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Multi-epitope Folate Receptor Alpha Peptide Vaccine, GM-CSF, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer

Primary Purpose

Bilateral Breast Carcinoma, Breast Inflammatory Carcinoma, Stage IB Breast Cancer AJCC v7

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Laboratory Biomarker Analysis
Multi-epitope Folate Receptor Alpha Peptide Vaccine
Placebo Administration
Sargramostim
Sponsored by
Academic and Community Cancer Research United
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bilateral Breast Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Age >= 18 years
  • Female
  • Resected unilateral or bilateral primary carcinoma of the breast without clinical evidence of metastatic disease (after neoadjuvant chemotherapy and/or adjuvant chemotherapy), negative for estrogen receptor (ER) and progesterone receptor (PR) (cut-off for positivity is > 10% positive tumor cells with nuclear staining), and negative for HER2 as defined by one of the four situations delineated below:

    • HER2 immunohistochemistry (IHC) expression of 0 or 1+ and in-situ hybridization non-amplified
    • HER2 IHC expression of 0 or 1+ and in-situ hybridization not done
    • HER2 IHC expression of 2+ and in-situ hybridization non-amplified
    • IHC not done and in-situ hybridization non-amplified
    • Note: central review is not required
    • Note: If biopsy and surgical specimens are discordant from each other with regard to ER, PR, and/or HER2 status, a patient will be allowed to enroll assuming at least one of the specimens meets the above criteria and no endocrine therapy use is planned going forward
  • Completed planned breast CANCER surgeries, any radiation therapy, and any chemotherapy, whichever is last, >= 90 days but not >= 546 days prior to randomization

    • Note: Reconstructive and prophylactic surgeries are allowed after randomization (during study treatment)
  • Patient had at least one of the following:

    • Biopsy or surgery-proven regional node involvement by cancer
    • T1c, T2, T3, or T4 disease (with inflammatory disease allowed) identified at the time of surgery or clinically identified prior to neoadjuvant chemotherapy
    • No complete response to neoadjuvant chemotherapy (those who did achieve complete response are still eligible if a pre-chemotherapy regional nodal biopsy identified cancer or if the pre-chemotherapy tumor measured > 1 cm)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1
  • Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to randomization
  • Platelet count >= 75,000/uL obtained =< 14 days prior to randomization
  • Aspartate transaminase (AST) =< 3 x upper limit of normal (ULN) obtained =< 14 days prior to randomization
  • Creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization
  • Negative serum pregnancy test done =< 14 days prior to randomization, for women of childbearing potential only
  • Provide informed written consent
  • Willing to return to enrolling institution for follow-up
  • Willing to provide tissue and blood samples for correlative research studies

Exclusion Criteria:

  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

    • Pregnant women
    • Nursing women
    • Women of childbearing potential who are unwilling to employ adequate contraception
  • Clinical evidence of local recurrence or distant metastases; Note: New primary tumors are allowed, both contralaterally and ipsilaterally, but a prior breast cancer must have been more than 5 years beforehand
  • Known hypersensitivity reaction to GM-CSF
  • Active autoimmune disease that has required systemic treatment =< 30 days (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) prior to randomization; Note: replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment; patients with vitiligo, Graves disease, or psoriasis not requiring systemic treatment within the past 30 days are not excluded; patients with Celiac disease controlled with diet modification are not excluded
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

    • NOTE: Localized fungal or viral infections including of the skin, nails, mouth, and genital area are allowed
  • History of other cancer < 5 years prior to consent (except non-melanoma skin cancer or carcinoma in situ of the uterine cervix) or current receipt of treatment another cancer (e.g., monoclonal antibody, small molecule pathway inhibitor)
  • Treatment with systemic corticosteroid or immune-modulators =< 7 days prior to randomization
  • Concurrent treatment with other experimental drugs or any other systemic anticancer therapy (due to unknown drug-vaccine potential interactions). Use of experimental or other targeted therapy > 3 months prior is allowed as long as it is not Her2-directed

