QUILT-3.060: NANT Pancreatic Cancer Vaccine: Molecularly Informed Integrated Immunotherapy in Subjects With Pancreatic Cancer Who Have Progressed on or After Standard-of-care Therapy

Study Overview
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Brief Summary
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This is a phase 1b/2 study to evaluate the safety and efficacy of metronomic combination therapy in subjects with pancreatic cancer who have progressed on or after previous SoC chemotherapy. Phase 2 will be based on Simon's two-stage optimal design.

Detailed Description
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Treatment will be administered in two phases, an induction and a maintenance phase, as described below. Subjects will continue induction treatment for up to 1 year. Treatment in the study will be discontinued if the subject experiences progressive disease (PD) or unacceptable toxicity (not corrected with dose reduction), withdraws consent, or if the Investigator feels it is no longer in the subject's best interest to continue treatment. Those who have a complete response (CR) in the induction phase will enter the maintenance phase of the study. Subjects may remain on the maintenance phase of the study for up to 1 year. Treatment will continue in the maintenance phase until the subject experiences PD or unacceptable toxicity (not corrected with dose reduction), withdraws consent, or if the Investigator feels it is no longer in the subject's best interest to continue treatment. The maximum time on study treatment, including both the induction and maintenance phases, is 2 years.

Official Title
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NANT Pancreatic Cancer Vaccine: Molecularly Informed Integrated Immunotherapy Combining Innate High-affinity Natural Killer (haNK) Cell Therapy With Adaptive T-cell Therapy (Adenovirus, Yeast, Fusion Protein Vaccine) in Subjects With Pancreatic Cancer Who Have Progressed on or After Standard-of-care Therapy

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Biological: ALT-803
* Biological: ETBX-011
* Biological: GI-4000
* Biological: haNK for infusion
* Biological: avelumab
* Biological: bevacizumab
* Drug: Capecitabine
* Drug: Cyclophosphamide
* Drug: Fluorouracil
* Drug: Leucovorin
* Drug: nab-Paclitaxel
* Drug: lovaza
* Drug: Oxaliplatin
* Procedure: SBRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old. Able to understand and provide a signed informed consent that fulfills the relevant IRB or Independent Ethics Committee (IEC) guidelines. Histologically-confirmed pancreatic cancer with progression on or after SoC therapy. ECOG performance status of 0 to 2. Have at least 1 measurable lesion of ≥ 1.5 cm. Must have a recent formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimen following the conclusion of the most recent anticancer treatment and be willing to release the specimen. 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. If safety concerns preclude collection of a biopsy during the screening period, a tumor biopsy specimen collected prior to the conclusion of the most recent anticancer treatment may be used. Must be willing to provide blood samples prior to the start of treatment on this study. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of treatment, if considered safe by the Investigator. 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: History of persistent grade 2 or higher (CTCAE Version 4.03) hematological toxicity resulting from previous therapy. Within 5 years prior to first dose of study treatment, any evidence of other active malignancies or brain metastasis except controlled basal cell carcinoma; prior history of in situ cancer (eg, breast, melanoma, cervical); prior history of prostate cancer that is not under active systemic treatment (except hormonal therapy) and with undetectable prostate-specific antigen (PSA) (< 0.2 ng/mL); bulky (≥ 1.5 cm) disease with metastasis in the central hilar area of the chest and involving the pulmonary vasculature. 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, autoimmune disease associated with lymphoma). History of organ transplant requiring immunosuppression. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). Requires whole blood transfusion to meet eligibility criteria. Inadequate organ function, evidenced by the following laboratory results: White blood cell (WBC) count < 3,500 cells/mm3 Absolute neutrophil count < 1,500 cells/mm3. Platelet count < 100,000 cells/mm3. Hemoglobin < 9 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 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. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 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. 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), hepatitis B virus (HBV), or hepatitis C virus (HCV). 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NANT Pancreatic Cancer Vaccine<br>A combination of agents will be administered to subjects in this study: ALT-803, ETBX-011, GI-4000, haNK, avelumab, bevacizumab, capecitabine, cyclophosphamide, fluorouracil, leucovorin, nab-paclitaxel, omega-3-acid ethyl esters, oxaliplatin, SBRT | Biological: ALT-803<br>* Recombinant human super agonist interleukin-15 (IL-15) complex<br>Biological: ETBX-011<br>* Ad5 [E1-, E2b-]-CEA<br>Biological: GI-4000<br>* Vaccine derived from recombinant Saccharomyces cerevisiae yeast expressing mutant Ras proteins<br>Biological: haNK for infusion<br>* NK-92 [CD16.158V, ER IL-2]<br>Biological: avelumab<br>* Recombinant human anti-PD-L1 IgG1 monoclonal antibody<br>Biological: bevacizumab<br>* Recombinant human anti-VEGF IgG1 monoclonal<br>Drug: Capecitabine<br>* 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine<br>Drug: Cyclophosphamide<br>* 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate<br>Drug: Fluorouracil<br>* 5-fluoro-2,4 (1H,3H)-pyrimidinedione<br>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: 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>Drug: lovaza<br>* Omega-3-acid ethyl esters<br>Drug: Oxaliplatin<br>* cis-[(1 R,2 R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)- O,O'] platinum<br>Procedure: SBRT<br>* Stereotactic Body Radiation Therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs), graded using the NCI CTCAE Version 4.03. | Phase 1b primary endpoint | 8 weeks | 
| Objective response rate by RECIST | Phase 2 primary endpoint | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate by RECIST | Phase 1b secondary endpoint | 8 weeks | 
| Progression-free survival by RECIST during Phase 1b | Phase 1b secondary endpoint | 8 weeks | 
| Progression-free survival by irRC during Phase 1b | Phase 1b secondary endpoint | 8 weeks | 
| Overall survival | Phase 1b secondary endpoint | 8 weeks | 
| Duration of response | Phase 1b secondary endpoint | 1 year | 
| Disease control rate (confirmed complete response, partial response, or stable disease lasting for at least 2 months). | Phase 1b secondary endpoint | 1 year | 
| Patient-reported outcomes of pancreatic cancer symptoms | Phase 1b secondary endpoint | 8 weeks | 
| Progression-free survival by RECIST during Phase 2 | Phase 2 secondary endpoint | 1 year | 
| Progression-free survival by irRC during Phase 2 | Phase 2 secondary endpoint | 1 year | 
| Overall survival | Phase 2 secondary endpoint | 1 year | 
| Duration of response | Phase 2 secondary endpoint | 1 year | 
| Disease control rate (confirmed complete response, partial response, or stable disease lasting for at least 2 months). | Phase 2 secondary endpoint | 1 year | 
| Patient-reported outcomes of pancreatic cancer symptoms | Phase 2 secondary endpoint | 1 year |