Eribulin Mesylate and Everolimus in Treating Patients With Triple-Negative Metastatic Breast Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02120469
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 27
• Locations: 3
• Arm: 1
• Actual Duration (Months): 65.1
• Patients Per Site: 9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase I/IB trial studies the side effects and best dose of eribulin mesylate and everolimus in treating patients with breast cancer that does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 protein (triple-negative) and has spread to other places in the body (metastatic). Eribulin mesylate and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor-negative; Stage IV Breast Cancer; Triple-negative Breast Carcinoma	Drug: everolimus; Drug: eribulin mesylate; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the safety and tolerability of everolimus and eribulin (eribulin mesylate), and determine the recommended Phase IB dose (RP2D) of the drug combination in patients with resistant metastatic triple negative breast cancer (TNBC). (Phase I) II. To evaluate the event-free survival (EFS) rate for patients with resistant metastatic TNBC at the RP2D of everolimus and eribulin to determine if the drug combination is worthy of further study. (Phase IB)

SECONDARY OBJECTIVES:

1. To determine response rate in patients with resistant metastatic TNBC. (Phase IB) II. To determine overall survival (OS) in patients with resistant metastatic TNBC. (Phase IB) III. To determine toxicity in patients with resistant metastatic TNBC. (Phase IB) IV. To determine pharmacokinetics (PK) for everolimus and eribulin in patients with resistant metastatic TNBC. (Phase IB) V. To collect blood, skin punch biopsies, and tumor biopsies before and after treatment from all patients and perform proteomic analysis to determine the level of inhibition of the phosphatidylinositol 3 kinase (PI3K) pathway in tumor cells versus non-therapeutic targets. (Phase IB)

OUTLINE: This is a dose-escalation study of everolimus.

Patients receive everolimus orally (PO) once daily (QD) on days 1-21 and eribulin mesylate intravenously (IV) on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 21 days and then periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/IB Trial of Eribulin and Everolimus in Patients With Triple Negative Metastatic Breast Cancer
• Actual Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: Mar 20, 2019
• Actual Study Completion Date: Mar 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (everolimus, eribulin mesylate) Patients receive everolimus PO QD on days 1-21 and eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: everolimus; Given PO; Other Names: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001 ; Drug: eribulin mesylate; Given IV; Other Names: B1939 E7389 ER-086526 halichrondrin B analog ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Optional correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D) [First cycle on treatment, up to 21 days]

   DLT defined as an adverse event (AE) or abnormal laboratory value as at least possibly related to the study medication and meets any of the criteria per NCI CTCAE v4.0.

2. Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB) [Up to 2 years]

   Progression determined using response evaluation criteria in solid tumors (RECIST) version 1.1 or showed clinical progression. RECIST criteria for progression includes: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Rates and associated 95% confidence limits will be estimated.

Secondary Outcome Measures

1. Number of Participants With Grade 3 or Higher Toxicities (Phase IB) [On treatment, 21 days per cycle up to 2 years]

   Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for grade 3 or higher toxicities attributed to eribulin mesylate or everolimus.

2. Best Response Using the RECIST (Phase IB) [Up to 2 years]

   RECIST Criteria: Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

3. Median Overall Survival (Phase IB) [From start of treatment to death due to any cause, assessed up to 2 years]

   Kaplan Meier methods will be used to estimate the median and 95% confidence limits across all dose levels per protocol plan.

4. Median Progression Free Survival (Phase IB) [Form the date treatment begins until the first date on which recurrence, progression, or death due to any cause, assessed up to 2 years]

   Kaplan Meier methods will be used to estimate the median and 95% confidence limits over all dose levels per protocol plan.