    • NOTE: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, and other medications commonly used to treat nononcologic, non-autoimmune conditions are allowed
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
  • Prior or concurrent use of trastuzumab or other Her2-directed therapy
  • Prior or concurrent use of a PD-1 or PD-L1 checkpoint inhibitor (including pembrolizumab) unless the use was >= 3 months prior to randomization

Sites / Locations

  • Mayo Clinic in Arizona
  • City of Hope Comprehensive Cancer Center
  • Mayo Clinic in Florida
  • University of Miami Miller School of Medicine-Sylvester Cancer Center
  • University of Chicago Comprehensive Cancer Center
  • Carle Cancer Center NCI Community Oncology Research Program
  • Ochsner Medical Center Jefferson
  • Massachusetts General Hospital Cancer Center
  • Dana-Farber Cancer Institute
  • Mayo Clinic in Rochester
  • Inova Fairfax Hospital
  • Marshfield Medical Center-Marshfield

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (FRalpha peptide vaccine, sargramostim)

Arm II (placebo, sargramostim)

Arm Description

Patients receive cyclophosphamide PO BID on days 1-7 and 15-21 of cycle 1 only. Starting cycle 2, patients receive multi-epitope folate receptor alpha peptide vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression or unacceptable toxicity.

Patients receive cyclophosphamide as in Arm I. Starting cycle 2, patients receive placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Disease-free survival
Will be estimated using the method of Kaplan-Meier. Will use the stratified log-rank tests.

Secondary Outcome Measures

Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events 4.0
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed by primary disease site to determine toxicity patterns. Will use the Cochran-Mantel Haenszel chi-squared test with study stratification factors. Will use logistic regression to test differences in proportions while controlling for the known covariates.
Overall survival
Will be estimated using the method of Kaplan-Meier. Will use the stratified log-rank tests.
Vaccine induced folate receptor [FR]alpha-specific T cell responses defined as the proportion of patients with at least a 2-fold increase in the number of cells/plasma concentration
Will be determined along with its corresponding 95% confidence interval.
FRalpha levels
FRalpha levels at baseline will be examined as a prognostic factor in the vaccine immune response. A multivariable Cox proportional hazard model will be used to assess baseline FRalpha levels as a potential prognostic factor for immune response.

Full Information

First Posted
December 29, 2016
Last Updated
January 12, 2023
Sponsor
Academic and Community Cancer Research United
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03012100
Brief Title
Multi-epitope Folate Receptor Alpha Peptide Vaccine, GM-CSF, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer
Official Title
Double Blind, Parallel Groups, Controlled, Randomized Phase II Trial to Evaluate Vaccination With Folate Receptor Alpha Peptide Vaccine With GM-CSF as Vaccine Adjuvant Following Oral Cyclophosphamide Versus GM-CSF/Placebo to Prevent Recurrence in Patients With Triple Negative Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 31, 2017 (Actual)
Primary Completion Date
August 30, 2022 (Actual)
Study Completion Date
July 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Academic and Community Cancer Research United
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This randomized phase II trial studies how well multi-epitope folate receptor alpha peptide vaccine, sargramostim (GM-CSF), and cyclophosphamide work to prevent the recurrence of stage 1-3 triple negative breast cancer. Vaccines made from a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving multi-epitope folate receptor alpha peptide vaccine, sargramostim (GM-CSF), and cyclophosphamide may work well together to prevent cancer recurrence after surgery and other standard treatments for triple negative breast cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To show that multi-epitope folate receptor alpha peptide vaccine (folate receptor [FR]alpha peptide vaccine) with sargramostim (GM-CSF) adjuvant will prolong the disease-free survival (DFS) compared to GM-CSF adjuvant treatment in patients with triple negative breast cancer. SECONDARY OBJECTIVE: I. To compare the safety and tolerability of metronomic cyclophosphamide followed by FRalpha peptide vaccine with GM-CSF versus GM-CSF alone. CORRELATIVE RESEARCH OBJECTIVES: I. To determine whether high level of antibody and cellular immune response toward the FRalpha measured at baseline is a prognostic factor for vaccine immune response and/or cancer relapse. II. To determine whether the level of tumor expression of FRalpha at baseline is a prognosis factor for vaccine immune response and/or cancer relapse. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive cyclophosphamide orally (PO) twice daily (BID) on days 1-7 and 15-21 of cycle 1 only. Starting cycle 2, patients receive multi-epitope folate receptor alpha peptide vaccine with sargramostim intradermally (ID) on day 1. Treatment repeats every 28 days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive cyclophosphamide as in Arm I. Starting cycle 2, patients receive placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bilateral Breast Carcinoma, Breast Inflammatory Carcinoma, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Triple-Negative Breast Carcinoma, Unilateral Breast Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
280 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (FRalpha peptide vaccine, sargramostim)
Arm Type
Experimental
Arm Description
Patients receive cyclophosphamide PO BID on days 1-7 and 15-21 of cycle 1 only. Starting cycle 2, patients receive multi-epitope folate receptor alpha peptide vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression or unacceptable toxicity.
Arm Title
Arm II (placebo, sargramostim)
Arm Type
Placebo Comparator
Arm Description
Patients receive cyclophosphamide as in Arm I. Starting cycle 2, patients receive placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for cycles 2-7 and every 6 months for cycles 8-14 in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Biological
Intervention Name(s)
Multi-epitope Folate Receptor Alpha Peptide Vaccine
Other Intervention Name(s)
FR Alpha Peptide Vaccine
Intervention Description
Given ID
Intervention Type
Other
Intervention Name(s)
Placebo Administration
Intervention Description
Given ID
Intervention Type
Biological
Intervention Name(s)
Sargramostim
Other Intervention Name(s)
23-L-Leucinecolony-Stimulating Factor 2, DRG-0012, Leukine, Prokine, rhu GM-CFS, Sagramostim, Sargramostatin
Intervention Description
Given ID
Primary Outcome Measure Information:
Title
Disease-free survival
Description
Will be estimated using the method of Kaplan-Meier. Will use the stratified log-rank tests.
Time Frame
Through study completion (average of 5 years)
Secondary Outcome Measure Information:
Title
Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events 4.0
Description
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed by primary disease site to determine toxicity patterns. Will use the Cochran-Mantel Haenszel chi-squared test with study stratification factors. Will use logistic regression to test differences in proportions while controlling for the known covariates.
Time Frame
Through study completion (average of 5 years)
Title
Overall survival
Description
Will be estimated using the method of Kaplan-Meier. Will use the stratified log-rank tests.
Time Frame
Through study completion (average of 5 years)
Title
Vaccine induced folate receptor [FR]alpha-specific T cell responses defined as the proportion of patients with at least a 2-fold increase in the number of cells/plasma concentration
Description
Will be determined along with its corresponding 95% confidence interval.
Time Frame
Through study completion (average of 5 years)
Title
FRalpha levels
Description
FRalpha levels at baseline will be examined as a prognostic factor in the vaccine immune response. A multivariable Cox proportional hazard model will be used to assess baseline FRalpha levels as a potential prognostic factor for immune response.
