Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax

This study is currently recruiting participants.
Verified January 2014 by San Antonio Military Medical Center
Sponsor:
Collaborators:
Genentech
Galena Biopharma, Inc.
Information provided by (Responsible Party):
Jarrod P. Holmes, MD, FACP, San Antonio Military Medical Center
ClinicalTrials.gov Identifier:
NCT01570036
First received: March 25, 2012
Last updated: January 10, 2014
Last verified: January 2014
  Purpose

The study will be a multi-center, prospective, randomized, single-blinded, placebo-controlled Phase II trial of Herceptin + NeuVax(TM) vaccine (E75 peptide/GM-CSF) versus Herceptin + GM-CSF alone. The target study population is NP (or NN if negative for both ER and PR) breast cancer patients with HER2 1+ and 2+ expressing tumors who are disease-free after standard of care therapy. Disease-free subjects after standard of care multi-modality therapy will be screened and HLA-typed. E75 is a CD8-eliciting peptide vaccine that is restricted to HLA-A2+ or HLA-A3+ patients (approximately two-thirds of the US population).


Condition Intervention Phase
Breast Cancer
Drug: Herceptin
Drug: NeuVax vaccine
Drug: GM-CSF
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Prevention
Official Title: Combination Immunotherapy With Herceptin and the HER2 Vaccine E75 in Low and Intermediate HER2-expressing Breast Cancer Patients to Prevent Recurrence

Resource links provided by NLM:


Further study details as provided by San Antonio Military Medical Center:

Primary Outcome Measures:
  • Disease-free survival (DFS) [ Time Frame: Disease-free survival at 24 months ] [ Designated as safety issue: No ]
    Disease-free survival (DFS) for all patients regardless of randomization will be determined by patients' own physicians at the individual study sites during routine follow-up screening. This will occur 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 objective of the study is disease-free survival (DFS) at 24 months.

  • Disease-free survival (DFS) [ Time Frame: Disease-free survival up to 36 months ] [ Designated as safety issue: No ]
    Disease-free survival (DFS) for all patients regardless of randomization will be determined by patients' own physicians at the individual study sites during routine follow-up screening. This will occur at months 30 and 36 after completion of primary therapies with clinical exam, and laboratory and radiographic surveillance. The secondary objective of the study is disease-free survival (DFS) at 36 months.


Secondary Outcome Measures:
  • Cardiac toxicity [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    Each patient, regardless of randomization, will undergo cardiac assessment (ejection fraction) at baseline Multiple Gated Acquisition scan (MUGA) preferred, echocardiogram (ECHO) allowed, consistency required) and at 3, 6, 12, and 24 months. Cardiac assessment will continue every six months if a patient experiences a greater than 10% reduction from baseline for the duration of the trial or until resolution.

  • Local and systemic toxicities [ Time Frame: Duration of vaccine or inoculation series and booster series ] [ Designated as safety issue: Yes ]
    Standard local and systemic toxicities will be collected and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 toxicity scale. For both the regular and 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. Patients will also return to the clinic 48-72 hours after each inoculation for questioning regarding systemic toxicity and to examine and measure the local reaction at the inoculation sites.


Estimated Enrollment: 300
Study Start Date: January 2013
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Herceptin + NeuVax vaccine
Patients randomized to this arm will receive Herceptin every 3 weeks as monotherapy for 1 year. The first Herceptin infusion will be given no sooner than 3 weeks and no later than 12 weeks after completion of standard of care chemotherapy/radiotherapy. Herceptin will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk. Patients will receive vaccinations of NeuVax vaccine (E75 peptide 1000mcg + GM-CSF 250mcg) administered intradermally every 3 weeks for 6 total vaccinations, 30-120 minutes after completion of Herceptin infusion. The NeuVax vaccine series will begin immediately after completion of the third Herceptin infusion. Patients will be blinded as to whether they are receiving NeuVax vaccine or GM-CSF. After completion of primary vaccine series, patients will receive four Neuvax vaccine booster inoculations to be administered at 12, 18, 24, and 30 months from date of first Herceptin infusion.
Drug: NeuVax vaccine
1000mcg of lyophilized E75 peptide is suspended in bacteriostatic water for injection and then frozen. At the time of vaccine administration, this frozen vial of suspended peptide is thawed and mixed thoroughly with 250mcg GM-CSF in the syringe. This constitutes the NeuVax vaccine. For patients randomized to the Herceptin + NeuVax vaccine arm, they will commence Herceptin monotherapy and then will begin the NeuVax vaccine series immediately after completion of the third Herceptin infusion. The vaccine series consists of NeuVax vaccine administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of Herceptin infusion.
Other Names:
  • E75 peptide (KIFGSLAFL, HER2/neu, 369-377)
  • GM-CSF (sargramostim)
Active Comparator: Herceptin + GM-CSF only
Patients randomized to this arm will receive Herceptin every 3 weeks as monotherapy for 1 year. The first Herceptin infusion will be given no sooner than 3 weeks and no later than 12 weeks after completion of standard of care chemotherapy/radiotherapy. Herceptin will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk. Patients will receive inoculations of GM-CSF only (250mcg) administered intradermally every 3 weeks for 6 total inoculations, 30-120 minutes after completion of Herceptin infusion. The GM-CSF only inoculation series will begin immediately after completion of the third Herceptin infusion. Patients will be blinded as to whether they are receiving NeuVax vaccine or GM-CSF only. After completion of six-inoculation primary vaccine series, patients will then receive a total of four GM-CSF only booster inoculations to be administered at 12, 18, 24, and 30 months from the date of the first Herceptin infusion.
Drug: Herceptin
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 Herceptin infusion will be given no sooner than three weeks and no later than 12 weeks after completion of chemotherapy/radiotherapy. Herceptin 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: Trastuzumab
Drug: GM-CSF
For patients randomized to the Herceptin + GM-CSF only arm, they will commence Herceptin monotherapy and then will begin the GM-CSF inoculation series immediately after completion of the third Herceptin infusion. The GM-CSF inoculation series consists of 250mcg GM-CSF administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of Herceptin infusion.
Other Name: Sargramostim

  Hide Detailed Description

Detailed Description:

In this study, the investigators intend to assess the ability of the combination of Herceptin and NeuVax vaccine (HER2 protein E75 peptide administered with the immunoadjuvant GM-CSF) given in the adjuvant setting to prevent recurrences in NP (or NN if negative for both estrogen (ER) and progesterone (PR) receptors) breast cancer patients with tumors that express low (1+) or intermediate (2+) levels of HER2. Enrolled patients will be randomized to receive Herceptin and NeuVax vaccine or Herceptin with GM-CSF alone (no NeuVax vaccine). The safety of the combination therapy will be documented, specifically to ensure that no additive cardiac toxicity results from combination HER2-directed therapy. Efficacy will be documented by comparing the DFS and immunological responses between treatment groups.

The primary efficacy endpoint is to compare DFS at 24 months between treatment groups. The primary safety issue is to prove there is no additive cardiac toxicity with combination HER2-directed therapy. A secondary endpoint of the trial is to compare DFS at 36 months. Immunologic responses to the vaccine will also be documented and correlated to clinical benefit.

The study will be a multi-center, prospective, randomized, single-blinded, placebo-controlled Phase II trial of Herceptin + NeuVax vaccine versus Herceptin + GM-CSF alone. The target study population is NP (or NN if negative for both ER and PR) breast cancer patients with HER2 1+ and 2+ expressing tumors who are disease-free after standard of care therapy. Disease-free subjects after standard of care multi-modality therapy will be screened and HLA-typed. E75 is a CD8-eliciting peptide vaccine that is restricted to HLA-A2+ or HLA-A3+ patients (approximately two-thirds of the US population).

HLA-A2+/A3+ patients who meet all other eligibility criteria will be randomized to receive Herceptin + NeuVax vaccine or Herceptin + GM-CSF alone. For both groups, Herceptin will be given every three weeks as monotherapy for one year, to be given upon completion of standard of care chemotherapy/radiotherapy. The first Herceptin infusion must be given no sooner than three weeks and no later than 12 weeks after completion of chemotherapy/radiotherapy. Herceptin will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk. Herceptin will be administered as described in Section 4.3. Patients randomized to the NeuVax vaccine arm will receive vaccinations of E75 peptide (1000 mcg) and GM-CSF (250 mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of Herceptin infusion. The NeuVax vaccine series will begin immediately after completion of the third Herceptin infusion. In extenuating circumstances, the first vaccination may be delayed to the fourth or fifth Herceptin infusion with prior approval from the Principal Investigator. Those patients randomized to the GM-CSF alone arm will receive vaccinations of GM-CSF (250 mcg) administered in an identical manner to those receiving NeuVax vaccine. Patients will be blinded as to whether they are receiving NeuVax vaccine or GM-CSF alone.

Upon completion of the vaccination series, booster inoculations (same dose and route) will be administered every six months x4 for total combination (Herceptin and vaccine) treatment duration of 30 months. The first booster inoculation will occur with the final Herceptin infusion, with subsequent boosters timed every six months from the first booster. Booster inoculations will occur for patients randomized to receive E75/GM-CSF as well as patients randomized to receive GM-CSF alone, and will consist of the same treatment drugs and dosing (i.e. E75/GM-CSF patients will be boosted with E75/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 documented with both in vitro phenotypic and functional assays as well as in vivo delayed type hypersensitivity (DTH) reactions. All patients will be followed for a total of 36 months to document disease-free status.

The investigators plan to enroll 300 patients (150 in each treatment arm) at a planned accrual rate of 12 patients per month (approximately one per study site per month). With accrual beginning in January 2012, enrollment of the last patient would be expected in January 2014 followed by a three-year follow-up period. The duration of the trial is expected to be five years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients will be included in the study based on the following criteria:

    • Women 18 years or older
    • Node-positive breast cancer (AJCC N1, N2, or N3)
    • Node-negative breast cancer if negative for both estrogen (ER) and progesterone (PR) receptors and has received chemotherapy as standard of care
    • Clinically cancer-free (no evidence of disease) after standard of care therapy (surgery, chemotherapy, radiation therapy as directed by NCCN guidelines). Hormonal therapy will continue per standard of care. Neoadjuvant chemotherapy is allowed.
    • Recovery from any toxicity(ies) associated with prior adjuvant therapy.
    • HER2 expression of 1+ or 2+ by IHC. FISH testing must be performed on IHC 2+ tumors and shown to be non-amplified (≤2.2).
    • HLA-A2 and/or HLA-A3 positive
    • LVEF >50%, or an LVEF within the normal limits of the institution's specific testing (MUGA or Echo)
    • ECOG 0,1
    • Signed informed consent
    • Adequate birth control (abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal ligation, oral contraception, IUD, or use of condoms or diaphragms)

Exclusion Criteria:

  • Patients will be excluded from the study based on the following criteria

    • Node-negative breast cancer (AJCC N0 or N0(i+)) unless negative for both estrogen (ER) and progesterone (PR) receptors and has received chemotherapy as standard of care
    • Clinical or radiographic evidence of distant or residual breast cancer
    • HER2 negative (IHC 0) or HER2 3+ or FISH amplified (FISH >2.2)
    • Non-HLA-A2/3 positivity
    • History of prior Herceptin therapy
    • NYHA stage 3 or 4 cardiac disease
    • LVEF <50%, or less than the normal limits of the institution's specific testing (MUGA or Echo)
    • Immune deficiency disease or HIV, HBV, HCV
    • Receiving immunosuppressive therapy including chemotherapy, chronic steroids, methotrexate, or other known immunosuppressive agents
    • ECOG ≥2
    • Tbili >1.8, creatinine>2, hemoglobin<10, platelets<50,000, WBC<2,000
    • Pregnancy (assessed by urine HCG)
    • Breast feeding
    • History of autoimmune disease
    • Active pulmonary disease requiring medication to include multiple inhalers
    • Involved in other experimental protocols (except with permission of the other study PI)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01570036

Contacts
Contact: Kimberly Young, RN, CCRC (707) 521-3814 KYoung@rrmg.com

Locations
United States, California
Redwood Regional Medical Group Recruiting
Santa Rosa, California, United States, 95403
Contact: Kimberly Young, RN, CCRC    707-521-3814    KYoung@rrmg.com   
Principal Investigator: Jarrod P. Holmes, MD         
United States, District of Columbia
Katzen Cancer Research Center, George Washington University Recruiting
Washington, District of Columbia, United States, 20037
Contact: Miriam Rundell    202-741-3379    mrundell@mfa.gwu.edu   
Principal Investigator: Lisa McGrail, MD         
United States, Hawaii
University of Hawaii Cancer Center Recruiting
Honolulu, Hawaii, United States, 96813
Contact: Motoko Ishii, RN    808-586-5855    mishii@cc.hawaii.edu   
Principal Investigator: Michelle Miyashiro, MD         
United States, Indiana
Memorial Hospital of South Bend Recruiting
South Bend, Indiana, United States, 46601
Contact: Lori Wiseman, CCRP    574-647-6821    lwiseman@beaconhealthsystem.org   
Principal Investigator: Thomas Reid, III, MD, PhD         
United States, Maryland
Medstar Health - Weinberg Cancer Institute at Franklin Square Recruiting
Baltimore, Maryland, United States, 21237
Contact: Jean M. Flack, BSN, OCN, CCRC    443-777-7364    jean.flack@medstar.net   
Principal Investigator: Mahsa Mohebtash, MD         
Medstar Health - Union Memorial Hospital Recruiting
Baltimore, Maryland, United States, 21218-2895
Contact: Heather Williams    410-261-8151    heather.williams@medstar.net   
Contact: Jean Flack    443-777-7364    jean.flack@medstar.net   
Principal Investigator: Mahsa Mohebtash, MD         
United States, Oregon
Legacy Health, Legacy Good Samaritan Medical Center Not yet recruiting
Portland, Oregon, United States, 97210
Contact: Jennifer Gluth    503-413-8199    jgluth@lhs.org   
Principal Investigator: Nathalie Johnson, MD         
United States, Pennsylvania
Thomas Jefferson University - Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Deborah Kilpatrick, RN    215-955-0017    Deborah.Kilpatrick@jefferson.edu   
Contact: Brooke Kennedy    215-955-6033    Brooke.Kennedy@jefferson.edu   
Principal Investigator: Adam Berger, MD         
Sub-Investigator: Tiffany Avery, MD         
Sub-Investigator: Rebecca Jaslow, MD         
Sub-Investigator: Massimo Cristofanilli, MD         
Sub-Investigator: Christina Brus, MD         
Sub-Investigator: Frederick Fellin, MD         
Sub-Investigator: Michael Ramirez, MD         
Sub-Investigator: Allison Zibelli, MD         
Sub-Investigator: Lewis Rose, MD         
Sub-Investigator: Atrayee Basu-Mallick, MD         
United States, Texas
University of Texas M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Sara E. Stassen, RN, BSN    713-563-1681    sestassen@mdanderson.org   
Contact: Elizabeth A. Mittendorf, MD, PhD    713-792-2362    eamitten@mdanderson.org   
Principal Investigator: Elizabeth A. Mittendorf, MD, PhD         
Cancer Care Centers of South Texas Recruiting
San Antonio, Texas, United States, 78217
Contact: Reaber Neal-Bryant, RN, CRC    210-424-2634    reaber.neal-bryant@usoncology.com   
Principal Investigator: Sharon Wilks, MD         
Texas Oncology - Deke Slayton Cancer Center Not yet recruiting
Webster, Texas, United States, 77598
Contact: Deborah Terry-Dettmer    281-332-7505    deborah.terry-dettmer@usoncololgy.com   
Principal Investigator: Alan Rodney, MD         
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Sonja Crandon    703-208-3148    sonja.crandon@usoncology.com   
Principal Investigator: Nicholas Robert, MD         
United States, Washington
Providence Regional Medical Center Recruiting
Everett, Washington, United States, 98201
Contact: Katie Lyon, CCRP    425-297-5531    katie.lyon@providence.org   
Principal Investigator: Jason Lukas, MD         
Sponsors and Collaborators
Jarrod P. Holmes, MD, FACP
Genentech
Galena Biopharma, Inc.
Investigators
Principal Investigator: Jarrod P. Holmes, MD Redwood Regional Medical Center
Study Director: COL George E. People, MD, FACS San Antonio Military Medical Center
  More Information

No publications provided

Responsible Party: Jarrod P. Holmes, MD, FACP, Medical Oncologist - Redwood Regional Medical Group, San Antonio Military Medical Center
ClinicalTrials.gov Identifier: NCT01570036     History of Changes
Other Study ID Numbers: 368255, 1137008 / 20130058
Study First Received: March 25, 2012
Last Updated: January 10, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by San Antonio Military Medical Center:
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
male breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 21, 2014