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

Pilot Safety Trial of Preoperative Chemotherapy Combined With Dendritic Cell Vaccine in Patients With Locally Advanced, Triple-Negative Breast Cancer or ER-Positive, Her2-Negative Breast Cancer

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.

The secondary objectives of this trial are to determine pathologic complete response rates; 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; and to assess the feasibility of immunizing LA TNBC and ER+/HER2- BC patients with patient-specific tumor antigens.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Biological: LA TNBC: DC vaccine+Preop chemo; Biological: ER+/HER2-BC:DC vaccine+Preop chemo

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 remains the most 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). Several 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.

Our goals are to boost T cell immunity targeted against breast cancer utilizing a tumor antigen-loaded DC vaccine, to enhance chemotherapy effectiveness and decrease tumor metastagenicity, and to decrease the recurrence rates of LA TNBC and ER+/HER2- BC. Patients will be treated with a combination of antigen-loaded DC vaccinations along with standard preoperative chemotherapy, to improve immunogenicity and to increase the pCR rate achieved with standard therapy. The trial will consist of 2 patient cohorts: TNBC and ER+/HER2- BC.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

- 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 either:

   1. locally advanced TNBC defined as invasive ductal cancer; ER- tumors with <10% of tumor nuclei immunoreactive; PR- tumors with <10% of tumor nuclei immunoreactive; T3 or T4 disease, regardless of nodal status (T2 disease is eligible if there are positive lymph nodes present by physical exam or imaging evaluation or histological evaluation, OR
   2. High-risk ER+ breast cancer defined as grade 3 invasive ductal or mixed ductal/lobular cancers, or grade 2 with Ki67 ≥20%; node positive as evidenced by physical exam or imaging evaluation or histological evaluation.

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, cyclophosphamide and carboplatine.
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).The use of an LHRH agonist during chemotherapy in premenopausal women who wish to preserve ovarian function is allowed, but is not required.
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LA TNBC: DC vaccine+Preop chemo; LA TNBC patients will receive standard preop AC followed by TCb chemo for 24 weeks. Chemo and DC vaccinations will be given intratumoral and subcutaneous for 4 times prior surgery. During the AC cycles, vaccines will be given on any day between Days 9-12 of Cycles 1 and 3 of AC. Vaccines will be given on any day between Days 11-15 of Cycles 1 and 3 of TCb. Patients will undergo biopsies of their cancer prior to treatment and 1-2 days prior to or on Day 1 of Cycle 4 of AC. After this, patients will have 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, rotating injection sites in the upper arm. The 1st vaccination will occur after the surgery and prior to radiation; 2nd will occur 30 days ± 3 days after radiation; the 3rd will occur 90 days ± 3 days after the 2nd boost.	Biological: LA TNBC: DC vaccine+Preop chemo; LA TNBC patients will receive standard preop AC followed by TCb chemo for 24 weeks. Chemo and DC vaccinations will be given intratumoral and subcutaneous for 4 times prior surgery. During the AC cycles, vaccines will be given on any day between Days 9-12 of Cycles 1 and 3 of AC. Vaccines will be given on any day between Days 11-15 of Cycles 1 and 3 of TCb. Patients will undergo biopsies of their cancer prior to treatment and 1-2 days prior to or on Day 1 of Cycle 4 of AC. After this, patients will have 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, rotating injection sites in the upper arm. The 1st vaccination will occur after the surgery and prior to radiation; 2nd will occur 30 days ± 3 days after radiation; the 3rd will occur 90 days ± 3 days after the 2nd boost.; Other Names: DC Vaccine - Dendritic Cell Vaccine; Preop chemo: Doxorubicin; Preop chemo: cyclophosphamide; Preop chemo: Paclitaxel; Preop chemo: Carboplatin
EXPERIMENTAL: ER+/HER2-BC:DC vaccine+Preop chemo; ER+/HER2- BC patients will receive standard preop AC followed by weekly T given for 22 weeks. Chemo and DC vaccinations will be given intratumoral and subcutaneous, for 4 times prior surgery. During the AC cycles, vaccines will be given any day between Days 9-12 of Cycles 1 and 3 of AC. Vaccines will be given on Day 1 during Cycle 2 or Cycle 3 and on Day 1 during either Cycle 8 or Cycle 9 of T. Vaccine will be given after T infusion is completed. Patients will undergo biopsies of their cancer prior to treatment and 1-2 days prior to or on Day 1 of Cycle 4 of AC. Patients will have 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, rotating injection sites in the upper arm. The 1st vaccination will occur after surgery and prior to radiation; the 2nd will occur 30 days ± 3 days after radiation; and the 3rd will occur 90 days ± 3 days after the 2nd boost.	Biological: ER+/HER2-BC:DC vaccine+Preop chemo; ER+/HER2- BC patients will receive standard preop AC followed by weekly T given for 22 weeks. Chemo and DC vaccinations will be given intratumoral and subcutaneous, for 4 times prior surgery. During the AC cycles, vaccines will be given any day between Days 9-12 of Cycles 1 and 3 of AC. Vaccines will be given on Day 1 during Cycle 2 or Cycle 3 and on Day 1 during either Cycle 8 or Cycle 9 of T. Vaccine will be given after T infusion is completed. Patients will undergo biopsies of their cancer prior to treatment and 1-2 days prior to or on Day 1 of Cycle 4 of AC. Patients will have 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, rotating injection sites in the upper arm. The 1st vaccination will occur after surgery and prior to radiation; the 2nd will occur 30 days ± 3 days after radiation; and the 3rd will occur 90 days ± 3 days after the 2nd boost.; Other Names: Preop chemo: Carboplatin; DC Vaccination - Dendritic cell vaccination; Preop chemo - doxorubicin; Preop chemo - cyclophosphamide; Preop chemo - paclitaxel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of DC Vaccine Combined With Chemotherapy	Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 . This will include 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.).	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response Rate	Results are only reported for Arm 1, "LA TNBC: DC vaccine+preop chemo patients". Arm 2 did not enroll any patients. The pathologic specimen will be graded per the tumor regression grading schema provided by the University of Texas MD Anderson Cancer Center "Residual Cancer Burden Calculator" at http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3. The following parameters are required from pathologic examination in order to calculate RCB: largest 2 dimensions of residual tumor bed in the breast; entire largest cross-sectional area of residual tumor bed; percentage of the tumor bed area that contains carcinoma; percentage of carcinoma in tumor bed that is in situ; number of positive (metastatic) lymph nodes; largest diameter of largest nodal metastasis. A pathologic complete response is defined as NO pathologic evidence of invasive disease in the breast or axillary lymph nodes. RCB-I (minimal cancer burden); RCB-II (moderate burden); and RCB-III (extensive burden).	1 year
Disease-free Survival	Results are only reported for Arm 1, "LA TNBC: DC vaccine+preop chemo patients". Arm 2, "ER+/HER2- BC: DC vaccine+preop chemo patients" did not enroll any patients with these hormone receptor criteria. Analysis of disease-free survival ("DFS", reported in months) was calculated from the first day of treatment up to 36 months.	36 months

Collaborators and Investigators

• Sponsor: Baylor Research Institute

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2014
• Primary Completion (ACTUAL): September 18, 2019
• Study Completion (ACTUAL): September 18, 2019

Study Registration Dates

• First Submitted: December 4, 2013
• First Submitted That Met QC Criteria: December 17, 2013
• First Posted (ESTIMATE): December 23, 2013

Study Record Updates

• Last Update Posted (ACTUAL): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Breast Cancer; Cyclophosphamide; Carboplatin; Doxorubicin; Paclitaxel; Dendritic cell vaccine
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Carboplatin; Paclitaxel; Vaccines; Albumin-Bound Paclitaxel; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: 013-154

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No