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 histologically-confirmed stage IV TNBC (patients who had metastatic disease within 6 months of lumpectomy or mastectomy for treatment of TNBC may be excused from repeat biopsy)

• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly obtained samples cannot be provide (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the study principle investigator (PI)

• Patients must have had prior treatment with anthracyclines and/or taxanes (resistant) or platinum including adjuvant or neoadjuvant therapy

• Both measurable as well as non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, will be allowed

• Patients with chemotherapy for metastatic disease (patients with 0-3 prior lines of chemotherapy for metastatic breast cancer [MBC])

• Life expectancy of >= 3 months

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

• Hemoglobin >= 9.0 g/dl

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Creatinine =< 1.5 times the upper limit of normal (ULN)

• Total bilirubin less =< to 1 times ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< to 2.5 times the ULN if no liver metastases; for patients with known liver metastases, AST and ALT must be =< to 5 times the ULN

• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for up to 8 weeks after ending treatment; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

• Be willing to use dexamethasone mouthwash as directed

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered > 3 weeks prior to entering the study

• Patients may not be receiving any other investigational agents

• Patients with symptomatic brain metastases are excluded from this clinical trial

• Uncontrolled current illness including, but not limited to, ongoing or active infection (> grade 2 based on the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version [v]4.0), symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women

• Prior eribulin use

• Patients with human immunodeficiency virus (HIV), chronic hepatitis B, or chronic hepatitis C (known from the existing medical record)

• Concomitant use with strong or moderate cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/P-glycoprotein (PgP) inhibitors and CYP3A4/PgP inducers

• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after ending treatment; highly effective contraception methods include combination of any two of the following:

• Use of oral, injected or implanted hormonal methods of contraception or

• Placement of an intrauterine device (IUD) or intrauterine system (IUS)

• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

• Total abstinence

• Male/female sterilization

Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential

• Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment

• Noncompliant with oral medication and/or dexamethasone mouth wash

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010
2	City of Hope Rancho Cucamonga	Rancho Cucamonga	California	United States	91730
3	South Pasadena Cancer Center	South Pasadena	California	United States	91030

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yuan Yuan, MD, PhD, City of Hope Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 8, 2019

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT02120469
• Other Study ID Numbers: 14036; NCI-2014-00844; 14036
• First Posted: Apr 22, 2014
• Last Update Posted: Jul 5, 2022
• Last Verified: Jun 1, 2022

• Additional relevant MeSH terms: Breast Neoplasms; Everolimus

Study Results

Participant Flow

Arm/Group Title	Dose Level B1	Dose Level A1	Dose Level A2
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 5mg; eribulin 1.4mg/m^2 Patients receive 5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 7.5mg; eribulin 1.4mg/m^2 Patients receive 7.5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	13	10	4
COMPLETED	12	10	3
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Dose Level B1	Dose Level A1	Dose Level A2	Total
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	5mg everolimus; 1.4 mg/m^2 eribulin mesylate Patients receive 5mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	7.5mg everolimus; 1.4 mg/m^2 eribulin mesylate Patients receive 7.5mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	13	10	4	27
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56	52.5	50.5	55
Sex: Female, Male (Count of Participants)
Female	13 100%	10 100%	4 100%	27 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 23.1%	4 40%	2 50%	9 33.3%
Not Hispanic or Latino	10 76.9%	6 60%	2 50%	18 66.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	10 76.9%	5 50%	3 75%	18 66.7%
Asian/Pacific Islander	1 7.7%	1 10%	1 25%	3 11.1%
Black	1 7.7%	1 10%	0 0%	2 7.4%
Unknown	1 7.7%	3 30%	0 0%	4 14.8%
Region of Enrollment (Count of Participants)
United States	13 100%	10 100%	4 100%	27 100%
ECOG performance status (Count of Participants)
Fully active, able to carry on all pre-disease performance without restriction	4 30.8%	3 30%	1 25%	8 29.6%
Restricted in physically strenuous activity but ambulatory and able to do work of a light nature	8 61.5%	4 40%	3 75%	15 55.6%
Ambulatory and capable of all selfcare but unable to carry out any work activities	1 7.7%	3 30%	0 0%	4 14.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D)
Description	DLT defined as an adverse event (AE) or abnormal laboratory value as at least possibly related to the study medication and meets any of the criteria per NCI CTCAE v4.0.
Time Frame	First cycle on treatment, up to 21 days

Outcome Measure Data

Analysis Population Description

Number analyzed for DLT only include participants that are evaluable. A1: 1 participant was not evaluable due to progression prior to completion of first two cycles and 1 participant was not evaluable due to toxicity attributed to diabetes. A2: 1 participant was not evaluable due to HER2+ repeat biopsy. B1: 1 participant was not evaluable due to HER2+ repeat biopsy.

