Omega -3-acid ethyl esters 19. Radiation Title of Study: NANT triple negative breast cancer (TNBC) 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 TNBC who have progressed on or after standard -of-care therapy. Confidential and Proprietary 9 NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Study Number: QUILT -3.067 Study Phase: Phase 1b/2 (Simon’s two- stage optimal design). Study Objectives: Phase 1b • The primary objective is to evaluate the overall safety profile of the NANT TNBC vaccine regimen in subjects with TNBC who have progressed on or after standard-of- care (SoC) therapy. • Secondary objectives are to obtain preliminary estimates of efficacy by objective response rate (ORR), progression -free survival (PFS), overall survival (OS), duration of response (DOR), disease contro l rate (DCR) , and quality of life (QoL) by patient-reported outcomes (PROs). • Exploratory objectives include the assessment of tumor molecular profiles (genomics, transcriptomics, and proteomics), therapy-induced changes in immune responses, and molecular changes in circulating tumor DNA (ctDNA) and RNA (ctRNA); and their correlations with subject outcomes. Phase 2 • The primary objective is to determine the efficacy of the NANT TNBC vaccine regimen as assessed by ORR. • Secondary objectives are to obtain addit ional measures of safety and efficacy (PFS, OS, DOR, DCR , and QoL by PROs). • Exploratory objectives include the assessment of tumor molecular profiles, therapy - induced changes in immune responses, and molecular changes in ctDNA and ctRNA; and their correlat ions with subject outcomes. Study Design: This is a phase 1b/2 study to evaluate the safety and efficacy of metronomic combination therapy in subjects with TNBC who have progressed on or after previous SoC chemotherapy. Phase 2 will be based on Simon’s tw o-stage optimal design. Preliminary assessment of the safety of the treatment regimen will occur by the NantKwest Safety Review Committee (SRC). Enrollment into the phase 1b portion will continue if data from the initial 3 subjects suggest that the combination therapy is tolerable. 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 Investig ator 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), Confidential and Proprietary 10 NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 withdraws consent, or if the Investigator feels it is no longer in the subject’s best interest to con tinue treatment. The maximum time on study treatment, including both the induction and maintenance phases, is 2 years. Exploratory tumor molecular profiling will be conducted on samples collected prior to treatment on this study, 8 weeks after the start of treatment, and during potential prolonged induction and maintenance phases (depending on response), as described in Section 6.4.1. Separate blood t ubes will be collected every 6 weeks in the induction phase and every 8 weeks in the maintenance phase during routine blood draws for exploratory immunology and ctDNA/ctRNA analyses, as described in Section 6.4.2 and Section 6.4.3, respectively. Tumors will be assessed at screening, and tumor response will be assessed every 8 weeks during the induction phase, and every 12 weeks during the maintenance phase by computed tomography (CT) of target and non- target lesions in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and immune -related response criteria (irRC). Prospective Tumor Molecular Profiling Prospective tumor molecular profiling will be conducted to inform RAS mutational status, and will be used to determine whether GI -4000 will be administered. GI-4000 admi nistration will be initiated as soon as results from tumor molecular profiling are available. All subjects will receive all other agents regardless of their tumor molecular profile. Prospective tumor molecular profiling will be performed on FFPE tumor tissue and whole blood (subject -matched normal comparator against the tumor tissue) collected prior to treatment on this study. Treatment with all study drugs except GI-4000 may be initiated before FFPE tumor tissue and/or results from prospective tumor molecular profiling are available; in the event that this occurs, treatment of subjects with tumors positive for specific RAS mutations targeted by GI-4000 will begin as soon as molecular profiling results are available. More information on the collection of tum or tissue and whole blood is described