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Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-risk HER2+ Breast Cancer Patients (HER3+)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02297698
Recruitment Status : Active, not recruiting
First Posted : November 21, 2014
Last Update Posted : December 23, 2019
Sponsor:
Collaborators:
Genentech, Inc.
Sellas Life Sciences Group
Information provided by (Responsible Party):
Cancer Insight, LLC

Tracking Information
First Submitted Date  ICMJE November 14, 2014
First Posted Date  ICMJE November 21, 2014
Last Update Posted Date December 23, 2019
Study Start Date  ICMJE October 2014
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 19, 2014)
Invasive Disease-free survival (DFS) [ Time Frame: Initiation of trastuzumab monotherapy through the end of the patient's fifth year of participation in the study. ]
Compare invasive DFS between the two treatment groups from time of initiation of trastuzumab maintenance therapy (trasuzumab monotherapy) to time of invasive local, regional or distant recurrence, new primary, or death due to any cause. Disease state will be determined by the patients' own physicians at the individual study sites during their routine follow-up screening. This will occur for all enrolled patients, regardless of randomization, approximately every three months for the first 24 months after completion of primary therapies and every six months thereafter with clinical exam, and laboratory and radiographic surveillance. The primary outcome measure of the trial is invasive DFS.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2014)
  • Distant recurrence-free survival (DRFS) [ Time Frame: Initiation of trastuzumab monotherapy through the end of the patient's fifth year of participation in the study. ]
    DRFS will be assessed as part of the patient's disease state as determined by their physician at the individual study sites during routine follow-up screening. Determination of DRFS will allow for continued follow-up on patients with local or regional recurrence.
  • Local and systemic toxicities [ Time Frame: From the date of initiation of the vaccine or inoculation series and booster series up to 36 months. ]
    Standard local and systemic toxicities will be collected and graded per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 graded toxicity scale. For both the inoculations during the primary vaccine/inoculation series and the booster inoculations, patients will be monitored closely for one hour after inoculation with questioning, serial exams and vital signs every 15 minutes to observe for a hypersensitivity reaction. Additionally, patients will return to their study site 48-72 hours after inoculation for questioning regarding any systemic toxicity and local injection site reactions. When they return to their study site, the local reaction at the inoculation sites will be examined and measured.
  • Evaluate in vivo and in vitro immune responses [ Time Frame: From the date of the first inoculation of Trastuzumab monotherapy to the end of the patient's fifth year of participation in the study. ]
    Immune responses will be primarily documented using the delayed type hypersensitivity (DTH) reaction and using the dextramer assay to enumerate peptide-specific CTL. Each of these measurements will be performed regardless of randomization. DTH reactions will be measured prior to initiation of the primary vaccine/inoculation series, one month ± 1 week after completion of the primary vaccine/inoculation series, and one month ± 1 week after the final booster inoculation. Dextramer measurements will be performed prior to initiating the primary vaccine/inoculation series as well as one month ± 1 week after completion of the vaccine/inoculation series. Additionally, these assays may be performed pre- and post-each booster. Alternatively, these assayed time points may also be performed all at once on frozen and banked cells.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-risk HER2+ Breast Cancer Patients
Official Title  ICMJE Phase II Trial of Combination Immunotherapy With Nelipepimut-S + GM-CSF (NeuVax™) and Trastuzumab in High-risk HER2+ Breast Cancer Patients
Brief Summary

This will be a multi-center, prospective, randomized, single-blinded, placebo-controlled phase II trial of trastuzumab + nelipepimut-S/GM-CSF versus trastuzumab + GM-CSF alone. Our target study population is high-risk HER2-positive breast cancer patients. High-risk HER2-positive breast cancer patients are defined as:

Those with HER2-positive breast cancer, regardless of hormone receptor status, who receive neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy, and fail to achieve a pCR.

Those with HER2-positive breast cancer, regardless of hormone receptor status, who undergo surgery as a first intervention and are found to have ≥ 4 positive lymph nodes.

Those with HER2-positive, hormone receptor negative breast cancer who undergo surgery as a first intervention and are found to have 1-3 positive lymph nodes.

Disease-free subjects after standard of care multi-modality therapy will be screened and HLA-typed.

Detailed Description

In this study, the investigators intend to assess the ability of the combination of trastuzumab and the HER2 vaccine nelipepimut-S (administered with the immunoadjuvant GM-CSF) given in the adjuvant setting to prevent recurrences in patients with high-risk HER2-positive breast cancer. High-risk is defined as those patients that do not achieve a pCR after neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy or those who undergo upfront surgery and are found to have greater than or equal to four positive lymph nodes regardless of hormone receptor status or 1-3 positive lymph nodes and are hormone receptor negative.