Arm/Group Title	Dose Level B1	Dose Level A1	Dose Level A2
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 5mg; eribulin 1.4mg/m^2 Patients receive 5mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 7.5mg; eribulin 1.4mg/m^2 Patients receive 7.5mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	12	8	3
Count of Participants [Participants]	4 30.8%	4 40%	2 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dose Level B1, Dose Level A1, Dose Level A2
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Dose level B1 (eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily) was defined as the highest dose with acceptable toxicity (RP2D).

2. Primary Outcome

Title	Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB)
Description	Progression determined using response evaluation criteria in solid tumors (RECIST) version 1.1 or showed clinical progression. RECIST criteria for progression includes: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Rates and associated 95% confidence limits will be estimated.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

2 participants (1 on dose level A2 and 1 on dose level B1) were not evaluable for response because they were determined to be HER2+ on repeat biopsy.

Arm/Group Title	Dose Level B1	Dose Level A1	Dose Level A2
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 5mg; eribulin 1.4mg/m^2 Patients receive 5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 7.5mg; eribulin 1.4mg/m^2 Patients receive 7.5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	12	10	3
Count of Participants [Participants]	10 76.9%	8 80%	3 75%

3. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher Toxicities (Phase IB)
Description	Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for grade 3 or higher toxicities attributed to eribulin mesylate or everolimus.
Time Frame	On treatment, 21 days per cycle up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level B1	Dose Level A1	Dose Level A2
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 5mg; eribulin 1.4mg/m^2 Patients receive 5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 7.5mg; eribulin 1.4mg/m^2 Patients receive 7.5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	13	10	4
Count of Participants [Participants]	8 61.5%	5 50%	3 75%

4. Secondary Outcome

Title	Best Response Using the RECIST (Phase IB)
Description	RECIST Criteria: Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

2 participants (1 on dose level A2 and 1 on dose level B1) were not evaluable for response because they were determined to be HER2+ on repeat biopsy.

Arm/Group Title	Dose Level B1	Dose Level A1	Dose Level A2
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 5mg; eribulin 1.4mg/m^2 Patients receive 5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	everolimus 7.5mg; eribulin 1.4mg/m^2 Patients receive 7.5 mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	12	10	3
Partial Remission	5 38.5%	3 30%	1 25%
Stable Disease	6 46.2%	2 20%	1 25%
Progressive Disease	1 7.7%	5 50%	1 25%

5. Secondary Outcome

Title	Median Overall Survival (Phase IB)
Description	Kaplan Meier methods will be used to estimate the median and 95% confidence limits across all dose levels per protocol plan.
Time Frame	From start of treatment to death due to any cause, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Everolimus, Eribulin Mesylate)
Arm/Group Description	Patients receive everolimus PO QD on days 1-21 and eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. everolimus: Given PO eribulin mesylate: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Optional correlative studies
Measure Participants	25
Median (95% Confidence Interval) [months]	8.3

6. Secondary Outcome

Title	Median Progression Free Survival (Phase IB)
Description	Kaplan Meier methods will be used to estimate the median and 95% confidence limits over all dose levels per protocol plan.
Time Frame	Form the date treatment begins until the first date on which recurrence, progression, or death due to any cause, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Everolimus, Eribulin Mesylate)
Arm/Group Description	Patients receive everolimus PO QD on days 1-21 and eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. everolimus: Given PO eribulin mesylate: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Optional correlative studies
Measure Participants	25
Median (95% Confidence Interval) [months]	2.6

Adverse Events

Time Frame	While on study, an average of 9 months
Arm/Group Title	Dose Level B1		Dose Level A1		Dose Level A2
Arm/Group Description	everolimus 5mg; eribulin 1.1mg/m^2; 10 mL dexamethasone mouthwash Patients receive 5mg everolimus PO QD on days 1-21 and 1.1 mg/m^2 eribulin mesylate IV on days 1 and 8 and 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, swish for 2 min and spit, 4 times daily. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.		everolimus 5mg; eribulin 1.4mg/m^2 Patients receive 5mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.		everolimus 7.5mg; eribulin 1.4mg/m^2 Patients receive 7.5mg everolimus PO QD on days 1-21 and 1.4 mg/m^2 eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Dose Level B1		Dose Level A1		Dose Level A2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)		10/10 (100%)		3/4 (75%)
Serious Adverse Events
	Dose Level B1		Dose Level A1		Dose Level A2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		3/10 (30%)		1/4 (25%)
Blood and lymphatic system disorders
Febrile neutropenia	0/13 (0%)		1/10 (10%)		0/4 (0%)
Gastrointestinal disorders
Abdominal pain	0/13 (0%)		0/10 (0%)		1/4 (25%)
Mucositis oral	0/13 (0%)		0/10 (0%)		1/4 (25%)
Infections and infestations
Infections and infestations - other	0/13 (0%)		0/10 (0%)		1/4 (25%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/13 (0%)		0/10 (0%)		1/4 (25%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/13 (7.7%)		2/10 (20%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Dose Level B1		Dose Level A1		Dose Level A2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		10/10 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	10/13 (76.9%)		9/10 (90%)		4/4 (100%)
Cardiac disorders
Aortic valve disease	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Atrial fibrillation	0/13 (0%)		1/10 (10%)		0/4 (0%)
Atrioventricular block first degree	0/13 (0%)		1/10 (10%)		0/4 (0%)
Cardiac disorders - Other, specify	1/13 (7.7%)		4/10 (40%)		0/4 (0%)
Heart failure	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Mitral valve disease	1/13 (7.7%)		2/10 (20%)		0/4 (0%)
Pericardial effusion	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Sinus bradycardia	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Sinus tachycardia	6/13 (46.2%)		8/10 (80%)		2/4 (50%)
Tricuspid valve disease	2/13 (15.4%)		0/10 (0%)		0/4 (0%)
Eye disorders
Blurred vision	1/13 (7.7%)		0/10 (0%)		1/4 (25%)
Gastrointestinal disorders
Abdominal distension	1/13 (7.7%)		0/10 (0%)		1/4 (25%)
Abdominal pain	4/13 (30.8%)		3/10 (30%)		0/4 (0%)
Bloating	0/13 (0%)		1/10 (10%)		0/4 (0%)
Constipation	6/13 (46.2%)		5/10 (50%)		1/4 (25%)
Diarrhea	6/13 (46.2%)		2/10 (20%)		2/4 (50%)
Dry mouth	2/13 (15.4%)		0/10 (0%)		0/4 (0%)
Dyspepsia	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Dysphagia	2/13 (15.4%)		1/10 (10%)		2/4 (50%)
Flatulence	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Gastrointestinal disorders - Other, specify	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Hemorrhoids	0/13 (0%)		1/10 (10%)		0/4 (0%)
Mucositis oral	9/13 (69.2%)		5/10 (50%)		4/4 (100%)
Nausea	8/13 (61.5%)		4/10 (40%)		2/4 (50%)
Oral pain	0/13 (0%)		3/10 (30%)		3/4 (75%)
Vomiting	2/13 (15.4%)		1/10 (10%)		1/4 (25%)
General disorders
Death NOS	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Edema face	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Edema limbs	0/13 (0%)		3/10 (30%)		2/4 (50%)
Facial pain	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Fatigue	12/13 (92.3%)		8/10 (80%)		2/4 (50%)
Fever	2/13 (15.4%)		1/10 (10%)		0/4 (0%)
Gait disturbance	1/13 (7.7%)		0/10 (0%)		2/4 (50%)
General disorders and administration site conditions - Other, specify	0/13 (0%)		0/10 (0%)		1/4 (25%)
Infusion site extravasation	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Localized edema	2/13 (15.4%)		1/10 (10%)		0/4 (0%)
Non-cardiac chest pain	4/13 (30.8%)		1/10 (10%)		0/4 (0%)
Pain	4/13 (30.8%)		4/10 (40%)		0/4 (0%)
Infections and infestations
Gum infection	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Infections and infestations - Other, specify	1/13 (7.7%)		2/10 (20%)		1/4 (25%)
Laryngitis	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Lung infection	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Mucosal infection	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Rash pustular	0/13 (0%)		1/10 (10%)		0/4 (0%)
Sinusitis	0/13 (0%)		1/10 (10%)		0/4 (0%)
Upper respiratory infection	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Urinary tract infection	3/13 (23.1%)		2/10 (20%)		0/4 (0%)
Injury, poisoning and procedural complications
Fall	0/13 (0%)		1/10 (10%)		1/4 (25%)
Fracture	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/13 (0%)		1/10 (10%)		0/4 (0%)
Alanine aminotransferase increased	4/13 (30.8%)		1/10 (10%)		2/4 (50%)
Alkaline phosphatase increased	2/13 (15.4%)		2/10 (20%)		1/4 (25%)
Aspartate aminotransferase increased	5/13 (38.5%)		5/10 (50%)		3/4 (75%)
Blood bilirubin increased	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
CD lymphocytes decreased	0/13 (0%)		1/10 (10%)		0/4 (0%)
Lymphocyte count decreased	5/13 (38.5%)		6/10 (60%)		3/4 (75%)
Neutrophil count decreased	11/13 (84.6%)		9/10 (90%)		4/4 (100%)
Platelet count decreased	2/13 (15.4%)		5/10 (50%)		1/4 (25%)
Weight loss	8/13 (61.5%)		2/10 (20%)		2/4 (50%)
White blood cell decreased	10/13 (76.9%)		9/10 (90%)		4/4 (100%)
Metabolism and nutrition disorders
Alkalosis	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Anorexia	5/13 (38.5%)		2/10 (20%)		1/4 (25%)
Dehydration	1/13 (7.7%)		0/10 (0%)		1/4 (25%)
Hypercalcemia	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Hyperglycemia	0/13 (0%)		5/10 (50%)		1/4 (25%)
Hyperkalemia	0/13 (0%)		1/10 (10%)		0/4 (0%)
Hypermagnesemia	0/13 (0%)		0/10 (0%)		1/4 (25%)
Hypertriglyceridemia	0/13 (0%)		1/10 (10%)		0/4 (0%)
Hypoalbuminemia	3/13 (23.1%)		4/10 (40%)		1/4 (25%)
Hypocalcemia	1/13 (7.7%)		2/10 (20%)		1/4 (25%)
Hypoglycemia	0/13 (0%)		0/10 (0%)		2/4 (50%)
Hypokalemia	4/13 (30.8%)		7/10 (70%)		1/4 (25%)
Hypomagnesemia	0/13 (0%)		3/10 (30%)		1/4 (25%)
Hyponatremia	3/13 (23.1%)		5/10 (50%)		1/4 (25%)
Hypophosphatemia	4/13 (30.8%)		3/10 (30%)		1/4 (25%)
Obesity	0/13 (0%)		0/10 (0%)		1/4 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/13 (7.7%)		1/10 (10%)		1/4 (25%)
Back pain	5/13 (38.5%)		2/10 (20%)		0/4 (0%)
Bone pain	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Chest wall pain	1/13 (7.7%)		1/10 (10%)		1/4 (25%)
Flank pain	1/13 (7.7%)		0/10 (0%)		1/4 (25%)
Generalized muscle weakness	2/13 (15.4%)		2/10 (20%)		2/4 (50%)
Joint range of motion decreased	0/13 (0%)		1/10 (10%)		0/4 (0%)
Muscle weakness upper limb	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Musculoskeletal and connective tissue disorder - Other, specify	2/13 (15.4%)		0/10 (0%)		0/4 (0%)
Myalgia	1/13 (7.7%)		0/10 (0%)		1/4 (25%)
Neck pain	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Pain in extremity	4/13 (30.8%)		3/10 (30%)		0/4 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/13 (7.7%)		1/10 (10%)		1/4 (25%)
Nervous system disorders
Dizziness	2/13 (15.4%)		0/10 (0%)		2/4 (50%)
Dysgeusia	4/13 (30.8%)		0/10 (0%)		1/4 (25%)
Dysphasia	0/13 (0%)		1/10 (10%)		0/4 (0%)
Headache	6/13 (46.2%)		2/10 (20%)		1/4 (25%)
Movements involuntary	0/13 (0%)		0/10 (0%)		1/4 (25%)
Nervous system disorders - Other, specify	0/13 (0%)		1/10 (10%)		3/4 (75%)
Neuralgia	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Paresthesia	0/13 (0%)		1/10 (10%)		2/4 (50%)
Peripheral sensory neuropathy	7/13 (53.8%)		6/10 (60%)		1/4 (25%)
Presyncope	0/13 (0%)		1/10 (10%)		0/4 (0%)
Somnolence	0/13 (0%)		1/10 (10%)		0/4 (0%)
Spasticity	2/13 (15.4%)		0/10 (0%)		0/4 (0%)
Syncope	0/13 (0%)		1/10 (10%)		0/4 (0%)
Tremor	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Psychiatric disorders
Agitation	0/13 (0%)		0/10 (0%)		1/4 (25%)
Anxiety	0/13 (0%)		1/10 (10%)		2/4 (50%)
Confusion	0/13 (0%)		0/10 (0%)		2/4 (50%)
Depression	0/13 (0%)		1/10 (10%)		2/4 (50%)
Hallucinations	0/13 (0%)		0/10 (0%)		1/4 (25%)
Insomnia	3/13 (23.1%)		3/10 (30%)		2/4 (50%)
Personality change	0/13 (0%)		1/10 (10%)		1/4 (25%)
Psychiatric disorders - Other, specify	0/13 (0%)		0/10 (0%)		1/4 (25%)
Renal and urinary disorders
Hematuria	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Proteinuria	3/13 (23.1%)		2/10 (20%)		0/4 (0%)
Renal and urinary disorders - Other, specify	0/13 (0%)		1/10 (10%)		0/4 (0%)
Urinary frequency	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Urinary tract pain	2/13 (15.4%)		0/10 (0%)		0/4 (0%)
Urinary urgency	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Cough	7/13 (53.8%)		4/10 (40%)		0/4 (0%)
Dyspnea	5/13 (38.5%)		3/10 (30%)		1/4 (25%)
Epistaxis	0/13 (0%)		1/10 (10%)		0/4 (0%)
Hoarseness	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Hypoxia	4/13 (30.8%)		1/10 (10%)		0/4 (0%)
Nasal congestion	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Pleural effusion	2/13 (15.4%)		3/10 (30%)		0/4 (0%)
Pleuritic pain	1/13 (7.7%)		1/10 (10%)		0/4 (0%)
Pneumonitis	3/13 (23.1%)		0/10 (0%)		0/4 (0%)
Postnasal drip	2/13 (15.4%)		1/10 (10%)		0/4 (0%)
Productive cough	1/13 (7.7%)		0/10 (0%)		1/4 (25%)
Pulmonary hypertension	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders - Other, specify	2/13 (15.4%)		1/10 (10%)		1/4 (25%)
Sore throat	2/13 (15.4%)		2/10 (20%)		0/4 (0%)
Wheezing	3/13 (23.1%)		2/10 (20%)		0/4 (0%)
Skin and subcutaneous tissue disorders
Alopecia	3/13 (23.1%)		2/10 (20%)		2/4 (50%)
Dry skin	0/13 (0%)		1/10 (10%)		1/4 (25%)
Erythema multiforme	0/13 (0%)		1/10 (10%)		0/4 (0%)
Hyperhidrosis	2/13 (15.4%)		0/10 (0%)		0/4 (0%)
Pruritus	3/13 (23.1%)		0/10 (0%)		0/4 (0%)
Rash acneiform	2/13 (15.4%)		0/10 (0%)		1/4 (25%)
Rash maculo-papular	2/13 (15.4%)		1/10 (10%)		0/4 (0%)
Skin and subcutaneous tissue disorders - Other, specify	3/13 (23.1%)		2/10 (20%)		1/4 (25%)
Vascular disorders
Hot flashes	1/13 (7.7%)		0/10 (0%)		0/4 (0%)
Hypertension	10/13 (76.9%)		9/10 (90%)		2/4 (50%)
Hypotension	5/13 (38.5%)		1/10 (10%)		0/4 (0%)
Lymphedema	1/13 (7.7%)		2/10 (20%)		1/4 (25%)

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.