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 af ter standard - of-care therapy. Study Number: QUILT -3.067 NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 5 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 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 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 response s; 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 objectiv es 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 their correlations 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 desi gn. 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 r eduction), 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. Treatment will continue in the ma intenance phase until the subject experiences confirmed PD or unacceptable toxicity (not corrected with dose reduction), withdraws consent, or if the Investigator NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 5 Confidential and Proprietary 6 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. 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 p rolonged 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 p hase during routine blood draws for exploratory immunology analyses, as described in Section 6.4.2. 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 administra tion 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, paraf fin-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 col lection of tumor 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. Induction Phase: The induction phase will consist of repeated 3 -week cycles for a maximum treatment period of 1 year. 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 ( 32 mg/m2 IV) 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: NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 5 Confidential and Proprietary 7 • Ad5-based vaccines: ETBX -011 (CEA), ETBX -051 (Brachyury) , ETBX -061 (MUC1) (1 × 1011 virus particles [VP]/vaccine/dose subcutaneously [SC]) • Yeast -based vaccines: GI -4000 (RAS), GI-6207 (CEA), and GI -6301 ( Brachyury) (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 8, every 3 weeks: • Aldoxorubicin HCl ( 100 mg/m2 IV) • SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for up to 4 cycles) Days 8 –12, every 3 weeks: • Cyclophosphamide (25 mg PO daily) Day 9, every 3 weeks: • N-803 (15 μg/kg SC) • Avelumab (10 mg/kg IV) • haNK (2 × 109 cells/dose IV) Day 11, every 3 weeks: • haNK (2 × 109 cells/dose IV) Day 15, every 3 weeks: • Nab-paclitaxel (100 mg IV) • SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for up to 4 cycles) Day 16, every 3 weeks: • haNK (2 × 109 cells/dose IV) 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 4-week cycles consisting of 2 weeks of treatment followed by a 2-week rest period. Each cycle will consist of the following dosing regimen: Day 1, every 4 weeks: • Aldoxorubicin HCl (60 mg/m2 IV) • Nab-paclitaxel (100 mg IV) Days 1 –5, every 4 weeks: NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 5 Confidential and Proprietary 8 • Cyclophosph amide ( 25 mg PO BID) Days 1, 3, and 5 , every 4 weeks: • Capecitabine (650 mg/m2 PO BID, up to a maximum of 1 ,000 mg per dose) Day 2, every 2 weeks: • N-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/vaccine/dose SC) • Yeast -based vaccines: GI-4000 (RAS), GI -6207 (CEA), GI -6301 (Brachyury) (40 YU/vaccine/dose SC) Prospective tumor molecular profilin g will determine whether GI -4000 will be administered, as described above. Days 8 –12, every 4 weeks: • Cyclophosphamide (25 mg PO daily) If a subject has had a dose reduction for any agent in the induction phase and that dose is lower than the maintenance ph ase starting dose for that agent, the subject may continue receiving the lower dose in the maintenance phase. Phase 1b Primary Endpoint: • Incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs), graded using the National Cancer Institut e (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Secondary Endpoints: • ORR by RECIST Version 1.1 . • ORR by irRC. • PFS by RECIST Version 1.1 . • PFS by irRC. • OS. • DOR by RECIST Version 1.1 and irRC . • DCR (confirmed CR, PR, or stable disease [SD] lasting for at least 2 months) by RECIST Version 1.1 and irRC . • QoL by PROs. NANT TNBC Vaccine NantKwest, Inc. Clinical Trial Protocol: QUILT -3.067 Amendment 5 Confidential and Proprietary 9 Exploratory Endpoints: • Tumor molecular profiles and correlations with subject outcomes. • Therapy -induced changes in immune responses and correlations with subject outcomes. Phase 2 Primary Endpoint: • ORR by RECIST Version 1.1. Secondary Endpoints: • ORR by irRC. • PFS by RECIST Version 1.1 . • PFS by irRC. • OS. • DOR by RECIST Version 1.1 and irRC . • DCR (confirmed CR, PR, or SD lasting for at least 2 months) by RECIST Version 1.1 and irRC. • QoL by PROs. • Incidence of treatment-emergent AEs, SAEs, graded using the NCI CTCAE Version 4.03. Exploratory Endpoints: • Tumor molecular profiles and correlations with subject outcomes. • Therapy -induced changes in immune responses and correlations with s ubject outcomes. In the phase 1b portion of the study, response will be assessed by a local independent radiologist ; in the phase 2 portion of the study, the primary assessment of response will be based on BICR. A charter for the conduct of BICR will be prepared by the vendor selected to perform the independent review. Enrollment (planned): In the phase 1b portion of the study, 6 to 24 subjects will be enrolled. The initial 3 subjects will be enrolled in a staggered fashion, with a 21 -day interval between each subject. In the phase 2 portion of the study, 23 subjects will be enrolled in the first stage of Simon’s two -stage optimal design. If the study proceeds to the second stage of Simon’s two -stage optimal design, an additional 32 subjects will be enrolled in the second stage, for a total of 55 subjects in the phase 2 portion of the study. The maximum total enrollment for the study is 79 subjects. Eligibility Criteria: Inclusion Criteria: 1. Age ≥ 18 years old. 2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or Independent Ethics Committee (IEC) guidelines.