Following surgery, patients will be screened and HLA-typed (consent #1). Nelipepimut-S is a CD8-eliciting peptide vaccine that is restricted to HLA-2+ or HLA-A3+ or HLA-A24+ or HLA-A26+ patients (approximately 80% of the US population). HLA-A2+/A3+/A24+/orA26+ patients who meet all other eligibility criteria will be randomized to receive trastuzumab + nelipepimut-S/GM-CSF or trastuzumab + GM-CSF alone (consent #2). The trastuzumab will be administered to all patients consistent with current standard of care. Patients randomized to the nelipepimut-S/GM-CSF arm will receive vaccinations of nelipepimut-S (1000 mcg) and GM-CSF (250 mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series. Patients randomized to the GM-CSF alone arm will receive inoculations of GM-CSF (250 mcg) administered in an identical manner to those receiving nelipepimut-S/GM-CSF. Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone.

Upon completion of the primary vaccination/inoculation series, booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 6 months ± 2 weeks after the completion of the PVS, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following time points after completion of the PVS: 6 months ± 2 weeks, 12 months ± 2 weeks, 18 months ± 2 weeks, 24 months ± 2 weeks. Booster inoculations will occur for patients randomized to receive nelipepimut-S/GM-CSF as well as patients randomized to receive GM-CSF alone, and will consist of the same treatment drugs and dosing (i.e., nelipepimut-S/GM-CSF patients will be boosted with nelipepimut-S/GM-CSF while GM-CSF alone patients will be boosted with GM-CSF alone). Patient blinding will be maintained throughout the study.

Subjects will be followed for safety issues, immunologic response and clinical recurrence. Patients will be monitored 48-72 hours after each inoculation for reaction to the inoculation as well as documentation of any adverse effects experienced. Immunologic response will be monitored primarily by in vivo delayed type hypersensitivity (DTH) reactions but also may be documented by other immunologic assays. All patients will be followed for a total of 36 months from the time of initiation of trastuzumab maintenance therapy to document disease-free status.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Biological: NeuVax vaccine
    At the time of vaccine administration, a frozen solution of E75 acetate (1.5 mg/mL) is thawed and 1000mcg E75 peptide mixed thoroughly with 250mcg GM-CSF. This constitutes the NeuVax vaccine. Patients randomized to this arm will receive vaccinations of nelipepimut-S/GM-CSF administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series.
    Other Name: nelipepimut-S
  • Drug: Trastuzumab
    Herceptin will be administered to patients every three weeks as monotherapy for one year, to be given upon completion of standard of care chemotherapy/radiotherapy. The first trastuzumab infusion will be given no sooner than three weeks and no later than 12 weeks after completion of chemotherapy/radiotherapy. Trastuzumab will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk.
    Other Name: Herceptin
  • Drug: GM-CSF
    For patients randomized to the GM-CSF alone arm, they will receive inoculations of GM-CSF (250mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first injection will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series.
    Other Names:
    • Leukine
    • Sargramostim
Study Arms  ICMJE
  • Experimental: Trastuzumab + NeuVax
    Patients randomized to this arm will receive vaccinations of nelipepimut-S (1000 μg) and GM-CSF (250 μg) (NeuVax vaccine) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumbab to overlap with the PVS. Upon completion of the primary vaccination series (PVS), booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 6 months ± 2 weeks after the completion of the PVS, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following time points after completion of the PVS: 6 months ± 2 weeks, 12 months ± 2 weeks, 18 months ± 2 weeks and 24 months ± 2 weeks.
    Interventions:
    • Biological: NeuVax vaccine
    • Drug: Trastuzumab
    • Drug: GM-CSF
  • Active Comparator: Trastuzumab + GM-CSF
    Patients randomized to this arm will receive inoculations of GM-CSF (250 μg) administered in an identical manner to those receiving nelipepimut-S/GM-CSF (NeuVax). Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone. Upon completion of the primary vaccination series (PVS), booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 6 months ± 2 weeks after the completion of the PVS, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following time points after completion of the PVS: 6 months ± 2 weeks, 12 months ± 2 weeks, 18 months ± 2 weeks and 24 months ± 2 weeks.
    Interventions:
    • Drug: Trastuzumab
    • Drug: GM-CSF
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 19, 2014)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status 0,1
  • AJCC stage I - III non-inflammatory, HER2-positive (according to ASCO-CAP guidelines 5) breast cancer
  • Completed neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy and underwent surgery with final pathology showing evidence of residual disease in the breast or axilla (residual ductal carcinoma in situ or microinvasive disease not eligible) or underwent surgery as a first intervention and was found to be pathologically node-positive: ≥ 4 positive lymph nodes (pN2 or pN3) regardless of hormone receptor status or 1-3 positive lymph nodes (pN1) if hormone receptor negative. Patients with micrometastases (pN1mi) are not eligible.
  • Completed an approved regimen of neoadjuvant or adjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy with plan for completion of one year of trastuzumab therapy.
  • Completed appropriate surgical therapy to include:

    1. Total mastectomy and axillary staging with sentinel lymph node dissection or axillary lymph node dissection (level I/II). Patients with a positive sentinel lymph node must have undergone a completion axillary lymph node dissection.
    2. Breast conserving surgery (BCS) and axillary staging with sentinel lymph node dissection or axillary lymph node dissection. Patients undergoing surgery as a first intervention with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II unless they had clinically node negative T1-T2 tumors and fewer than 3 involved lymph nodes. Patients receiving neoadjuvant chemotherapy that have a positive sentinel lymph node must have undergone a completion axillary lymph node dissection.
    3. Completed or receiving appropriate radiation therapy if indicated:

For patients undergoing total mastectomy surgery as a first intervention, post-mastectomy radiation to the chest wall, infraclavicular and supraclavicular areas is required for patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 1-3 positive lymph nodes, post-mastectomy radiation to the chest wall, infraclavicular, supraclavicular, and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.

  • For patients undergoing breast conserving surgery (BCS) as a first intervention, whole breast irradiation with or without a boost, and radiation to the infraclavicular and supraclavicular areas is required for patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is not required but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 1-3 positive lymph nodes, whole breast irradiation with or without a boost is required. Radiation to the infraclavicular, supraclavicular, and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating medical oncologist.
  • For patient's undergoing mastectomy after neoadjuvant chemotherapy post-mastectomy radiation to the chest wall, infraclavicular and supraclavicular areas is required for patients presenting with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes identified pathologically at the time of surgery. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes identified pathologically, post-mastectomy radiation to the chest wall, infraclavicular, supraclavicular and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.
  • For patient's undergoing BCS after neoadjuvant chemotherapy, whole breast irradiation with or without a boost is required. For patients with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes identified pathologically at the time of surgery, radiation to the infraclavicular and supraclavicular areas is required. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes identified pathologically, radiation to the infraclavicular, supraclavicular and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.

    • HLA-A2+ or HLA-A3+ or HLA-A24+ or HLA-A26+
    • LVEF >50%, or an LVEF within the normal limits of the institution's specific testing (MUGA or ECHO)
    • Adequate organ function as determined by the following laboratory values:

      1. ANC ≥ 1,000/μL
      2. Platelets ≥ 75,000/μL
      3. Hgb ≥ 9 g/dL
      4. Creatinine ≤ 1.5 x upper limit of normal (ULN) of institution's range or Creatinine clearance ≥ 50%
      5. Total bilirubin ≤ 1.5 ULN of institution's range
      6. ALT and AST ≤ 1.5 ULN of institution's range
      7. For women of child-bearing potential, agreement to use adequate birth control (abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal ligation, oral contraception, IUD, or use of condoms or diaphragms)
    • Signed informed consent

Exclusion criteria:

  • AJCC Stage IV breast cancer
  • NYHA stage 3 or 4 congestive heart failure
  • Immune deficiency disease or known history of HIV, HBV, HCV
  • Receiving immunosuppressive therapy including chronic steroids, methotrexate, or other known immunosuppressive agents
  • Pregnancy (assessed by urine HCG)
  • Breast feeding
  • Any active autoimmune disease requiring treatment, with the exception of vitiligo
  • Active pulmonary disease requiring medication to include multiple inhalers (>3 inhalers including one containing steroids)
  • Involved in other experimental protocols except with permission of other PI
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02297698
Other Study ID Numbers  ICMJE 2014-0443
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Cancer Insight, LLC
Study Sponsor  ICMJE Cancer Insight, LLC
Collaborators  ICMJE
  • Genentech, Inc.
  • Sellas Life Sciences Group
Investigators  ICMJE
Study Director: COL (ret) George E Peoples, MD, FACS Cancer Insight, LLC
PRS Account Cancer Insight, LLC
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP