Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax - Full Text View

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:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Sargramostim Trastuzumab

U.S. FDA Resources

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 HLA-A2+/A3+ patients who meet all eligibility criteria and who are randomized to this arm will receive Herceptin 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. 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 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. Patients will be blinded as to whether they are receiving NeuVax vaccine or GM-CSF only.	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 HLA-A2+/A3+ patients who meet all eligibility criteria and who are randomized to this arm will receive Herceptin 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. 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 three weeks for six 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.	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. 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

Arms

Assigned Interventions

Experimental: Herceptin + NeuVax vaccine

HLA-A2+/A3+ patients who meet all eligibility criteria and who are randomized to this arm will receive Herceptin 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. 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 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. Patients will be blinded as to whether they are receiving NeuVax vaccine or GM-CSF only.

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

HLA-A2+/A3+ patients who meet all eligibility criteria and who are randomized to this arm will receive Herceptin 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. 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 three weeks for six 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.

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. 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

Show Detailed Description

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 (≤2.0).
- 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 >2.0)
- 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

Sponsors and Collaborators

COL George Peoples, MD, FACS

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

Publications:

Sears AK, Perez SA, Clifton GT, Benavides LC, Gates JD, Clive KS, Holmes JP, Shumway NM, Van Echo DC, Carmichael MG, Ponniah S, Baxevanis CN, Mittendorf EA, Papamichail M, Peoples GE. AE37: a novel T-cell-eliciting vaccine for breast cancer. Expert Opin Biol Ther. 2011 Nov;11(11):1543-50. Epub 2011 Sep 6. Review.

Responsible Party:	COL George Peoples, MD, FACS, Chief, Surgical Oncology, Brooke Army Medical Center; Director and Principal Investigator, Cancer Vaccine Development Program, 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:	February 15, 2013
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 June 18, 2013