Estrogen Receptor Negative, HER2/Neu Negative, Progesterone Receptor-negative, Stage IV Breast Cancer, Triple-negative Breast Carcinoma
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. 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: I. 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.
Interventions
DRUGeverolimus
Given PO
DRUGeribulin mesylate
Given IV
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Optional correlative studies
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level B1 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. | 13 |
| Dose Level A1 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. | 10 |
| Dose Level A2 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. | 4 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | HER-2/neu-amplified | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Dose Level B1 | Dose Level A2 | Dose Level A1 |
|---|---|---|---|---|
| Age, Continuous | 55 years | 56 years | 50.5 years | 52.5 years |
| ECOG performance status Ambulatory and capable of all selfcare but unable to carry out any work activities | 4 Participants | 1 Participants | 0 Participants | 3 Participants |
| ECOG performance status Fully active, able to carry on all pre-disease performance without restriction | 8 Participants | 4 Participants | 1 Participants | 3 Participants |
| ECOG performance status Restricted in physically strenuous activity but ambulatory and able to do work of a light nature | 15 Participants | 8 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 3 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 10 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian/Pacific Islander | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Unknown | 4 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 18 Participants | 10 Participants | 3 Participants | 5 Participants |
| Region of Enrollment United States | 27 Participants | 13 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Female | 27 Participants | 13 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 13 | 10 / 10 | 3 / 4 |
| other Total, other adverse events | 13 / 13 | 10 / 10 | 4 / 4 |
| serious Total, serious adverse events | 1 / 13 | 3 / 10 | 1 / 4 |
Outcome results
Primary
Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D)
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level B1 | Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D) | 4 Participants |
| Dose Level A1 | Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D) | 4 Participants |
| Dose Level A2 | Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D) | 2 Participants |
Primary
Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB)
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level B1 | Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB) | 10 Participants |
| Dose Level A1 | Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB) | 8 Participants |
| Dose Level A2 | Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB) | 3 Participants |
Secondary
Best Response Using the RECIST (Phase IB)
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
Population: 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 | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level B1 | Best Response Using the RECIST (Phase IB) | Stable Disease | 6 Participants |
| Dose Level B1 | Best Response Using the RECIST (Phase IB) | Partial Remission | 5 Participants |
| Dose Level B1 | Best Response Using the RECIST (Phase IB) | Progressive Disease | 1 Participants |
| Dose Level A1 | Best Response Using the RECIST (Phase IB) | Stable Disease | 2 Participants |
| Dose Level A1 | Best Response Using the RECIST (Phase IB) | Partial Remission | 3 Participants |
| Dose Level A1 | Best Response Using the RECIST (Phase IB) | Progressive Disease | 5 Participants |
| Dose Level A2 | Best Response Using the RECIST (Phase IB) | Partial Remission | 1 Participants |
| Dose Level A2 | Best Response Using the RECIST (Phase IB) | Progressive Disease | 1 Participants |
| Dose Level A2 | Best Response Using the RECIST (Phase IB) | Stable Disease | 1 Participants |
Secondary
Median Overall Survival (Phase IB)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level B1 | Median Overall Survival (Phase IB) | 8.3 months |
Secondary
Median Progression Free Survival (Phase IB)
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level B1 | Median Progression Free Survival (Phase IB) | 2.6 months |
Secondary
Number of Participants With Grade 3 or Higher Toxicities (Phase IB)
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level B1 | Number of Participants With Grade 3 or Higher Toxicities (Phase IB) | 8 Participants |
| Dose Level A1 | Number of Participants With Grade 3 or Higher Toxicities (Phase IB) | 5 Participants |
| Dose Level A2 | Number of Participants With Grade 3 or Higher Toxicities (Phase IB) | 3 Participants |