Clinical trial NCT02593227: Folate Receptor Alpha Peptide Vaccine With GM-CSF in Patients With Triple Negative Breast Cancer
Official title: A Randomized Multicenter Phase II Trial to Evaluate the Safety and Immunogenicity of Two Doses of Vaccination With Folate Receptor Alpha Peptides With GM-CSF in Patients With Triple Negative Breast Cancer Defined as Primary Tumor That is Her2-neu and Low (< 10%) ER/PR Nuclear Staining
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: TNBC
Lead sponsor: Marker Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-11-01
Enrollment: 80
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase II trial evaluates the safety and immunogenicity of two doses of the Folate Receptor Alpha (FRα) peptide vaccine mixed with GM-CSF as a vaccine adjuvant, with or without a immune priming with cyclophosphamide, as a consolidation therapy after neoadjuvant or adjuvant treatment of patients with Stage IIb-III triple negative breast cancer (TNBC).

Detailed description: Triple negative breast cancers (TNBCs) occur in approximately 20-25% of all patients with breast cancer and are associated with a poor prognosis. Patients with TNBCs derive no benefit from targeted therapies. Excluding those patients who demonstrate a pathologic complete response following neoadjuvant chemotherapy, which is a minor fraction (i.e. 15%), overall survival is only 45% at 7 years.

Following standard of care, there are windows of opportunity to further and safely treat patients to prevent recurrence. Stimulating the immune system to produce T cells immunity specific for tumor antigens may significantly delay recurrence and cure patients.

The proposed vaccine is intended to induce T cells to survey for the reemergence of TNBCs and to prevent recurrence in the adjuvant setting. The vaccine strategy is antigen-specific and targets the Folate Receptor Alpha (FRα). FRα is an ideal target because of its limited expression in the healthy tissues and it high expression in 86% of TNBCs. Studies have shown that it is a biologically important marker that is associated with poorer clinical outcome and is retained in metastatic lesions.

The FRα vaccine include a pool of 5 peptides that are immunogenic epitopes and safely generate tissue-surveying CD4 T cell immune responses in patients tested in a recently completed phase I clinical trial.

Eligibility criteria: Inclusion Criteria:

1. Female patient, age 18 years or older;
2. Completely resected unilateral or bilateral primary carcinoma of the breast
3. Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures;
4. Primary tumor was negative for ER, PR (cut-off for positivity is \>10% positive tumor cells with nuclear staining) and negative for Her2-neu (0 or 1+ on immunohistochemistry and/or normal gene copy number by in-situ hybridization); Central review is not required.
5. Completed primary treatment (surgery and radio/chemotherapy in adjuvant and/or neo-adjuvant setting) \<360 days prior to first vaccination.
6. Completed last cycle of chemotherapy or radiation \> 60 days prior to first vaccination
7. Either clinical or pathological Stage I (T1c), II, or III according to AJCC 7th edition

   * Note that patients with (i) non-invasive breast cancer (DCIS) alone, (ii) incidental (microscopic) nodal cancer without a primary tumor (pN1mi), or (iii) metastatic disease are excluded.
   * Resected tumor: No evidence of gross tumor at the surgical resection margin noted in the final surgery report. No evidence of gross residual adenopathy
8. Karnofsky index \>= 70%;
9. Life expectancy of at least 5 years, disregarding the diagnosis of cancer;
10. Adequate Blood, renal and hepatic function, as determined within 28 days from registration:

    * ANC ≥ 1,500 / mm3
    * Platelet ≥ 100,000 / uL
    * Hgb \> 9 g/dL
    * Creatinine ≤ 1.5 x ULN or 24-hour urine \< Grade 2
    * Urinalysis with \< 2+ proteinuria
    * Serum albumin ≥ 3 g/dL
    * SGOT (AST) ≤ 3 x ULN
11. Anti-nuclear antibody (ANA) negative or low-positive institutional range, as determined within 28 days from registration. Intermediate values (usually defined by a titer of ≤1:80, or as indicated by institutional range) are acceptable if there are, in the opinion of the Investigator, no early signs of an autoimmune disease.
12. Primary tumor is available for shipment to central laboratory for analysis of FRα expression by IHC.
13. Patients must be, in the opinion of the Investigator, available and compliant for treatment and follow-up.

Exclusion Criteria:

1. Clinical evidence of distant metastases per practice guidelines for breast cancer;
2. Inflammatory breast cancer or tumor with deep adherence or cutaneous invasion;
3. Known hypersensitivity reaction to the GM-CSF adjuvant; Any known contra-indication to GM-CSF or Cyclophosphamide treatment;
4. Pregnant or lactating patients. Patients of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to registration and must implement adequate contraceptive measures during study treatment;
5. Active autoimmune disease requiring therapy within the past 2 years (Note: patients with vitiligo, Grave's disease or psoriasis not requiring systemic treatment within the past 2 years are not excluded);
6. Other uncontrolled illness or medical condition, such as active infection, symptomatic heart failure (New York Heart Association class III or IV; moderate to severe objective evidence of cardiovascular disease), unstable angina pectoris, myocardial infarction or stroke within last 6 months, psychiatric illness that may limit compliance with study requirement or interfere with the understanding and giving of informed consent;
7. Prior active secondary malignancy \< 5 years prior to consent (except non-melanomatous skin cancer or carcinoma in situ of the uterine cervix) or currently receiving other specific treatment for this cancer (including monoclonal antibody or pathway inhibitor);
8. Completed treatment with systemic corticosteroid or immune-modulators \< 30 days prior to registration;
9. Planned treatment with other experimental drugs or any other non-hormonal anti-cancer therapy;
10. Immunocompromised patients, including patients with known HIV infection;
11. Symptomatic thyroid disease, unless negative for thyroid antibodies (TSH receptor, TPO, thyroglobulin).

Primary outcomes:
measure: Immune response
timeFrame: 3 years
Secondary outcomes:
measure: Folate receptor alpha expression
timeFrame: Baseline
measure: Relapse Free Survival
timeFrame: 3 years
measure: Safety and tolerability (treatment emergent adverse events and injection site reactions)
timeFrame: 3 years
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland - Greenebaum Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Kansas City
country: United States
facility: MidAmerica Division,Inc
state: Missouri
city: Paramus
country: United States
facility: The Valley Hospital
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Montefiore Medical Center, Einstein Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care
state: Ohio
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology Presbyterian Cancer Center Dallas
state: Texas
Study officials:
affiliation: Marker Therapeutics, Inc.
name: Richard Kenney, MD
role: STUDY_DIRECTOR
References: