Paclitaxel, USP 18. 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 adenoviral and yeast -based vaccines to induce T -cell responses in subjects with TNBC who have progressed on or after standard- of-care therapy. Study Number: QUILT -3.067 NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 3 Confidential and Proprietary 5 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 objectiv es are to obtain preliminary estimates of efficacy by objective response rate (ORR), progression -free survival (PFS), overall survival (OS), duration of response (DOR), disease control 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 using RECIST Version 1.1 based on Blinded Independent Central Review (BICR) . • Secondary objectives are to obtain additional 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 cor relations 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 two-stage optimal design. The initial 3 subjects will be enrolled in a staggered fashion, with a 21 -day interval between each subject to enable the capture and monitoring of any acute and subacute toxicities. 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 confirmed 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 who experience ongoing stable disease (SD) or an ongoing partial response (PR) at 1 year may enter the maintenance phase at the Investigator’s discretion. Subjects may remain on the maintenance phase of the study for up to 1 year. NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 3 Confidential and Proprietary 6 Treatment will continue in the maintenance phase until the subject experiences confirmed 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 continu e 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 tre atment, and during potential prolonged induction and maintenance phases (depending on response), as described in Section 6.4.1. Separate blood tubes 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 a nalyses, 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) or magnetic resonance imaging (MRI) 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). In order to document PD, unscheduled tumor assessments may be done if the Investigator observes any signs and symptoms of PD. Experimental treatment may continue and an imaging assessment should be done 4 –6 weeks after the initial PD assessment to rule out tumor pseudoprogression. If pseudoprogression is observed, the subject is allowed to continue experimental treatment and response assessments will continue every 8 or 12 weeks and will be evaluated per irRC. For responding subjects (PR or CR), a confirmatory response assessment should be done 4–6 weeks after the initial response. Subjects who withdraw from the study for reasons other than progression are encouraged not to initiate another anticancer treatment unless/until progression has been documented at a follow -up visit. 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 administration 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 formalin -fixed, paraffin-embedded ( FFPE ) tumor tissue and whole blood (subject- matched normal comparator against the tumor tissue) collected prior to treatment on this study, as described in Section 3.1.1. More information on the collection of tumor tissue and whole b lood is described in Section 6.4.1.2 and is similar to the collection of samples for the exploratory tumor molecular profiling. Induction Phase: The induction phase will consist of repeated 3- week cycles for a maximum treatment period of 1 year. Concurrent SBRT will be given during the first two 3- week cycles. Radiation will be administered to no more than 5 tumor sites using SBRT, as described in Sec tion 5.1.5.1. The induction phase of study treatment will be conducted in accordance with the following dosing regimen: Day 1, every 3 weeks: • Bevacizumab (5 mg/kg IV) , for the first 2 cycles only • Leucovorin (20 mg/m2 IV bolus) • Nab-paclitaxel (125 mg IV) • Cisplatin (40 mg/m2 IV) NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 3 Confidential and Proprietary 7 Days 1 –5, every 3 weeks: • 5-FU (1500 mg/m2 continuous IV infusion over 85–96 hours) • Cyclophosphamide (25 mg by mouth [PO] twice a day [BID]) Day 5 (± 1 day), every 3 weeks for 3 cycles then every 9 weeks thereafter: • Ad5-based vaccines: ETBX -011 (CEA) , ETBX -051 (Brachyury), ETBX -061 (MUC1) (1 × 1011 virus particles [VP]/vaccine/dose subcutaneously [SC]) Day 8, every 3 weeks: • Aldoxorubicin HCl (80 mg/m2 IV) • Cisplatin (20 mg/m2 IV) • SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for the first 2 cycles only) Days 8 –12, every 3 weeks: • Cyclophosphamide (25 mg PO daily) Day 9, every 3 weeks: • Avelumab (10 mg/kg IV) • ALT -803 (15 μg/kg SC) • haNK (2 × 109 cells/dose IV) Day 11, every 3 weeks: • haNK (2 × 109 cells/dose IV) Day 11, every 3 weeks for 3 cycles and every 9 weeks thereafter: • Yeast -based vaccines: GI-4000 (RAS), GI -6207 (CEA) , and GI-6301 (MUC1) (40 yeast units [YU]/vaccine/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. Day 15, every 3 weeks: • SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for the first 2 cycles only) Day 16, every 3 weeks: • haNK (2 × 109 cells/dose IV) Day 18, every 3 weeks: • haNK (2 × 109 cells/dose IV) NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 3 Confidential and Proprietary 8 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 con sist of repeated 2 -week cycles. The maintenance phase of study treatment will be conducted in accordance with the following dosing regimen: Day 1, every 2 weeks: • Aldoxorubicin HCl (60 mg/m2 IV) • Nab-paclitaxel (100 mg IV) Days 1 –5, every 2 weeks: • Capecitabine (650 mg/m2 PO BID , up to a maximum of 1,000 mg per dose) • Cyclophosphamide ( 25 mg PO BID) Day 2, every 2 weeks: • ALT -803 (15 µg/kg SC) • Avelumab (10 mg/kg IV over 1 hour) • haNK (2 × 109 cells/dose IV) Day 5 (± 1 day) , every 8 weeks thereafter: • Ad5-based vaccines: ETBX -011 (CEA) , ETBX -051 (Brachyury), ETBX -061 (MUC1) (1 × 1011 VP/v accine/dose SC) • Yeast -based vaccines: GI-4000 (RAS), GI -6207 (CEA), GI -6301 (Brachyury) (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 administere d, as described above. Days 8 –12, every 2 weeks: • Cyclophosphamide (25 mg PO daily) NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 3 Confidential and Proprietary 9 Phase 1b Primary Endpoint: • Incidence of treatment- emergent adverse events (AEs) and serious AEs (SAEs), graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Secondary Endpoints: • ORR by RECIST Version 1.1.