Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax
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.
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 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 sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01570036.
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.
Trial PhasePhase II
Trial Typeprevention
Lead OrganizationGeorge E. Peoples
- Primary ID368255
- Secondary IDsNCI-2015-00026, 1137008 / 20130058
- ClinicalTrials.gov IDNCT01570036