Safety Study Of Anakinra Combined With Chemotherapy And Dendritic Cell Vaccine to Treat Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Baylor Research Institute
Sponsor:
Information provided by (Responsible Party):
Baylor Research Institute
ClinicalTrials.gov Identifier:
NCT02018458
First received: December 4, 2013
Last updated: June 23, 2014
Last verified: June 2014
  Purpose

The primary objective of this study is to determine the safety and feasibility of combining cyclin B1/WT-1/CEF (antigen)-loaded DC vaccination with preoperative chemotherapy, and to combine DC vaccination with preoperative chemotherapy in addition to IL-1 blockade with anakinra in patients with locally advanced triple-negative breast cancer (LA TNBC).

The secondary objectives of this trial are to determine pathologic complete response rates, with and without anakinra; disease-free survival; to assess immune biomarkers of immunity (antigen-specific CD8+ T cell immunity and TH2 T cells) in breast cancer biopsy specimens and blood samples in patients receiving DC vaccinations, with and without IL-1 blockade with anakinra; and to assess the feasibility of immunizing LA TNBC patients with patient-specific tumor antigens.


Condition Intervention Phase
Breast Cancer
Biological: DC vaccination+Preop chemotherapy
Biological: DC vaccination+Preop chemo+anakinra
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Safety Trial of Anakinra Combined With Chemotherapy and Dendritic Cell Vaccine in Patients With Locally Advanced, Triple-Negative Breast Cancer

Resource links provided by NLM:


Further study details as provided by Baylor Research Institute:

Primary Outcome Measures:
  • Safety of DC vaccine combined with chemotherapy, and DC vaccine combined with chemotherapy and anakinra [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
    Toxicities in both groups will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 . Includes all patients (eligible and ineligible) who receive at least 1 inoculation of DC vaccine therapy. This safety population will also be used for the summaries and analysis of all safety parameters (drug exposure, tables of adverse events information, including serious adverse events, etc.).


Secondary Outcome Measures:
  • Pathologic complete response rate with and with out anakinra [ Time Frame: 4 year ] [ Designated as safety issue: No ]
    Patients will undergo surgical resection of residual breast and axillary malignant tissue after protocol-directed treatment. The pathologic specimen will be graded according to the tumor regression grading schema called the Residual Cancer Burden (RCB).

  • Disease free survival with and without anakinra [ Time Frame: 4 year ] [ Designated as safety issue: No ]
    Analysis of disease free survival in both groups will be done using standard & established statistical methods.


Estimated Enrollment: 20
Study Start Date: May 2014
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DC vaccination+Preop chemotherapy
Patients will receive standard preoperative doxorubicin/cyclophosphamide (4 cycles) followed by paclitaxel (4 cycles; AC/T) chemotherapy, administered every 2 weeks for 16 weeks combined with antigen-loaded intratumoral and subcutaneous DC vaccinations. Followed by this, patients will undergo definitive surgery, locoregional radiation therapy to the breast or chest wall and regional lymphatics per standard of care, and will receive 3 boost DC vaccinations subcutaneously in the ventral surface of the upper arm, with antigen-loaded DCs. The 1st vaccination booster will occur after the surgery and prior to radiation; the 2nd booster will occur one month after radiation is completed; and the 3rd booster will occur 3 months after the 2nd boost.
Biological: DC vaccination+Preop chemotherapy
Patients will receive standard preoperative doxorubicin/cyclophosphamide (4 cycles) followed by paclitaxel (4 cycles; AC/T) chemotherapy, administered every 2 weeks for 16 weeks combined with antigen-loaded intratumoral and subcutaneous DC vaccinations. Followed by this, patients will undergo definitive surgery, locoregional radiation therapy to the breast or chest wall and regional lymphatics per standard of care, and will receive 3 boost DC vaccinations subcutaneously in the ventral surface of the upper arm, with antigen-loaded DCs. The 1st vaccination booster will occur after the surgery and prior to radiation; the 2nd booster will occur one month after radiation is completed; and the 3rd booster will occur 3 months after the 2nd boost.
Other Names:
  • DC Vaccine - Dendritic Cell Vaccine
  • Preop chemo: Doxorubicin
  • Preop chemo: cyclophosphamide
  • Preop chemo: Paclitaxel
Experimental: DC vaccination+Preop chemo+anakinra
Patients will have DC vaccine plus preoperative chemotherapy; anakinra 100 mg 7 days, followed by 7 days off, then repeating, subcutaneously for 16 weeks.
Biological: DC vaccination+Preop chemo+anakinra
Patients will have DC vaccine plus preoperative chemotherapy; anakinra 100 mg 7 days, followed by 7 days off, then repeating, subcutaneously for 16 weeks.
Other Names:
  • DC Vaccination - Dendritic cell vaccination
  • Preop chemo - doxorubicin
  • Preop chemo - cyclophosphamide
  • Preop chemo - paclitaxel
  • anakinra - Kineret

Detailed Description:

Recent studies have shown that human breast cancers can be immunogenic, and that enhancing the immune effector function already present may augment the cytotoxic effects of standard therapies.

Vaccination is an attractive strategy because of its expected inducement of both therapeutic T cell immunity (effector T cells) and protective T cell immunity (tumor-specific memory T cells that can control tumor relapse). Clinical studies have now demonstrated that immunity against tumor antigens can be enhanced in cancer patients by vaccination with ex vivo-generated tumor antigen-loaded dendritic cells (DCs). This strategy capitalizes on the unique capacity of DCs to prime lymphocytes and to regulate and maintain immune responses.

In addition, blockade of interleukin-1β (IL-1β) represents a novel approach to breast cancer immunotherapy. Cancer cells induce interleukin-1β (IL-1 β) secretion from DCs and monocytes in a contact-dependent fashion. This is mediated by cancer cell-derived TGF- β. IL-1 β induces Thymic stromal lymphopoietin ( TSLP) production from breast cancer cells lines in a dose and contact dependent manner. TSLP-neutralizing antibodies are found to block up regulation of OX40L by tumor- infiltrating mDCs, and consequently block mDCs' capacity to generate iTH2 cells (CD4+ T cells) and to accelerate tumor development in vivo.33 Thus, interference with the TSLP-OX40L-IL13 axis will allow modification of cancer-associated inflammation and thereby offer a novel therapeutic approach for patients with TNBC. Results showed high levels of IL-1 β in the breast cancer microenvironment. Anakinra is a recombinant soluble non-glycosylated homolog of human IL-1Rα that competitively inhibits binding of IL-1α and IL-1 β to the receptor type. Administration of the IL-1R antagonist, anakinra, is thought to prevent tumor growth in vivo, blocks OX40L+ expression on DCs, and blocks iTH2 generation in vivo.

Our goals are to boost T cell immunity targeted against breast cancer utilizing a tumor antigen-loaded DC vaccine, to reverse the immune suppressive tumor microenvironment by IL-1 blockade, to enhance chemotherapy effectiveness and decrease tumor metastagenicity, and to decrease the recurrence rates of LA TNBC. Patients with LA TNBC will be treated with a combination of antigen-loaded DC vaccinations along with standard preoperative chemotherapy, to improve TNBC immunogenicity and to increase the pCR rate achieved with standard therapy. The trial will consist of 2 patient cohorts. In the first group, patients will receive DC vaccinations in combination with preoperative chemotherapy. In the second group, IL-1 blockade with anakinra will be added to the treatment regimen.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

- Inclusion Criteria:

A patient will be considered for enrollment in this study if all of the following criteria are met:

  1. Female patients ≥18 years of age.
  2. Have locally advanced TNBC with T3-T4 disease, and positive lymph nodes (radiologically or histologically positive), defined as invasive ductal cancers, ER- tumors with <10% of tumor nuclei immunoreactive
  3. HER2-negative breast cancer. If HER2-, it is defined as follows:

    1. FISH-negative (FISH ratio <2.0), or
    2. IHC 0-1+, or
    3. IHC 2+ AND FISH-negative (FISH ratio<2.0)
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
  5. Adequate hematologic function, defined by:

    1. Absolute neutrophil count (ANC) >1500/mm3
    2. Platelet count ≥100,000/mm3
    3. Hemoglobin >9 g/dL (in the absence of red blood cell transfusion)
  6. Adequate liver function, defined by:

    1. AST and ALT ≤2.5 x the upper limit of normal (ULN)
    2. Total bilirubin ≤1.5 x ULN
  7. Adequate renal function, defined by:

    a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥60 ml/min

  8. Patients with previous history of invasive cancers (including breast cancer) are eligible if definitive treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease.
  9. Eligible for treatment with paclitaxel, doxorubicin, and cyclophosphamide.
  10. Patient must be accessible for treatment and follow-up.
  11. Patients must be willing to undergo research biopsies to obtain breast cancer tissue for whole exome sequencing and evaluation of tumor immune microenvironment.
  12. All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.

    • Exclusion Criteria:

A patient will be ineligible for inclusion in this study any of the following criteria are met:

  1. Evidence of metastatic disease on bone scan and CT scan of chest/abdomen (or PET CT scan). Patients with intrathoracic metastatic adenopathy are eligible.
  2. Active infection or unexplained fever >38.5°C during screening.
  3. Active infections including viral hepatitis and HIV.
  4. Active asthma or other condition requiring steroid therapy.
  5. Autoimmune disease including lupus erythematosus or rheumatoid arthritis. Topical or inhaled corticosteroids are allowed.
  6. Patients who are currently receiving or who have received previous systemic therapy for breast cancer (eg, chemotherapy, antibody therapy, targeted agents).
  7. Women who are pregnant or lactating. All patients with reproductive potential must agree to use effective contraception from time of study entry until at least 3 months after the last administration of study drug.
  8. Have a NYHA Class III or IV CHF or LVEF <55%. Patients with significant cardiac disease history within 1 year or ventricular arrhythmias requiring medication are also excluded.
  9. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation such as:

    1. severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
    2. uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
    3. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).
  10. History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the patient at high risk for treatment complications.
  11. Any other investigational or anti-cancer treatments while participating in this study.
  12. Any other cancer
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02018458

Contacts
Contact: Grace Townsend 2148188382 grace.townsend@baylorhealth.edu
Contact: Silviya Meletath 2148204987 silviya.meletath@baylorhealth.edu

Locations
United States, Texas
Baylor University Medical Center Recruiting
Dallas, Texas, United States, 75246
Principal Investigator: Joyce O' Shaughnessy, MD         
Sub-Investigator: Karolina Palucka, PhD         
Sponsors and Collaborators
Baylor Research Institute
Investigators
Principal Investigator: Joyce O' Shaughnessy, MD Baylor Health Care System
  More Information

No publications provided

Responsible Party: Baylor Research Institute
ClinicalTrials.gov Identifier: NCT02018458     History of Changes
Other Study ID Numbers: 013-154
Study First Received: December 4, 2013
Last Updated: June 23, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Baylor Research Institute:
Dendritic cell vaccine
Anakinra
Breast Cancer
Doxorubicin
Paclitaxel
Cyclophosphamide

Additional relevant MeSH terms:
Triple Negative Breast Neoplasms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Liposomal doxorubicin
Cyclophosphamide
Doxorubicin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014