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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

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Other: Laboratory Biomarker Analysis Biological: Multi-epitope Folate Receptor Alpha Peptide Vaccine Other: Placebo Biological: Sargramostim Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : March 31, 2017
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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

Biological: Sargramostim
Given ID
Other Names:
  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin

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.
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

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03012100


Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Nicole Ritacca    480-301-4161    Ritacca.Nicole@mayo.edu   
Principal Investigator: Donald W. Northfelt         
United States, District of Columbia
MedStar Georgetown University Hospital Withdrawn
Washington, District of Columbia, United States, 20007
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Pulkit Mathur    904-953-3803    Mathur.Pulkit@mayo.edu   
Principal Investigator: Alvaro Moreno-Aspitia         
University of Miami Miller School of Medicine-Sylvester Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Onaidy T. Torres    305-243-3379    OTorres@med.miami.edu   
Principal Investigator: Carmen J. Calfa         
United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Simona Olberkyte    773-702-4848    solberkyte@medicine.bsd.uchicago.edu   
Principal Investigator: Rita Nanda         
Carle Cancer Center NCI Community Oncology Research Program Recruiting
Urbana, Illinois, United States, 61801
Contact: MaryEllen Sherwood    217-326-1881    MaryEllen.Sherwood@Carle.com   
Principal Investigator: Kendrith M. Rowland         
United States, Louisiana
Ochsner Medical Center Jefferson Recruiting
New Orleans, Louisiana, United States, 70121
Contact: Socea A. May    504-842-2373    Socea.may@ochsner.org   
Principal Investigator: John T. Cole         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Steven J. Isakoff    617-726-6500    sisakoff@partners.org   
Principal Investigator: Steven J. Isakoff         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Lori L. Henrichs    507-538-7665    Henrichs.lori@mayo.edu   
Principal Investigator: Kathryn J. Ruddy         
United States, Virginia
Inova Fairfax Hospital Withdrawn
Falls Church, Virginia, United States, 22042
United States, Wisconsin
Marshfield Clinic Recruiting
Marshfield, Wisconsin, United States, 54449
Contact: Brenda K. Maronde    715-389-7542    maronde.brenda@marshfieldresearch.org   
Principal Investigator: Arlene A. Gayle         
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
Principal Investigator: Kathryn Ruddy Academic and Community Cancer Research United

Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT03012100     History of Changes
Other Study ID Numbers: 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 )
First Posted: January 6, 2017    Key Record Dates
Last Update Posted: December 14, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Unilateral Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Vaccines
Cyclophosphamide
Folic Acid
Vitamin B Complex
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Hematinics
Vitamins
Micronutrients
Growth Substances