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

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ClinicalTrials.gov Identifier: NCT03012100
Recruitment Status : Recruiting
First Posted : January 6, 2017
Last Update Posted : December 14, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

December 29, 2016
January 6, 2017
December 14, 2018
March 31, 2017
July 31, 2021   (Final data collection date for primary outcome measure)
Disease-free survival [ Time Frame: Through study completion (average of 5 years) ]
Will be estimated using the method of Kaplan-Meier. Will use the stratified log-rank tests.
Same as current
Complete list of historical versions of study NCT03012100 on ClinicalTrials.gov Archive Site
  • Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events 4.0 [ Time Frame: Through study completion (average of 5 years) ]
    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 [ Time Frame: Through study completion (average of 5 years) ]
    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 [ Time Frame: Through study completion (average of 5 years) ]
    Will be determined along with its corresponding 95% confidence interval.
  • FRalpha levels [ Time Frame: Through study completion (average of 5 years) ]
    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.
  • FRalpha levels [ Time Frame: Through study completion (average of 5 years) ]
    FR alpha 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 FR alpha levels as a potential prognostic factor for immune response.
  • Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events 4.0 [ Time Frame: Through study completion (average of 5 years) ]
    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 [ Time Frame: Through study completion (average of 5 years) ]
    Will be estimated using the method of Kaplan-Meier. Will use the stratified log-rank tests.
  • Vaccine induced FRalpha-specific T cell responses defined as the proportion of patients with at least a 2-fold increase in the number of cells/plasma concentration [ Time Frame: Through study completion (average of 5 years) ]
    Will be determined along with its corresponding 95% confidence interval.
Not Provided
Not Provided
 
Multi-epitope Folate Receptor Alpha Peptide Vaccine, Sargramostim, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer
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
This randomized phase II trial studies how well multi-epitope folate receptor alpha peptide vaccine, sargramostim, and cyclophosphamide work in treating patients with 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, and cyclophosphamide may work better in treating patients with triple negative breast cancer.

PRIMARY OBJECTIVES:

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 OBJECTIVES:

I. To compare the safety and tolerability of metronomic cyclophosphamide followed by FRalpha peptide vaccine with GM-CSF versus GM-CSF alone.

TERTIARY 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 course 1 only. Starting course 2, patients receive multi-epitope folate receptor alpha peptide vaccine with sargramostim intradermally (ID) on day 1. Treatment repeats every 28 days for courses 2-7 and every 6 months for courses 8-14 in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cyclophosphamide as in Arm I. Starting course 2, patients receive placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for courses 2-7 and every 6 months for courses 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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
  • Bilateral Breast Carcinoma
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Progesterone Receptor Negative
  • 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
  • Stage IV Breast Cancer AJCC v6 and v7
  • Triple-Negative Breast Carcinoma
  • Unilateral Breast Carcinoma
  • Drug: Cyclophosphamide
    Given PO
    Other Names:
    • (-)-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
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Multi-epitope Folate Receptor Alpha Peptide Vaccine
    Given ID
    Other Name: FR Alpha Peptide Vaccine
  • Other: Placebo
    Given ID
    Other Names:
    • placebo therapy
    • PLCB
    • sham therapy
  • Biological: Sargramostim
    Given ID
    Other Names:
    • 23-L-Leucinecolony-Stimulating Factor 2
    • DRG-0012
    • Leukine
    • Prokine
    • rhu GM-CFS
    • Sagramostim
    • Sargramostatin
  • Experimental: Arm I (FRalpha peptide vaccine, sargramostim)
    Patients receive cyclophosphamide PO BID on days 1-7 and 15-21 of course 1 only. Starting course 2, patients receive multi-epitope folate receptor alpha peptide vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for courses 2-7 and every 6 months for courses 8-14 in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cyclophosphamide
    • Other: Laboratory Biomarker Analysis
    • Biological: Multi-epitope Folate Receptor Alpha Peptide Vaccine
    • Biological: Sargramostim
  • Placebo Comparator: Arm II (placebo, sagramostim)
    Patients receive cyclophosphamide as in Arm I. Starting course 2, patients receive placebo vaccine with sargramostim ID on day 1. Treatment repeats every 28 days for courses 2-7 and every 6 months for courses 8-14 in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cyclophosphamide
    • Other: Laboratory Biomarker Analysis
    • Other: Placebo
    • Biological: Sargramostim
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
280
Same as current
July 31, 2023
July 31, 2021   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Completely resected unilateral or bilateral primary carcinoma of the breast without clinical evidence of disease, 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 surgeries and any radiation therapy >= 60 days prior to randomization

    • Note: Reconstructive and prophylactic surgeries are allowed after randomization (during study treatment)
  • Completed last cycle of chemotherapy (which can be given in the adjuvant and/or neoadjuvant setting) >= 90 days but not >= 365 days prior to randomization
  • Patient had at least one of the following:

    • Pathologic N1-3
    • Pathologic T2, T3 T4
    • Neoadjuvant chemotherapy and did not achieve complete response at time of surgery (those who did achieve complete response are still eligible if a pre-chemotherapy regional nodal biopsy identified cancer)
  • 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
  • Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0 obtained =< 14 days prior to randomization; Note: patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of protein in 24 hours
  • 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:

    • 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; also, all patients must have either 1) a positron emission tomography (PET)/computed tomography (CT) or 2) a CT of chest, abdomen and pelvis and a bone scan =< 1 year prior to enrollment; if one or more of these is concerning for distant metastases, follow-up imaging and/or biopsy should be performed to rule out distant metastases prior to randomization
  • 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
  • History of other cancer < 5 years prior to consent (except non-melanoma skin cancer or carcinoma in situ of the uterine cervix) or receiving other specific treatment for this cancer (monoclonal antibody, small molecule pathway inhibitor)
  • Treatment with systemic corticosteroid or immune-modulators =< 30 days prior to randomization
  • Concurrent treatment with other experimental drugs or any other systemic anticancer therapy (due to unknown drug-vaccine potential interactions)

    • 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
  • Prior or concurrent use of a PD-1 or PD-L1 checkpoint inhibitor including pembrolizumab unless the use was >= 3 months prior to randomization
Sexes Eligible for Study: Female
18 Years and older   (Adult, Older Adult)
No
United States
 
 
NCT03012100
RU011501I
NCI-2016-01878 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RU011501I ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Academic and Community Cancer Research United
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Principal Investigator: Kathryn Ruddy Academic and Community Cancer Research United
Academic and Community Cancer Research United
December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP