QUILT-3.057: NANT Neoadjuvant Triple- Negative Breast Cancer (TNBC) Vaccine

Study Overview
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Brief Summary
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This is a randomized open-label phase 2 study to evaluate the efficacy and safety (as assessed by pCR) of the NANT Neoadjuvant TNBC Vaccine regimen (experimental arm) compared to the SoC dose-dense regimen of doxorubicin/cyclophosphamide followed by paclitaxel (control arm).

Detailed Description
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Treatment will be administered in 2 phases, a neoadjuvant phase and a postoperative phase. The neoadjuvant phase will be 18 weeks for patients enrolled in the experimental arm and 16 weeks for those enrolled in the control arm. Following the neoadjuvant phase, all subjects will undergo determination of their current response status and appropriate breast surgery and node dissection after which assessment for pCR will be conducted following completion of neoadjuvant systemic therapy. Pathologists interpreting surgical specimens for pCR assessment will be blinded to the treatment arm. All subjects, regardless of whether or not they have achieved a pCR, will then enter the postoperative phase where they will receive adjuvant treatment. A small portion of the corresponding neoadjuvant therapy, either nab-paclitaxel or paclitaxel, will be administered as adjuvant treatment postoperatively. Adjuvant treatment will continue in the postoperative phase until the subject experiences unacceptable toxicity (not correctable with dose reduction), withdraws consent, or if the Investigator feels it is no longer in the subject's best interest to continue treatment.

Official Title
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An Open-Label Randomized Phase 2 Trial Of The NANT NEOADJUVANT Triple-Negative Breast Cancer (TNBC) VACCINE VS Standard-Of-Care For The Neoadjuvant Treatment Of Subjects With TNBC

Conditions
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Triple Negative Breast Cancer (TNBC)

Intervention / Treatment
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* Drug: Leucovorin
* Drug: 5-Fluorouracil
* Drug: Aldoxorubicin HCl
* Drug: nab-Paclitaxel
* Biological: ETBX-011
* Biological: ETBX-051
* Biological: ETBX-061
* Biological: GI-4000
* Biological: GI-6207
* Biological: GI-6301
* Drug: Avelumab
* Biological: ALT-803
* Biological: haNK
* Drug: Cyclophosphamide
* Drug: Doxorubicin HCL
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Able to understand and provide a signed informed consent that fulfills the relevant IRB or Independent Ethics Committee (IEC) guidelines. Histologically confirmed stage II or III TNBC. Subjects must be treatment naïve. TNBC is defined as breast cancer that lacks estrogen receptor (ER) and progesterone receptor (PgR) expression, and human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Have at least 1 measurable lesion of ≥ 1.0 cm. Must have a recent FFPE tumor biopsy specimen and be willing to release the specimen for prospective and exploratory tumor molecular profiling. If an historic specimen is not available, the subject must be willing to undergo a biopsy during the screening period, if considered safe by the Investigator. Must be willing to provide blood samples prior to the start of treatment on this study for prospective tumor molecular profiling and exploratory analyses. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 1 year after completion of therapy, and non-sterile male subjects must agree to use a condom for up to 4 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and abstinence. Exclusion Criteria: Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment-related complications. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, and autoimmune disease associated with lymphoma). History of organ transplant requiring immunosuppression. History of or active inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis). Inadequate organ function, evidenced by the following laboratory results: Absolute neutrophil count (ANC) < 1,000 cells/mm^3. Platelet count < 75,000 cells/mm^3. Uncorrectable grade 3 anemia (hemoglobin < 8 g/dL). Total bilirubin greater than the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome). Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases). Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver metastases, or >10 × ULN in subjects with bone metastases). Serum creatinine > 2.0 mg/dL or 177 μmol/L. Serum anion gap > 16 mEq/L or arterial blood with pH < 7.3. Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication. Serious myocardial dysfunction defined by echocardiogram (ECHO) as absolute LVEF 10% below the institution's lower limit of predicted normal. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy. Positive results of screening test for human immunodeficiency virus (HIV). Current chronic daily treatment (continuous for > 3 months) with systemic corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed. Known hypersensitivity to any component of the study medication(s). Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction with any of the study medications. Concurrent or prior use of a strong cytochrome P450 (CYP)3A4 inhibitor (including ketoconazole, itraconazole, posaconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, and grapefruit products) or strong CYP3A4 inducers (including phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St John's Wort) within 14 days before study day 1. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8 inducer (rifampin) within 14 days before study day 1. Participation in an investigational drug study or history of receiving any investigational treatment within 14 days prior to screening for this study, except for testosterone-lowering therapy in men with prostate cancer. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. Concurrent participation in any interventional clinical trial. Pregnant and nursing women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment will be administered in 2 phases, a neoadjuvant phase and a postoperative phase. For the experimental arm, subjects will receive treatment in the neoadjuvant phase for six 3-week cycles (ie, 18 weeks total). For the control arm, subjects will receive neoadjuvant treatment for a total of 16 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>NANT Neoadjuvant Triple Negative Breast Cancer Vaccine A combination of agents will be administered to subjects in this study: cyclophosphamide, 5-fluorouracil, leucovorin, nab-paclitaxel, avelumab, aldoxorubicin HCl, ALT-803, haNK, GI-4000, GI-6207, GI-6301, ETBX-011, ETBX-051 and ETBX-061 | Drug: Leucovorin<br>* L-Glutamic acid, N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-, calcium salt<br>Drug: 5-Fluorouracil<br>* 5-fluoro-2,4 (1H,3H)-pyrimidinedione<br>Drug: Aldoxorubicin HCl<br>* albumin-binding prodrug of doxorubicin HCl<br>Drug: nab-Paclitaxel<br>* Benzenepropanoic acid, β-(benzoylamino)-α-hydroxy-(2aR, 4S, 4aS, 6R, 9S, 11S, 12S, 12aR, 12bS)-6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a, 3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-dodecahydro-4,11-dihydroxy-4a, 8, 13, 13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-y1ester,(αR,βS)-(9CI) bound to albumin<br>Biological: ETBX-011<br>* Ad5 [E1-, E2b-]-CEA<br>Biological: ETBX-051<br>* Ad5 [E1-, E2b-]-Brachyury vaccine<br>Biological: ETBX-061<br>* Ad5 [E1-, E2b-]-mucin 1[MUC1]<br>Biological: GI-4000<br>* Vaccine derived from recombinant Saccharomyces cerevisiae yeast expressing mutant Ras proteins<br>Biological: GI-6207<br>* CEA yeast vaccine<br>Biological: GI-6301<br>* Brachyury yeast vaccine<br>Drug: Avelumab<br>* Avelumab<br>Biological: ALT-803<br>* Recombinant human super agonist interleukin-15 (IL-15) complex<br>Biological: haNK<br>* NK-92 [CD16.158V, ER IL-2]<br>Drug: Cyclophosphamide<br>* 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate<br>|
| Active Comparator: Group B<br>Standard treatment with a combination of doxorubicin, cyclophosphamide and paclitaxel. | Drug: Cyclophosphamide<br>* 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate<br>Drug: Doxorubicin HCL<br>* Doxorubicin HCL<br>Drug: paclitaxel<br>* paclitaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response Rate | Compare the efficacy of the NANT neoadjuvant TNBC Vaccine treatment vs standard-of-care (SoC) therapy as assessed by pathologic complete response (pCR) rate in the breast and axilla. | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of safety as determined by incidence or treatment-emergent adverse events | Incidence of treatment -emergent adverse events | 36 months | 
| Evaluate additional measures of efficacy by event-free survival | Time from randomization to first occurrence of advancement of disease | 36 months | 
| Overall survival | Time from date of first treatment to death from any cause | 36 months | 
| Locoregional relapse | Presence of any disease recurrence, including location | 36 months | 
| Distant metastatic rates at 1 year | Number of patients with a metastatic lesion | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNBC