Vaccination of Triple Negative Breast Cancer Patients

A Combined Phase i/II Efficacy Study of a Carbohydrate Mimotope-based Vaccine With MONTANIDE™ ISA 51 VG STERILE Combined With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

The purpose of this study is to evaluate a new investigational cancer vaccine, P10s-PADRE in combination with standard neoadjuvant chemotherapy and surgery in patients with clinical stage I, II or III triple negative breast cancer (TNBC). This study will compare the vaccine plus standard neoadjuvant chemotherapy and surgery to standard neoadjuvant chemotherapy and surgery alone.

Study Overview

• Status: Completed
• Conditions: Breast Neoplasms; Triple Negative Breast Cancer
• Intervention / Treatment: Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Paclitaxel; Biological: P10s-PADRE with MONTANIDE™ ISA 51 VG

Detailed Description

The purpose of this study is to evaluate an investigational agent, P10s-PADRE, a peptide mimotope-based vaccine, in combination with standard neoadjuvant chemotherapy in patients with clinical stage I, II or III estrogen-receptor (ER) negative, progesterone receptor (PR) negative and HER2-negative (= triple negative - TN) breast cancer. P10s-PADRE will be administered with MONTANIDE™ ISA 51 VG as adjuvant. Human breast cancers that express Tumor Associated Carbohydrate Antigens (TACAs) can be immunogenic, and enhancing the anti-TACA antibodies and immune effector function already present may augment the cytotoxic effects of standard therapies.

A randomized two-arm, open-label, multi-center phase I/II trial is designed with the goal being to evaluate the efficacy of combining vaccination of the P10s-PADRE formulation with neoadjuvant chemotherapy. Patients will be randomly assigned in a 2:1 ratio to standard chemotherapy plus P10s-PADRE or to standard chemotherapy alone. Efficacy will be based on the rate of pathologic Complete Response (pCR) observed among TN breast-cancer patients treated with the combination as compared with the group of patients who receive standard chemotherapy alone.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Females of all races with biopsy-proven clinical stage I, II, or III TNBC (ER-negative, PR-negative and HER2-negative) who will undergo SoC neoadjuvant treatment
• Age 18 years and older
• ECOG Performance Status 0 or 1
• White blood cell (WBC) count ≥ 3,000/mm3 within 3 weeks prior to registration
• Platelet count ≥ 100,000/mm3 within 3 weeks prior to registration
• Bilirubin ≤ 2 x institutional upper limit (IUL) of normal obtained within 3 weeks prior to registration
• Serum glutamic-oxaloacetic transaminase (SGOT) or aspartate aminotransferase test (AST) ≤ 2 x IUL of normal obtained within 3 weeks prior to registration
• Serum glutamic-pyruvic transaminase (SGPT) or alanine aminotransferase test (ALT) ≤ 2 x IUL of normal obtained within 3 weeks prior to registration
• Serum creatinine ≤ 1.8 mg/dl obtained within 3 weeks prior to registration
• Must sign an informed consent document approved by the UAMS IRB

Exclusion Criteria:

• ER-positive, PR-positive, HER2-positive, inflammatory, metastatic, stage IV or recurrent breast cancer.
• Active infection requiring treatment with antibiotics.
• Existing diagnosis or history of organic brain syndrome that might preclude participation in the full protocol.
• Existing diagnosis or history of significant impairment of basal cognitive function that might preclude participation in the full protocol.
• Other current malignancies. Subjects with prior history at any time of any in situ cancer, including lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or Clark I melanoma in situ or basal or squamous skin cancer are eligible, provided they are disease-free at the time of registration. Subjects with other malignancies are eligible if they have been continuously disease free for ≥ 5 years prior to the time of registration.
• Active autoimmune disorders or conditions of immunosuppression; Existing diagnosis or history of autoimmune disorders or conditions of immunosuppression that have been in remission for less than 6 months.
• Treatment with corticosteroids, including oral steroids (i.e. prednisone, dexamethasone [except when used as an antiemetic in SoC therapy]), continuous use of topical steroid creams or ointments or any steroid-containing inhalers. Subjects who discontinue the use of these classes of medication for at least 6 weeks prior to registration are eligible if, in the judgment of the treating physician, the subject is not likely to require these classes of drugs during the treatment period. Replacement doses of steroids for subjects with adrenal insufficiency are allowed.
• Pregnancy or breastfeeding (due to the unknown effects of peptide/mimotope vaccines on a fetus or infant). Women of childbearing potential must have a negative urine pregnancy test within 72 hours prior to starting week 1 and must be counseled to use an accepted and effective method of contraception (including abstinence) while on treatment and for a period of 18 months after completing or discontinuing treatment. Accepted methods of contraception include oral contraceptives, barrier methods, IUDs, and abstinence.
• Any other significant medical or psychiatric conditions, which, in the opinion of the enrolling investigator, may interfere with consent or compliance of the treatment regimen.
• Enrollment in any other clinical trial using investigational drug products or devices prior to first post-surgery study lab (Week 46 visit). Concurrent enrollment in observational studies is allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemo+Vaccine Arm; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.	Drug: Doxorubicin; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.; Drug: Cyclophosphamide; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.; Drug: Paclitaxel; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.; Biological: P10s-PADRE with MONTANIDE™ ISA 51 VG; Subjects randomized to the control arm will receive SoC neoadjuvant chemotherapy starting on week 1. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.; Other Names: P10s-PADRE/ MONTANIDE™ ISA 51 VG
Active Comparator: Chemotherapy Only Arm; Subjects randomized to the control arm will receive SoC neoadjuvant chemotherapy starting on week 1. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.	Drug: Doxorubicin; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.; Drug: Cyclophosphamide; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.; Drug: Paclitaxel; Subjects randomized to the chemo+vaccine arm will be immunized with P10s-PADRE in MONTANIDE™ ISA 51 VG a total of three times. The vaccine will be administered on weeks 1, 2 and 3 prior to chemotherapy. Then, they will start their SoC neoadjuvant chemotherapy on week 4. Doxorubicin and cyclophosphamide (AC) will be administered concurrently every two weeks for four cycles with pegfilgrastim (or equivalent growth factor) on day 2 of each AC cycle, followed by paclitaxel weekly x 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability Adverse Events	A Safety/Tolerability Event is defined as the occurrence of one of the following: A Serious Adverse Event, OR; A non-Serious Adverse Event of Grade = 3, 4, or 5, OR; A non-Serious Adverse Event of Grade = 2 whose Relationship to P10s-PADRE Vaccine was classified as Definite, Probable, or Possible	From the start of treatment to the time of definitive surgery (4-8 weeks after chemo); from Week 0 to Week 20-23
Pathologic Complete Response (pCR)	A tumor-response call of either ypT0N0 or ypTisN0 determined through surgical staging after neoadjuvant therapy. The staging system used to determine the tumor-response call is the AJCC Staging System described in a 2014 FDA Guidance for Industry. • A tumor-response call of "pyT0N0" is also equated with pCR in the published literature.	During and/or Immediately After Surgery
Pathological Tumor Size	Tumor size at surgery/pathology report	Surgery
Pathological Node Status: Number of Positive Lymph Nodes	Number of positive lymph nodes found out of dissected lymph nodes	Surgery
Pathological Node Status: Number of Dissected Lymph Nodes	Number of dissected lymph nodes at surgery for study participants	Surgery
Tumor Response	Participants had their tumors surgically removed and pathologically staged using the AJCC Staging criteria. The main method of pathologic staging for breast cancer is the TNM system which stands for (Tumor size, lymph Node status and Metastases). "yp" prior to TN means the tissue was staged after neoadjuvant therapy. The larger the number after "T" means the larger the size, and the larger the number after "N" means the number of affected nearby lymph nodes. Therefore, tumor gradings with T3Nx are worse than those with T0Nx. The two categories "pyT0N0" and "ypT0N0" are both considered to be synonymous with pCR in the published literature.	Surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fold Increase in P10s-MAP-Reactive Immunoglobulin Titers	The anti-P10s binding level was measured via ELISA method after incubation with a subject's serum samples. The endpoint titer was determined for each serum sample, and then fold change in endpoint titer in post-treatment weeks compared to pre-treatment week (Week 1) were calculated.	Weeks 7, 10, 15, 18, 23, 46, and 70
Frequencies of NK Cells - CD16	Using flow cytometry, the frequencies of NK cells were determined for samples collected from multiple timepoints from Week 1 to Week 70. Values were averaged for the percent of CD16+NK cells.	Week 1, 7, 10, 15, 18, 23, 46, 70
Frequencies of NK Cells - CD69	Using flow cytometry, the frequencies of NK cells were determined for samples collected from multiple timepoints from Week 1 to Week 70. Values were averaged for the percent of CD69+NK cells.	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Frequencies of NK Cells - NKp46	Using flow cytometry, the frequencies of NK cells were determined for samples collected from multiple timepoints from Week 1 to Week 70. Values were averaged for the percent of NKp46+NK cells.	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Frequencies of NK Cells - NKG2D	Using flow cytometry, the frequencies of NK cells were determined for samples collected from multiple timepoints from Week 1 to Week 70. Values were averaged for the percent of NKG2D+NK cells.	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Frequencies of T Cells - CD3+/CD4+	Using flow cytometry, the frequencies of CD3+/CD4+ T cells were determined for samples collected from multiple timepoints from Week 1 to Week 46. Values were averaged for the percent of CD4 T cells.	Weeks 1, 7, 10, 15, 18, 23, and 46
Frequencies of T Cells - CD3+/CD8+	Using flow cytometry, the frequencies of CD3+/CD8+ T cells were determined for samples collected from multiple timepoints from Week 1 to Week 46. Values were averaged for the percent of CD8 T cells.	Weeks 1, 7, 10, 15, 18, 23, and 46
Frequencies of Cells - CD69+/CD3+	Using flow cytometry, the frequencies of CD69+/CD3+ cells were determined for samples collected from multiple timepoints from Week 1 to Week 70. Values were averaged for the percent of CD69 T cells.	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Frequencies of Circulating Regulatory T Cells (Tregs)	Peripheral blood mononuclear cells (PBMCs) were isolated from samples collected from multiple timepoints from Week 1 to Week 46. Using flow cytometry, the frequencies of Tregs (CD4, CD25 and CD127) were analyzed for separately, and then summed. The units are reported in CD4+CD25+CD127 low/- percentage because CD127 is a recently discovered antigen associated with Tregs that is weakly expressed on Tregs, while the self-activated memory T cell CD127 is strongly expressed; therefore, CD4+CD25+CD127 low/- is used to represent Tregs now.	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Activation Profiles of NK Cells: CD16	The expression levels of activation markers on NK cells profile, specifically CD16, were determined for samples collected from multiple timepoints from Week 1 to Week 70. Data is reported in the units Median Fluorescence Intensity (MFI).	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Activation Profiles of NK Cells: CD69	The expression levels of activation markers on NK cells profile, specifically CD69, were determined for samples collected from multiple timepoints from Week 1 to Week 70. Data is reported in the units Median Fluorescence Intensity (MFI).	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Activation Profiles of NK Cells: NKp46	The expression levels of activation markers on NK cells profile, specifically NKp46, were determined for samples collected from multiple timepoints from Week 1 to Week 70. Data is reported in the units Median Fluorescence Intensity (MFI).	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Activation Profiles of NK Cells: NKG2D	The expression levels of activation markers on NK cells profile, specifically NKG2D, were determined for samples collected from multiple timepoints from Week 1 to Week 70. Data is reported in the units Median Fluorescence Intensity (MFI).	Weeks 1, 7, 10, 15, 18, 23, 46, and 70
Activation Profiles of T Cells - CD69 on CD3+	The expression levels of activation markers CD69 on T cells were determined by flow cytometry for samples collected from multiple timepoints from Week 1 to Week 70. Data is reported in the units Median Fluorescence Intensity (MFI).	Weeks 1, 7, 10, 15, 18, 23, 46, 70

Collaborators and Investigators

• Sponsor: University of Arkansas
• Investigators: Principal Investigator: Sindhu Malapati, MD, University of Arkansas

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2019
• Primary Completion (Actual): January 9, 2023
• Study Completion (Actual): January 9, 2023

Study Registration Dates

• First Submitted: October 17, 2016
• First Submitted That Met QC Criteria: October 17, 2016
• First Posted (Estimated): October 19, 2016

Study Record Updates

• Last Update Posted (Actual): November 7, 2024
• Last Update Submitted That Met QC Criteria: November 5, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: TNBC; HER2 positive; ER positive; PR positive; clinical stage I, II or III
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Adjuvants, Immunologic; Monatide (IMS 3015); Cyclophosphamide; Doxorubicin; Paclitaxel; Freund's Adjuvant
• Other Study ID Numbers: 206010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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