Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax

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.

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)