Trial Information

Combination Immunotherapy With Herceptin and the HER2 Vaccine E75 in Low and Intermediate HER2-expressing Breast Cancer Patients to Prevent Recurrence

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. 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.