in Section 6.4.1.2 and is similar to the collection of samples for the exploratory tumor molecular profiling. Subjects will receive GI -4000 if their tumor is positive for specific RAS mutations, as determined by whole genome sequencing. As described in Section 1.5.12, GI-4000 is 4 separate products from the GI-4000 series (GI-4014, GI-4015, GI- 4016, and GI-4020); each of these expresses a combination of mutated RAS oncoproteins. The specific RAS mutation will determine which GI -4000 product will be used for treatment (GI -4014 for G12V, GI-4015 for G12C, GI-4016 for G12D, GI-4020 for G12R or Q61H, and GI-4014, GI-4015, or GI-4016 for Q61L or Q61R). Induction Phase: The induction phase will consist of repeated 3- week cycles for a maximum treatment period of 1 year. The treatment regimen of aldoxorubicin HCl, ALT-803, avelumab, bevacizumab, cisplatin, cyclophosphamide, Ad5- based vaccines (ETBX -011, ETBX-051, and ETBX-061), 5-FU/leucovorin, yeast -based vaccines (GI -4000, GI-6207, GI-6301), haNK cells, nab-paclitaxel, and omega-3- acid ethyl esters will be repeated every 3 weeks. Concurrent SBRT will be given durin g the first two 3-week cycles. Radiation will be administered to no more than 5 tumor sites using SBRT, as described in Section 5.1.5.1 . The induction phase of study treatment will be conducted in accordance with the following dosing regimen: Daily: • Omega -3-acid ethyl esters (by mouth [PO] twice a day [BID] [3 × 1 g capsules and 2 × 1 g capsules]) Confidential and Proprietary 11 NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Day 1, every 3 weeks: • Bevacizumab (5 mg/kg IV ) Days 1 and 15, every 3 weeks: • Leucovorin (20 mg/m2 IV bolus) Days 1 –5 and 15– 19, every 3 weeks: • 5-FU (1500 mg/m2 continuous IV infusion over 85–96 hours) Days 1 –5, 8–12, and 15- 19 every 3 weeks: • Cyclophosphamide (50 mg PO BID) Days 1 and 8, every 3 weeks: • Nab-paclitaxel (125 mg IV) • Cisplatin (40 mg/m2 IV) Day 5 (every 3 weeks for 3 cycles then every 8 weeks thereafter): • ETBX -011, ETBX-051, ETBX-061 (1 × 1011 virus particles [VP]/vaccine/dose subcutaneously [SC]) Days 8 and 15 (every 3 weeks): • Aldoxorubicin HCl (80 mg/m2 IV on day 8; 30 mg/m2 IV on day 15) • SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for the first 2 cycles only) Day 9, every 3 weeks: • Avelumab (10 mg/kg IV over 1 hour) Days 9 and 16, every 3 weeks: • ALT -803 (10 μg/kg SC 30 minutes prior to haNK infusion) Days 9, 11, 16, and 18, every 3 weeks: • haNK (2 × 109 cells/dose IV) Day 11, every 3 weeks for 3 cycles and every 8 weeks thereafter: • GI-4000, GI-6207, and GI-6301 (40 yeast units [YU]/vacci ne/dose SC) Prospective tumor molecular profiling will determine whether GI-4000 will be administered, as described above. GI -4000 administration will be initiated as soon as results from tumor molecular profiling are available. Confidential and Proprietary 12 NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Maintenance Phase: The duration of the maintenance phase will be up to 1 year following completion of the last treatment in the induction phase. The maintenance phase will consist of repeated 2 -week cycles. The treatment regimen of aldoxorubicin HCl, ALT -803, avelumab, bevacizumab, cyclophosphamide, capecitabine, Ad5-based vaccines (ETBX -011, ETBX-051, and ETBX-061), yeast- based vaccines (GI -4000, GI-6207, and GI-6301), haNK cells, nab-paclitaxel, and omega-3- acid ethyl esters will be repeated every 2 weeks. The maintenance p hase of study treatment will be conducted in accordance with the following dosing regimen: Daily: • Omega -3-acid ethyl esters (PO BID [3 × 1 g capsules and 2 × 1 g capsules]) Day 1, every 2 weeks: • Aldoxorubicin HCl (60 mg/m2 IV) • Bevacizumab (5 mg/kg IV) • Nab-paclitaxel (100 mg IV) Days 1 –5, every 2 weeks: • Capecitabine (650 mg/m2 PO BID) Days 1 –5 and 8–12, every 2 weeks: • Cyclophosphamide (50 mg PO BID) Day 2, every 2 weeks: • ALT -803 (10 µg/kg SC, 30 minutes prior to haNK infusion) • Avelumab (10 mg/kg IV over 1 hour) • haNK (2 × 109 cells/dose IV) Day 5, every 8 weeks thereafter: • ETBX -011, ETBX-051, ETBX-061 (1 × 1011 VP/vaccine/dose SC) • GI-4000, GI-6207, GI-6301 (40 YU/vaccine/dose SC), 2 hours after administration of the Ad5-based vaccines Prospective tumor molecular profiling will determine whether GI-4000 will be administered, as described above. Confidential and Proprietary 13 NANT TNBC Vaccine NantKwest, Inc.