Breast Cancer Clinical Trial

Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax

Summary

The study will be a multi-center, prospective, randomized, single-blinded, placebo-controlled Phase II trial of Herceptin + NeuVax(TM) vaccine (E75 peptide/granulocyte macrophage-colony stimulating factor) (GM-CSF) versus Herceptin + GM-CSF alone. The target study population is node-positive (NP) (or node-negative [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 was restricted to HLA-A2+ or HLA-A3+ patients (approximately two-thirds of the US population), and has been extended to HLA-A24+ and HLA-A26+ as well.

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Full 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), and has been extended to HLA-A24+ and HLA-A26+ as well.

HLA-A2+/A3+/A24+/or A26+ 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 April, 2013, enrollment of the last patient would be expected in August 2017 followed by a three-year follow-up period. The duration of the trial is expected to be seven years.

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Eligibility 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 have 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 or Dual-ISH testing must be performed on IHC 2+ tumors and shown to be non-amplified by FISH (≤2.0) or by Dual-ISH (≤2.0).
HLA-A2, A3, A24, or A26 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)
Must start study treatment (receive first Herceptin infusion) 15between 3-12 weeks from completion of standard of care therapy.

4.1.3 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 FISHDual-ISH amplified (FISH >2.0); Dual-ISH >2.0
HLA-A2, A3, A24, A26 negative
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
Any active autoimmune disease requiring treatment, with the exception of vitiligo
Active pulmonary disease requiring medication to include multiple inhalers
Involved in other experimental protocols (except with permission of the other study PI)

Study is for people with:

Breast Cancer

Phase:

Phase 2

Estimated Enrollment:

275

Study ID:

NCT01570036

Recruitment Status:

Completed

Sponsor:

George E. Peoples

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There are 28 Locations for this study

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Samuel Oschin Comprehensive Cancer Institute - Cedars Sinai Medical Center
Beverly Hills California, 90211, United States
Sarcoma Oncology Research Center, LLC
Santa Monica California, 90403, United States
St. Joseph Heritage Healthcare
Santa Rosa California, 95403, United States
Sibley Memorial Hospital
Washington District of Columbia, 20016, United States
Katzen Cancer Research Center, George Washington University
Washington District of Columbia, 20037, United States
University of Miami
Deerfield Beach Florida, 33442, United States
University of Miami
Kendall Florida, 33176, United States
University of Miami
Miami Florida, 33136, United States
Florida Cancer Research Institute
Plantation Florida, 33324, United States
University of Miami
Plantation Florida, 33324, United States
H. Lee Moffitt Cancer Center & Research Institute, Inc
Tampa Florida, 33612, United States
University of Hawaii Cancer Center
Honolulu Hawaii, 96813, United States
Franciscan Health Indianapolis
Indianapolis Indiana, 46237, United States
Memorial Hospital of South Bend
South Bend Indiana, 46601, United States
Cancer Center of Kansas
Wichita Kansas, 67212, United States
Medstar Health - Union Memorial Hospital
Baltimore Maryland, 21218, United States
Medstar Health - Weinberg Cancer Institute at Franklin Square
Baltimore Maryland, 21237, United States
MedStar Health - Good Samaritan Hospital
Baltimore Maryland, 21239, United States
The Valley Hospital
Paramus New Jersey, 07652, United States
North Shore Hematology Oncology Associates
Bronx New York, 10469, United States
Tisch Cancer Institute/Icahn School of Medicine at Mount Sinai
New York New York, 10029, United States
Legacy Health, Legacy Good Samaritan Medical Center
Portland Oregon, 97210, United States
Thomas Jefferson University - Kimmel Cancer Center
Philadelphia Pennsylvania, 19107, United States
University of Texas M.D. Anderson Cancer Center
Houston Texas, 77030, United States
Texas Oncology (Cancer Care Centers of South Texas)
San Antonio Texas, 78217, United States
Virginia Cancer Specialists
Fairfax Virginia, 22031, United States
Providence Regional Medical Center
Everett Washington, 98201, United States
Swedish Cancer Institute
Seattle Washington, 98104, United States
Columbia St. Mary's
Milwaukee Wisconsin, 53211, United States

How clear is this clinincal trial information?

Study is for people with:

Breast Cancer

Phase:

Phase 2

Estimated Enrollment:

275

Study ID:

NCT01570036

Recruitment Status:

Completed

Sponsor:


George E. Peoples

How clear is this clinincal trial information?

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