Clinical trial NCT01570036: Combination Immunotherapy With Herceptin and the HER2 Vaccine NeuVax
Official title: Combination Immunotherapy With Herceptin and the HER2 Vaccine E75 in Low and Intermediate HER2-expressing Breast Cancer Patients to Prevent Recurrence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
male breast cancer
Lead sponsor: Cancer Insight, LLC
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
name: Sellas Life Sciences Group
First posted: 2012-04-04
Enrollment: 275
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

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)

Primary outcomes:
measure: Disease-free Survival (DFS)
timeFrame: Disease-free survival at 24 months
measure: Disease-free Survival (DFS)
timeFrame: Disease-free survival up to 36 months
Secondary outcomes:
measure: Percent Ejection Fraction - A Measure of Cardiac Toxicity
timeFrame: 24 months
measure: Local and Systemic Toxicities
timeFrame: Duration of vaccine or inoculation series and booster series, an average of 30 months.
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Samuel Oschin Comprehensive Cancer Institute - Cedars Sinai Medical Center
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center, LLC
state: California
city: Santa Rosa
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Washington
country: United States
facility: Katzen Cancer Research Center, George Washington University
state: District of Columbia
city: Deerfield Beach
country: United States
facility: University of Miami
state: Florida
city: Kendall
country: United States
facility: University of Miami
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Plantation
country: United States
facility: Florida Cancer Research Institute
state: Florida
city: Plantation
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute, Inc
state: Florida
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital of South Bend
state: Indiana
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Baltimore
country: United States
facility: Medstar Health - Union Memorial Hospital
state: Maryland
city: Baltimore
country: United States
facility: Medstar Health - Weinberg Cancer Institute at Franklin Square
state: Maryland
city: Baltimore
country: United States
facility: MedStar Health - Good Samaritan Hospital
state: Maryland
city: Paramus
country: United States
facility: The Valley Hospital
state: New Jersey
city: Bronx
country: United States
facility: North Shore Hematology Oncology Associates
state: New York
city: New York
country: United States
facility: Tisch Cancer Institute/Icahn School of Medicine at Mount Sinai
state: New York
city: Portland
country: United States
facility: Legacy Health, Legacy Good Samaritan Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University - Kimmel Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology (Cancer Care Centers of South Texas)
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Everett
country: United States
facility: Providence Regional Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Milwaukee
country: United States
facility: Columbia St. Mary's
state: Wisconsin
Study officials:
affiliation: Cancer Insight, LLC
name: COL (ret.) George E. Peoples, MD, FACS
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Insight, LLC
name: COL (ret.) George E. Peoples, MD, FACS
role: STUDY_DIRECTOR
References:
citation: Clifton GT, Hale D, Vreeland TJ, Hickerson AT, Litton JK, Alatrash G, Murthy RK, Qiao N, Philips AV, Lukas JJ, Holmes JP, Peoples GE, Mittendorf EA. Results of a Randomized Phase IIb Trial of Nelipepimut-S + Trastuzumab versus Trastuzumab to Prevent Recurrences in Patients with High-Risk HER2 Low-Expressing Breast Cancer. Clin Cancer Res. 2020 Jun 1;26(11):2515-2523. doi: 10.1158/1078-0432.CCR-19-2741. Epub 2020 Feb 18.