Fulvestrant With or Without Bortezomib in Patients With Inoperable Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer

The PFS distributions of the two treatment arms will be estimated by Kaplan-Meier.
PFS distributions will be compared by an unstratified log-rank test.

The PFS distributions of the two treatment arms will be estimated by Kaplan-Meier.
PFS distributions will be compared by an unstratified log-rank test.
Ninety-five percent confidence intervals for the Kaplan-Meier PFS estimates will be calculated using Greenwood's formulae.

Arm I (fulvestrant)

Arm A (fulvestrant)

Patients receive fulvestrant intramuscularly on day 1 (days -14, 1, and 15 of course 1 only).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with progressive disease may crossover to arm II.

Patients receive fulvestrant IM on day 1 (days -14, 1, and 15 of course 1 only).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with progressive disease may crossover to arm C.

Arm II (fulvestrant, bortezomib)

Arm B (fulvestrant, bortezomib)

Patients receive fulvestrant as in arm I and bortezomib IV on days 1, 8, and 15 (beginning in course 2).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15 (beginning in course 2).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Given intramuscularly

Given IM

Arm I (fulvestrant)

Arm A (fulvestrant)

Arm II (fulvestrant, bortezomib)

Arm B (fulvestrant, bortezomib)

Arm II (fulvestrant, bortezomib)

Arm B (fulvestrant, bortezomib)

Arm I (fulvestrant)

Arm A (fulvestrant)

Arm II (fulvestrant, bortezomib)

Arm B (fulvestrant, bortezomib)

<p>Inclusion Criteria:</p><ul><li>ELIGIBILITY CRITERIA FOR ARM A AND ARM B</li><li>Patients must have histologically or cytologically confirmed ER+ positive breast cancer</li><li>Patients must be postmenopausal, defined as: (1) a history of at least 12 months without spontaneous menstrual bleeding, (2) prior bilateral salpingo-oophorectomy, with or without hysterectomy, (3) age &gt;= 55 years with a prior hysterectomy with or without oophorectomy, (4) age &lt; 55 years with a prior hysterectomy without oophorectomy or unknown status, with a documented FSH level in postmenopausal range within 4 week s of registration, (5) receiving a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (eg, goserelin 3.6 mg q 4 weeks)</li><li>Patients must have stage IV disease or inoperable locally advanced disease</li><li>Patients may have measurable disease only, non-measurable disease only, or both (RECIST 1.1); it is anticipated that at least 50% of patients will have only non-measurable disease</li><li>Patients are required to have disease that is resistant to aromatase inhibitor (AI), which is defined either as relapse while receiving adjuvant A.I. therapy (ie, anastrazole, letrozole, or exemestane), and&#x2F;or disease progression after one or more A.I.s for metastatic disease; prior exposure to more than one AI is permitted</li><li>Patient may have had prior tamoxifen but are not required to</li><li>Patients may have received up to one prior chemotherapy regimen for metastatic disease</li><li>Patients may have received prior bevacizumab</li><li>Patients who have received up to 2 doses of fulvestrant given within a 4 week period prior to registration are eligible; the interval between the first fulvestrant dose and registration must be 6 weeks or less; patients may have received EITHER 250 mg or 500 mg of fulvestrant previously; if the patient has received 250 mg, they will receive the 500 mg loading dose on study day -14; if they already received 500 mg, they will begin the study on day +1</li><li>Life expectancy of greater than 3 months</li><li>ECOG performance status =&lt; 2 (Karnofsky &gt;= 60%)</li><li>Leukocytes &gt;= 3,000&#x2F;mcL</li><li>Absolute neutrophil count &gt;= 1,500&#x2F;mcL</li><li>Platelets &gt;= 100,000&#x2F;mcL</li><li>Total bilirubin within normal institutional limits</li><li>AST(SGOT)&#x2F;ALT(SGPT) =&lt; 2.5 x institutional upper limit of normal</li><li>Creatinine within normal institutional limits OR</li><li>Creatinine clearance &gt;= 60 mL&#x2F;min&#x2F;1.73
m^2 for patients with creatinine levels above institutional normal</li><li>Patients must be disease-free of prior invasive malignancies for &gt;= 5 years with the exception of: curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix</li><li>Patients must have the ability to understand and the willingness to sign a written informed consent document</li><li>The effects of bortezomib on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately</li><li>ELIGIBILITY CRITERIA FOR ARM C</li><li>Previously met all eligibility criteria for arms A and B and registered on trial to arm A (fulvestrant alone)</li><li>Disease progression on arm A and agreeable to crossover to arm C</li><li>Has received no intervening therapy (ie, alternative endocrine therapy, chemotherapy, biologic therapy) between disease progression on arm A and registration an arm C</li><li>ECOG performance status 0-2</li><li>Tumor measurements (eg, CT scan of chest&#x2F;abdomen&#x2F;pelvis) within 4 weeks of registration to arm C</li><li><p>Normal organ and marrow function as defined below (within 2 weeks of registration on arm C):</p><ul><li>Leukocytes &gt;= 3,000&#x2F;mcL</li><li>Absolute neutrophil count &gt;= 1,500&#x2F;mcL</li><li>Platelets &gt;= 100,000&#x2F;mcL</li><li>Total bilirubin within normal institutional limits</li><li>AST(SGOT)&#x2F;ALT(SGPT) =&lt; 2.5 x institutional upper limit of normal</li><li>Creatinine within normal institutional limits OR</li><li>Creatinine clearance &gt;= 60 mL&#x2F;min&#x2F;1.73
m^2 for patients with creatinine levels above institutional normal</li></ul></li></ul><p>Exclusion Criteria:</p><ul><li>EXCLUSION CRITERIA FOR ARM A AND ARM B</li><li>Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier</li><li>Patients may not be receiving any other investigational agents</li><li>Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events</li><li>Presence of rapidly progressive, life-threatening metastases; this includes patients with extensive hepatic involvement (&gt; 50% of the liver involved), symptomatic lymphangitic metastases, or brain or leptomeningeal involvement</li><li>History of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib or fulvestrant</li><li>Patients who are concomitantly receiving bortezomib and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy</li><li>Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness&#x2F;social situations that would limit compliance with study requirements</li><li>HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with bortezomib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated</li><li>Patients who have previously received fulvestrant</li><li>Patients who have previously received bortezomib</li><li>Concomitant anticancer treatment with the following exceptions: (1) bisphosphonates for bone metastases, (2) a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued</li><li>Grade 2 or more peripheral neuropathy because the dose limiting toxicity of bortezomib is neuropathy</li></ul>

<p>Inclusion Criteria:</p><ul><li>ELIGIBILITY CRITERIA FOR ARM A AND ARM B</li><li>Patients must have histologically or cytologically confirmed ER+ positive breast cancer</li><li>Patients must be postmenopausal, defined as: (1) a history of at least 12 months without spontaneous menstrual bleeding, (2) prior bilateral salpingo-oophorectomy, with or without hysterectomy, (3) age &gt;= 55 years with a prior hysterectomy with or without oophorectomy, (4) age &lt; 55 years with a prior hysterectomy without oophorectomy or unknown status, with a documented follicle-stimulating hormone (FSH) level in postmenopausal range within 4 week s of registration, (5) receiving a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (eg, goserelin 3.6 mg every [q] 4 weeks)</li><li>Patients must have stage IV disease or inoperable locally advanced disease</li><li>Patients may have measurable disease only, non-measurable disease only, or both (Response Evaluation Criteria in Solid Tumors [RECIST 1.1]); it is anticipated that at least 50% of patients will have only non-measurable disease</li><li>Patients are required to have disease that is resistant to aromatase inhibitor (AI), which is defined either as relapse while receiving adjuvant A.I. therapy (ie, anastrazole, letrozole, or exemestane), and&#x2F;or disease progression after one or more A.I.s for metastatic disease; prior exposure to more than one AI is permitted</li><li>Patient may have had prior tamoxifen but are not required to</li><li>Patients may have received up to one prior chemotherapy regimen for metastatic disease</li><li>Patients may have received prior bevacizumab</li><li>Patients who have received up to 2 doses of fulvestrant given within a 4 week period prior to registration are eligible; the interval between the first fulvestrant dose and registration must be 6 weeks or less; patients may have received EITHER 250 mg or 500 mg of fulvestrant previously; if the patient has received 250 mg, they will receive the 500 mg loading dose on study day -14; if they already received 500 mg, they will begin the study on day +1</li><li>Life expectancy of greater than 3 months</li><li>Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)</li><li>Leukocytes &gt;= 3,000&#x2F;mcL</li><li>Absolute neutrophil count &gt;= 1,500&#x2F;mcL</li><li>Platelets &gt;= 100,000&#x2F;mcL</li><li>Total bilirubin within normal institutional limits</li><li>Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])&#x2F;alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2.5 x institutional upper limit of normal</li><li>Creatinine within normal institutional limits OR</li><li>Creatinine clearance &gt;= 60 mL&#x2F;min&#x2F;1.73
m^2 for patients with creatinine levels above institutional normal</li><li>Patients must be disease-free of prior invasive malignancies for &gt;= 5 years with the exception of: curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix</li><li>Patients must have the ability to understand and the willingness to sign a written informed consent document</li><li>Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately</li><li>ELIGIBILITY CRITERIA FOR ARM C</li><li>Previously met all eligibility criteria for arms A and B and registered on trial to arm A (fulvestrant alone)</li><li>Disease progression on arm A and agreeable to crossover to arm C</li><li>Has received no intervening therapy (ie, alternative endocrine therapy, chemotherapy, biologic therapy) between disease progression on arm A and registration an arm C</li><li>ECOG performance status 0-2</li><li>Tumor measurements (eg, CT scan of chest&#x2F;abdomen&#x2F;pelvis) within 4 weeks of registration to arm C</li><li><p>Normal organ and marrow function as defined below (within 2 weeks of registration on arm C):</p><ul><li>Leukocytes &gt;= 3,000&#x2F;mcL</li><li>Absolute neutrophil count &gt;= 1,500&#x2F;mcL</li><li>Platelets &gt;= 100,000&#x2F;mcL</li><li>Total bilirubin within normal institutional limits</li><li>AST(SGOT)&#x2F;ALT(SGPT) =&lt; 2.5 x institutional upper limit of normal</li><li>Creatinine within normal institutional limits OR</li><li>Creatinine clearance &gt;= 60 mL&#x2F;min&#x2F;1.73
m^2 for patients with creatinine levels above institutional normal</li></ul></li></ul><p>Exclusion Criteria:</p><ul><li>EXCLUSION CRITERIA FOR ARM A AND ARM B</li><li>Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier</li><li>Patients may not be receiving any other investigational agents</li><li>Patients with known brain metastases should be excluded from this clinical trial</li><li>Presence of rapidly progressive, life-threatening metastases; this includes patients with extensive hepatic involvement (&gt; 50% of the liver involved), symptomatic lymphangitic metastases, or brain or leptomeningeal involvement</li><li>History of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib or fulvestrant</li><li>Patients who are concomitantly receiving bortezomib and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy</li><li>Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness&#x2F;social situations that would limit compliance with study requirements</li><li>HIV-positive patients on combination antiretroviral therapy are ineligible</li><li>Patients who have previously received fulvestrant</li><li>Patients who have previously received bortezomib</li><li>Concomitant anticancer treatment with the following exceptions: (1) bisphosphonates for bone metastases, (2) a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a selective estrogen receptor modulators (SERMs) or an AI; the GnRH analog may continue but the SERM or AI must be discontinued</li><li>Grade 2 or more peripheral neuropathy</li></ul>

Clinical benefit rate (CBR) (CR, PR, or SD)

Clinical benefit rate (CBR) (complete response [CR], partial response [PR], or stable disease [SD]), evaluated according to RECIST

Ninety-five percent confidence intervals will be calculated for the clinical benefit response proportion in each arm via binomial proportions.

Ninety-five percent confidence intervals will be calculated for the clinical benefit response proportion in each arm via binomial proportions.
Comparison of the clinical benefit rate between the treatment arms will be performed by the chi-square test or Fisher's exact test, as appropriate.

Up to 24 weeks

Up to 4 years

Percentage of progression-free

Percentage progression-free

Ninety-five percent confidence intervals will be calculated for the percent progression-free at 24 weeks in each arm via binomial proportions

Ninety-five percent confidence intervals will be calculated for the percent progression-free at 24 weeks in each arm via binomial proportions.
Comparison of the percent progression-free at 24 weeks between the treatment arms will be performed by the chi-square test or Fisher's exact test, as appropriate.

Up to 24 weeks

At 24 weeks

Overall response rate

Overall survival

Using Kaplan-Meier method.

Estimated using the Kaplan-Meier method.
The comparison of the overall survival distributions between the treatment arms will be performed by the log-rank test.

From first treatment day until death, assessed up to 4 years

The time from first treatment day until death, assessed up to 4 years

Toxicity as assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Toxicity as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

06520-8032

06520

Case Western Reserve University

University Hospitals Case Medical Center

Cleveland Clinic Foundation

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

2013-12-06

2014-02-10

2013-12-09

2014-02-11

<p>PRIMARY OBJECTIVES:</p><p>I. To determine if the addition of bortezomib to fulvestrant improves median progression free survival (PFS) compared with fulvestrant alone in postmenopausal women with ER-positive locally advanced inoperable or metastatic breast cancer who have disease that is resistant to aromatase inhibitor therapy (Arms A vs. B).</p><p>SECONDARY OBJECTIVES:</p><p>I. To determine if the addition of bortezomib to fulvestrant improves the clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day+1).</p><p>II.
To determine the percent of patients, treated with fulvestrant alone and fulvestrant plus bortezomib, who remain progression-free 24 weeks from day+1 (Arms A vs. B).</p><p>III.
To determine the overall survival of patients treated with fulvestrant alone and fulvestrant plus bortezomib.
(Arms A, B, C).</p><p>IV.
To determine the adverse event profile in patients treated with fulvestrant alone and fulvestrant plus bortezomib (Arms A, B, C).</p><p>V. To determine the clinical benefit rate at 12 and 24 weeks of fulvestrant plus bortezomib in patients who have progressed on the fulvestrant alone arm and crossover to receive the combination (Arm C).</p><p>TERTIARY OBJECTIVES:</p><p>I. To perform an exploratory analysis of the effects of bortezomib (plus fulvestrant) in intratumoral nuclear&#x2F;cytoplasmic ER ratio, unfolded protein response (BiP), apoptotis (cleaved caspase 3, Bcl-2 phospho JNK in patients with tumors accessible to biopsy who consent to optional post-treatment biopsy.</p><p>II.
To determine with cyclin D1 expression in pretreatment tumor specimens (from metastatic disease or the primary tumor if the former is not available) is predictive of clinical benefit with fulvestrant-bortezomib.</p><p>OUTLINE: Patients are randomized to 1 of 2 treatment arms.</p><p>Arm I: Patients receive fulvestrant intramuscularly on day 1 (days -14, 1, and 15 of course 1 only).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with progressive disease may crossover to arm II.</p><p>Arm II: Patients receive fulvestrant as in arm I and bortezomib IV on days 1, 8, and 15 (beginning in course 2).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</p><p>After completion of study therapy, patients are followed up every 3 months.</p>

<p>PRIMARY OBJECTIVES:</p><p>I. To determine if the addition of bortezomib to fulvestrant improves median progression free survival (PFS) compared with fulvestrant alone in postmenopausal women with estrogen receptor (ER)-positive locally advanced inoperable or metastatic breast cancer who have disease that is resistant to aromatase inhibitor therapy (Arms A vs. B).</p><p>SECONDARY OBJECTIVES:</p><p>I. To determine if the addition of bortezomib to fulvestrant improves the clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day +1).</p><p>II.
To determine the percent of patients, treated with fulvestrant alone and fulvestrant plus bortezomib, who remain progression-free 24 weeks from day +1 (Arms A vs. B).</p><p>III.
To determine the overall survival of patients treated with fulvestrant alone and fulvestrant plus bortezomib (Arms A, B, C).</p><p>IV.
To determine the adverse event profile in patients treated with fulvestrant alone and fulvestrant plus bortezomib (Arms A, B, C).</p><p>V. To determine the clinical benefit rate at 12 and 24 weeks of fulvestrant plus bortezomib in patients who have progressed on the fulvestrant alone arm and crossover to receive the combination (Arm C).</p><p>TERTIARY OBJECTIVES:</p><p>I. To perform an exploratory analysis of the effects of bortezomib (plus fulvestrant) in intratumoral nuclear&#x2F;cytoplasmic ER ratio, unfolded protein response (BiP), apoptosis (cleaved caspase 3), B-cell chronic lymphocytic leukemia (CLL)&#x2F;lymphoma 2 (Bcl-2) phospho c-Jun N-terminal kinase (JNK) in patients with tumors accessible to biopsy who consent to optional post-treatment biopsy.</p><p>II.
To determine with cyclin D1 expression in pretreatment tumor specimens (from metastatic disease or the primary tumor if the former is not available) is predictive of clinical benefit with fulvestrant-bortezomib.</p><p>OUTLINE: Patients are randomized to 1 of 2 treatment arms (Arms A or B).</p><p>ARM A: Patients receive fulvestrant intramuscularly (IM) on day 1 (days -14, 1, and 15 of course 1 only).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with progressive disease may crossover to arm C.</p><p>ARM B: Patients receive fulvestrant as in arm A and bortezomib intravenously (IV) on days 1, 8, and 15 (beginning in course 2).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</p><p>ARM C: Patients receive fulvestrant IM on day 1 and bortezomib IM on days 1, 8, and 15.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</p><p>After completion of study therapy, patients are followed up every 3 months.</p>

N01CM00070

N01CM62207

https://reporter.nih.gov/quickSearch/N01CM00070

https://reporter.nih.gov/quickSearch/N01CM62207