Time Frame
Through study completion (average of 5 years)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >= 18 years Female Resected unilateral or bilateral primary carcinoma of the breast without clinical evidence of metastatic disease (after neoadjuvant chemotherapy and/or adjuvant chemotherapy), negative for estrogen receptor (ER) and progesterone receptor (PR) (cut-off for positivity is > 10% positive tumor cells with nuclear staining), and negative for HER2 as defined by one of the four situations delineated below: HER2 immunohistochemistry (IHC) expression of 0 or 1+ and in-situ hybridization non-amplified HER2 IHC expression of 0 or 1+ and in-situ hybridization not done HER2 IHC expression of 2+ and in-situ hybridization non-amplified IHC not done and in-situ hybridization non-amplified Note: central review is not required Note: If biopsy and surgical specimens are discordant from each other with regard to ER, PR, and/or HER2 status, a patient will be allowed to enroll assuming at least one of the specimens meets the above criteria and no endocrine therapy use is planned going forward Completed planned breast CANCER surgeries, any radiation therapy, and any chemotherapy, whichever is last, >= 90 days but not >= 546 days prior to randomization Note: Reconstructive and prophylactic surgeries are allowed after randomization (during study treatment) Patient had at least one of the following: Biopsy or surgery-proven regional node involvement by cancer T1c, T2, T3, or T4 disease (with inflammatory disease allowed) identified at the time of surgery or clinically identified prior to neoadjuvant chemotherapy No complete response to neoadjuvant chemotherapy (those who did achieve complete response are still eligible if a pre-chemotherapy regional nodal biopsy identified cancer or if the pre-chemotherapy tumor measured > 1 cm) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to randomization Platelet count >= 75,000/uL obtained =< 14 days prior to randomization Aspartate transaminase (AST) =< 3 x upper limit of normal (ULN) obtained =< 14 days prior to randomization Creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization Negative serum pregnancy test done =< 14 days prior to randomization, for women of childbearing potential only Provide informed written consent Willing to return to enrolling institution for follow-up Willing to provide tissue and blood samples for correlative research studies Exclusion Criteria: Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: Pregnant women Nursing women Women of childbearing potential who are unwilling to employ adequate contraception Clinical evidence of local recurrence or distant metastases; Note: New primary tumors are allowed, both contralaterally and ipsilaterally, but a prior breast cancer must have been more than 5 years beforehand Known hypersensitivity reaction to GM-CSF Active autoimmune disease that has required systemic treatment =< 30 days (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) prior to randomization; Note: replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment; patients with vitiligo, Graves disease, or psoriasis not requiring systemic treatment within the past 30 days are not excluded; patients with Celiac disease controlled with diet modification are not excluded Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements NOTE: Localized fungal or viral infections including of the skin, nails, mouth, and genital area are allowed History of other cancer < 5 years prior to consent (except non-melanoma skin cancer or carcinoma in situ of the uterine cervix) or current receipt of treatment another cancer (e.g., monoclonal antibody, small molecule pathway inhibitor) Treatment with systemic corticosteroid or immune-modulators =< 7 days prior to randomization Concurrent treatment with other experimental drugs or any other systemic anticancer therapy (due to unknown drug-vaccine potential interactions). Use of experimental or other targeted therapy > 3 months prior is allowed as long as it is not Her2-directed NOTE: Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, and other medications commonly used to treat nononcologic, non-autoimmune conditions are allowed Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy Prior or concurrent use of trastuzumab or other Her2-directed therapy Prior or concurrent use of a PD-1 or PD-L1 checkpoint inhibitor (including pembrolizumab) unless the use was >= 3 months prior to randomization
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kathryn J Ruddy
Organizational Affiliation
Academic and Community Cancer Research United
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224-9980
Country
United States
Facility Name
University of Miami Miller School of Medicine-Sylvester Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Carle Cancer Center NCI Community Oncology Research Program
City
Urbana
State/Province
Illinois
ZIP/Postal Code
61801
Country
United States
Facility Name
Ochsner Medical Center Jefferson
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
Massachusetts General Hospital Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Inova Fairfax Hospital
City
Falls Church
State/Province
Virginia
ZIP/Postal Code
22042
Country
United States
Facility Name
Marshfield Medical Center-Marshfield
City
Marshfield
State/Province
Wisconsin
ZIP/Postal Code
54449
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Multi-epitope Folate Receptor Alpha Peptide Vaccine, GM-CSF, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer

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