MRI, or bone scan) will be obtained after every 12 weeks of treatment. In those patients who progress from any group, everolimus 5 mg/day will be added to letrozole and lapatinib will be reduced to 1,250 mg/day as per the SWOG phase I study of lapatinib and everolimus. letrozole: Drug is are to be taken orally. 2.5 mg once daily lapatinib: Drug is to be taken orally. 1,500 mg once daily in the first part of the study and then 1,250 mg once daily in the second part of the study (after initial progression) everolimus: Drug is to be taken orally. 5 mg once daily.
All Cause Mortality
	Letrozole in Combination With Lapatinib Followed by Everolimus
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Serious Adverse Events
	Letrozole in Combination With Lapatinib Followed by Everolimus
	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)
Blood and lymphatic system disorders
Decreased LVEF	1/7 (14.3%)	1
Gastrointestinal disorders
nausea	1/7 (14.3%)	1
General disorders
fatigue	1/7 (14.3%)	1
Renal and urinary disorders
rectal pain	1/7 (14.3%)	1
Other (Not Including Serious) Adverse Events
	Letrozole in Combination With Lapatinib Followed by Everolimus
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Anemia	2/7 (28.6%)	2
Leucopenia	1/7 (14.3%)	2
lymphedema	1/7 (14.3%)	2
Lymphopenia	1/7 (14.3%)	1
Ear and labyrinth disorders
Otitis Externa	1/7 (14.3%)	1
Endocrine disorders
elevated ALT & AST	5/7 (71.4%)	9
Eye disorders
right eyelid swelling	1/7 (14.3%)	1
Gastrointestinal disorders
abdominal pain	2/7 (28.6%)	2
Constipation	1/7 (14.3%)	1
diarrhea	5/7 (71.4%)	11
epigastric pain	1/7 (14.3%)	1
nausea	4/7 (57.1%)	6
General disorders
dehydration	1/7 (14.3%)	1
diaphoresis	1/7 (14.3%)	1
dizziness	2/7 (28.6%)	2
epistaxis	1/7 (14.3%)	1
Fatigue	3/7 (42.9%)	8
hair loss	2/7 (28.6%)	2
hypertriglyceridemia	2/7 (28.6%)	2
mouth ulcers	1/7 (14.3%)	1
mucositis	3/7 (42.9%)	6
numbness in toes	1/7 (14.3%)	1
pain	1/7 (14.3%)	1
right foot pain	1/7 (14.3%)	1
right hip pain	1/7 (14.3%)	1
right shoulder pain	1/7 (14.3%)	1
righted sided pain	1/7 (14.3%)	1
stomatitis	1/7 (14.3%)	1
vomiting	1/7 (14.3%)	1
weight gain	1/7 (14.3%)	1
weight loss	1/7 (14.3%)	1
Injury, poisoning and procedural complications
accidental everolimus overdose	1/7 (14.3%)	1
Metabolism and nutrition disorders
anorexia	2/7 (28.6%)	2
Musculoskeletal and connective tissue disorders
arthralgias	1/7 (14.3%)	1
Bone pain	1/7 (14.3%)	1
Fracture fibula	1/7 (14.3%)	1
hip pain	2/7 (28.6%)	2
joint pain	1/7 (14.3%)	1
myalgia	1/7 (14.3%)	1
right back pain	1/7 (14.3%)	1
Renal and urinary disorders
UTI	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
URI	2/7 (28.6%)	2
Skin and subcutaneous tissue disorders
rash	5/7 (71.4%)	10
right toe cellulitis	1/7 (14.3%)	1

Limitations/Caveats

The trial was terminated due to low accrual.

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.