Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax

• 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.

• 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 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.

• 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.

• Cardiac toxicity [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
  Each patient, regardless of randomization, will undergo cardiac assessment at baseline (Multiple Gated Aquisition scan (MUGA) preferred, echocardiogram (ECHO) allowed, consistency required) and every three months during Herceptin thrapy followed by every six months for a total of two years. Cardiac assessment will continue every six months if a patient experiences a greater than 10% reduction from baseline for the duration of the trial.
• 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.

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).

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.

• 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: 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)
• 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

• 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.
  Intervention: Drug: NeuVax vaccine
• 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.
  Interventions:

  • Drug: Herceptin
  • Drug: GM-CSF

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)

• Genentech
• Galena Biopharma, Inc.