Clinical trial NCT03563157
Conditions: Colorectal Cancer Metastatic mCRC
Keywords: Colorectal Cancer Metastatic Colorectal Cancer
Sponsor: ImmunityBio, Inc.
Start date: 2018-09-28; Completion date: 2019-08-21
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
QUILT 3.071 NANT Colorectal Cancer (CRC) Vaccine: This is a Phase 1b/2 study investigating the effect of NANT CRC vaccine vs regorafenib in subjects with CRC who were previously treated with SOC.

Detailed description:
NANT Colorectal Cancer (CRC) Vaccine: A phase 1b/2 Trial of the NANT CRC Vaccine vs Regorafenib in Subjects with Metastatic CRC Who Have Been Previously Treated with Standard-Of-Care Therapy

Arms: arm 1: A combination of agents will be administered to subjects in this study: Aldoxorubicin HCI, ETBX-011, ETBX-021, ETBX-051, ETBX-061, GI-4000, GI-6207, GI-6301, haNK, N-803, Avelumab, Capecitabine, Cetuximab, Cyclophosphamide, 5-Fluorouracil, Leucovorin, Nab-paclitaxel, Oxaliplatin, Regorafenib, SBRT. arm 2: Regorafenib will be administered to subjects in this study.
Interventions: intervention 1: Aldoxorubicin Hydrochloride intervention 2: ALT-803 intervention 3: ETBX-011 intervention 4: ETBX-021 intervention 5: ETBX-051 intervention 6: ETBX-061 intervention 7: GI-4000 intervention 8: GI-6207 intervention 9: GI-6301 intervention 10: haNK intervention 11: Avelumab intervention 12: Capecitabine intervention 13: Cetuximab intervention 14: Cyclophosphamide intervention 15: 5-Fluorouracil intervention 16: Leucovorin intervention 17: Nab-paclitaxel intervention 18: Oxaliplatin intervention 19: Regorafenib intervention 20: SBRT
Intervention descriptions: intervention 1: Aldoxorubicin Hydrochloride HCI intervention 2: Recombinant human super agonist interleukin-15 (IL-15) complex \[also known as IL-15N72D;IL-15RaSu/IgG1 Fe complex1\] intervention 3: Ad5 \[E1-, E2b-\]-CEA intervention 4: Ad5 \[E1-, E2b-\]-\[HER2\] intervention 5: Ad5 \[E1-, E2b-\]-Brachyury intervention 6: Ad5 \[E1-, E2b-\]-mucin 1 \[MUC1\] intervention 7: RAS yeast intervention 8: CEA yeast intervention 9: Brachyury yeast intervention 10: haNK™, NK-92 \[CD16.158V, ER IL-2\] intervention 11: BAVENCIO® injection intervention 12: XELODA® tablets intervention 13: ERBITUX® injection intervention 14: Cyclophosphamide Capsules intervention 15: 5-FU; Fluorouracil Injection intervention 16: Leucovorin Calcium intervention 17: ABRAXANE® for Injectable Suspension \[paclitaxel protein-bound particles for injectable suspension\] \[albumin-bound\] intervention 18: ELOXATIN® injection intervention 19: STIVARGA® tablets intervention 20: Stereotactic body radiation therapy

Protocol documents:
Prot_SAP_000.pdf: 
NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 
 
Confidential and Proprietary 
1 
 TITLE PAGE 
NANT COLORECTAL CANCER (CRC) VACCINE: A 
PHASE 1B/2 TRIAL OF THE NANT CRC VACCINE VS 
REGORAFENIB IN SUBJECTS WITH METASTATIC 
CRC WHO HAVE BEEN PREVIOUSLY TREATED 
WITH STANDARD-OF-CARE (SOC) THERAPY 
 
Study Number: 
QUILT-3.071 
IND Sponsor: 
NantKwest, Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Sponsor Contact:  
(For medical questions/emergencies) 
John H. Lee, MD 
Senior Vice President Adult Medical Affairs, 
NantKwest Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Email: John.Lee@NantKwest.com 
Cell Phone: +1-605-610-6391 
 
Protocol Version 
Date 
Version 1 
24 April 2018 


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STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with Good Clinical Practice (GCP) as described in the 
International Conference on Harmonization Guideline E6 (ICH E6) and in accordance with 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) and the general ethical 
principles outlined in the Declaration of Helsinki. The study will receive approval from an 
Institutional Review Board (IRB) prior to commencement. The Principal Investigator will assure 
that no deviation from or changes to the protocol will take place without prior agreement from 
NantKwest and documented approval from the IRB, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
Principal Investigator:  
 
Signed: _____________________________________ Date: ______________ 
 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
NantKwest, Inc. 
Name of Investigational Products: 
1. Aldoxorubicin hydrochloride (HCl) 
2. ALT-803 (recombinant human super agonist interleukin-15 (IL-15) complex [also known as 
IL 15N72D:IL-15RαSu/IgG1 Fc complex]) 
3. ETBX-011 (adenovirus serotype-5 [Ad5] [E1-, E2b-]-carcinoembryonic antigen [CEA] vaccine) 
4. ETBX-021 (Ad5 [E1-, E2b-]-human epidermal growth factor receptor 2 [HER2] vaccine) 
5. ETBX-051 (Ad5 [E1-, E2b-]-Brachyury vaccine) 
6. ETBX-061 (Ad5 [E1-, E2b-]-mucin 1 [MUC1] vaccine)  
7. GI-4000 (RAS yeast vaccine) 
8. GI-6207 (CEA yeast vaccine) 
9. GI-6301 (Brachyury yeast vaccine)  
10. haNK™, NK-92 [CD16.158V, ER IL-2], Suspension for Infusion (haNK™ for Infusion) 
Name of Approved Products: 
1. Avelumab (BAVENCIO® injection, for intravenous [IV] use) 
2. Capecitabine (XELODA® tablets, for oral use) 
3. Cetuximab (ERBITUX® injection, for IV infusion) 
4. Cyclophosphamide (Cyclophosphamide Capsules, for oral use; or Cyclophosphamide Tablets, 
USP) 
5. 5-Fluorouracil (5-FU; Fluorouracil Injection, for IV use only) 
6. Leucovorin (LEUCOVORIN Calcium for Injection, for IV or intramuscular [IM] use) 
7. Nab-paclitaxel (ABRAXANE® for Injectable Suspension [paclitaxel protein-bound particles for 
injectable suspension] [albumin-bound]) 
8. Oxaliplatin (ELOXATIN® injection for IV use) 
9. Regorafenib (STIVARGA® tablets, for oral use) 
10. Stereotactic body radiation therapy (SBRT) 
11. Trastuzumab (HERCEPTIN® injection, for IV use) 


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Name of Active Ingredients: 
Investigational Products  
1. Aldoxorubicin HCl 
2. ALT-803, recombinant human super agonist interleukin-15 (IL-15) complex (also known as 
IL 15N72D:IL-15RαSu/IgG1 Fc complex)  
3. Ad5 [E1-, E2b-]-CEA 
4. Ad5 [E1-, E2b-]-HER2 
5. Ad5 [E1-, E2b-]-Brachyury 
6. Ad5 [E1-, E2b-]-MUC1  
7. GI-4014 expressing mutations in RAS at codon 12 (G12V), and codon 61 (Q61R and Q61L); 
GI-4015 expressing mutations in RAS at codon 12 (G12C), and codon 61 (Q61R and Q61L); 
GI-4016 expressing mutations in RAS at codon 12 (G12D) and codon 61 (Q61R and Q61L) and 
GI-4020 expressing mutations in RAS at codon 12 (G12R) and codon 61 (Q61L and Q61H) 
8. Recombinant yeast based vaccine expressing the full length human carcinoembryonic antigen 
(CEA), with a modified gene coding sequence to code for a single amino acid substitution 
(asparagine to aspartic acid) at the native protein amino acid position 610 
9. Recombinant yeast based vaccine expressing the human Brachyury oncoprotein  
10. NK-92 [CD16.158V, ER IL2] cells 
Approved Products 
1. Avelumab 
2. Capecitabine 
3. Cetuximab 
4. Cyclophosphamide (anhydrous) 
5. Fluorouracil, USP 
6. Leucovorin (calcium salt) 
7. Paclitaxel, USP 
8. Oxaliplatin, USP 
9. Regorafenib 
10. Radiation 
11. Trastuzumab 


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Title of Study: 
NANT Colorectal Cancer (CRC) Vaccine: A phase 1b/2 trial of the NANT CRC vaccine vs. regorafenib 
in subjects with metastatic CRC who have been previously treated with standard-of-care (SoC) therapy 
Study Number: 
QUILT-3.071 
Study Phase: 
Phase 1b/Phase 2 (randomized and single-arm [using Simon’s two-stage optimal design]) 
Study Objectives: 
Phase 1b 
• 
The primary objective is to evaluate the overall safety profile of the NANT CRC vaccine 
regimen in subjects with recurrent or metastatic CRC who have been previously treated with 
SoC therapy that included fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy, an anti-VEGF inhibitor, and an anti-EGFR therapy if RAS wild-type. 
• 
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 responses, and 
molecular changes in circulating tumor DNA (ctDNA) and RNA (ctRNA); and their 
correlations with subject outcomes. 
Phase 2  
Randomized component – The randomized component of the phase 2 portion of the study will compare 
the NANT CRC Vaccine regimen to regorafenib monotherapy in subjects with recurrent or metastatic 
CRC who have previously been treated with SoC therapy that did not include regorafenib. 
• 
The primary objective is to compare efficacy as assessed by PFS using RECIST Version 1.1 
based on Blinded Independent Central Review (BICR). 
• 
Secondary objectives are to compare safety and additional measures of efficacy (PFS by 
irRC, ORR, 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 
correlations with subject outcomes. 
Single-arm component – The single-arm component of the phase 2 portion of the study will evaluate the 
NANT CRC Vaccine regimen in subjects with recurrent or metastatic CRC who have previously been 
treated with SoC therapy and regorafenib. 
• 
The primary objective is to evaluate the efficacy of the NANT CRC vaccine regimen as 
assessed by ORR using RECIST Version 1.1 based on BICR. 
• 
Secondary objectives are to evaluate safety and additional measures of efficacy (ORR by 
irRC, PFS, OS, DOR, DCR, and QoL by PROs). 


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• 
Exploratory objectives include the assessment of tumor molecular profiles, therapy-induced 
changes in immune responses, and molecular changes in ctDNA and ctRNA; 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 recurrent or metastatic CRC who have previously received SoC therapy. The phase 2 
portion of the study will consist of both a single-arm component and a randomized component. 
In phase 1b, the NANT CRC Vaccine will be assessed for safety. 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 NANT CRC Vaccine 
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. In total, 6 to 24 subjects will be enrolled in the phase 1b portion of the study. 
In the randomized component of the phase 2 portion, subjects who have received SoC therapy that did not 
include regorafenib for recurrent or metastatic CRC will be randomized to receive either the NANT CRC 
Vaccine or regorafenib monotherapy. Randomization will be stratified by tumor sidedness (left vs right), 
performance status (ECOG 0 vs 1), and RAS mutational status (positive vs negative). For the regorafenib 
arm of the randomized portion, subjects who progress on or after discontinuing regorafenib may be 
enrolled in the single-arm component described below after a 14-day washout period.  
The single-arm component of the phase 2 portion will enroll subjects who have progressed or experienced 
unacceptable toxicity on SoC and regorafenib, and subjects who have progressed on or after regorafenib 
treatment in the randomized phase 2 portion of this study.  
The NANT CRC Vaccine regimen will be administered in 2 phases, an induction and a maintenance 
phase, as described below. Subjects will continue induction treatment for up to 1 year. 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 and Sponsor’s discretion. Subjects may remain in the 
maintenance phase of the study for up to 1 year. The time on NANT CRC Vaccine treatment, including 
both the induction and maintenance phases, is up to 2 years. 
In the randomized component of the phase 2 portion of the study, the regorafenib arm will self-administer 
regorafenib every day for the first 21 days of every 28-day treatment cycle.  
At any time during the trial, treatment with the NANT CRC Vaccine or regorafenib will be discontinued 
if 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. 
Subjects who withdraw from the trial for reasons other than progression must agree not to initiate another 
anticancer treatment unless/until progression has been documented at a follow-up visit. 
For all subjects, 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 treatment 
periods (depending on response), as described in Section 6.4.1. Separate blood tubes will be collected 
every 4 or 8 weeks 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 for all subjects. Tumor response will be assessed every 8 or 
12 weeks until progression occurs, regardless of the treatment administered, by computed tomography 
(CT), magnetic resonance imaging (MRI), or positron emission tomography-computed tomography 
(PET-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). In order to document PD, 
unscheduled tumor assessments may be done if the Investigator observes any signs and symptoms of PD. 


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For responding subjects (PR or CR), a confirmatory response assessment should be done at 4 weeks after 
the initial response. 
Prospective Tumor Molecular Profiling 
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. More 
information on the collection 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. 
All subjects will be tested for RAS mutations. In the randomized component of the phase 2 study, 
RAS mutational status will be used in stratifying subjects during randomization.  
For subjects treated with the NANT CRC Vaccine, RAS mutational status will be used to determine which 
subjects will receive GI-4000. Subjects will receive GI-4000 if their tumor is positive for specific 
RAS mutations, as determined by whole genome sequencing.  
In addition, for subjects treated with the NANT CRC Vaccine, prospective tumor molecular profiling will 
be conducted to inform HER2 expression and will be used to determine whether ETBX-021 and 
trastuzumab will be administered. Subjects will receive ETBX-021 and trastuzumab if their tumor is 
HER2-positive (IHC 3+ or FISH positive), as determined by FDA-approved diagnostic tests. All other 
agents in the NANT Cancer Vaccine regimen will be administered regardless of tumor molecular profile. 
NANT CRC Vaccine: Induction Phase 
Treatment in the induction phase will consist of repeated 3-week cycles for a maximum treatment period 
of 1 year, as follows: 
Day 1, every 3 weeks:  
• 
Leucovorin (20 mg/m2 IV bolus) 
• 
Nab-paclitaxel (125 mg IV) 
• 
Oxaliplatin (40 mg/m2 IV over 1 hour) 
Days 1–5, every 3 weeks: 
• 
5-FU (1,500 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:  
• 
ETBX-011, ETBX-021, ETBX-051, and ETBX-061  
(1 × 1011 virus particles [VP]/vaccine/dose subcutaneously [SC]) 
Prospective tumor molecular profiling will determine whether ETBX-021 will be 
administered, as described above. 
Day 8, every 3 weeks: 
• 
Aldoxorubicin HCl (80 mg/m2 IV over 30 minutes) 
• 
Oxaliplatin (20 mg/m2 IV over 1 hour) 
• 
SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for the 
first 2 cycles only) 
• 
Trastuzumab (2 mg/kg IV infusion) 


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Prospective tumor molecular profiling will determine whether trastuzumab will be 
administered, as described above. 
Days 8–12, every 3 weeks: 
• 
 Cyclophosphamide (25 mg PO daily) 
Day 9, every 3 weeks: 
• 
Avelumab (10 mg/kg IV over 1 hour) 
• 
ALT-803 (10 μg/kg SC at least 30 minutes prior to haNK infusion) 
• 
haNK (2 × 109 cells/dose IV) 
Days 11, every 3 weeks:  
• 
haNK (2 × 109 cells/dose IV) 
Day 11, every 3 weeks for 3 cycles and every 9 weeks thereafter: 
• 
GI-4000, GI-6207, GI-6301 (40 yeast units [YU]/vaccine/dose SC) 
Prospective tumor molecular profiling will determine whether GI-4000 will be administered, 
as described above. 
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:  
• 
ALT-803 (10 μg/kg SC at least 30 minutes prior to haNK infusion) 
• 
haNK (2 × 109 cells/dose IV) 
• 
Cetuximab (250 mg/m2 IV) 
• 
Trastuzumab (2 mg/kg IV infusion) 
Prospective tumor molecular profiling will determine whether trastuzumab will be 
administered, as described above. 
Day 18, every 3 weeks:  
• 
haNK (2 × 109 cells/dose IV) 
 
NANT CRC Vaccine: 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, as follows: 
Day 1, every 2 weeks:  
• 
Aldoxorubicin HCl (60 mg/m2 IV) 
• 
Nab-paclitaxel (100 mg IV) 


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Days 1–5, every 2 weeks: 
• 
Capecitabine (650 mg/m2 PO BID; up to a maximum of 1,000 mg per dose) 
Days 1–5, every 2 weeks: 
• 
Cyclophosphamide (25 mg BID) 
Day 2, every 2 weeks:  
• 
Avelumab (10 mg/kg IV over 1 hour) 
• 
Cetuximab (250 mg/m2 IV) 
• 
Trastuzumab (2 mg/kg IV) 
• 
ALT-803 (10 µg/kg SC) (at least 30 minutes prior to haNK infusion) 
• 
haNK (2 × 109 cells/dose IV) 
Prospective tumor molecular profiling will determine whether trastuzumab will be 
administered, as described above. 
Day 5 (± 1 day), every 8 weeks thereafter: 
• 
ETBX-011, ETBX-021, 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 Ad-5 
based vaccines 
Prospective tumor molecular profiling will determine whether ETBX-021 and GI-4000 will 
be administered, as described above. 
Days 8-12, every 2 weeks 
• 
Cyclophosphamide (25 mg PO daily) 
Phase 1b 
Primary Endpoints: 
• 
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. 
• 
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 


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irRC. 
• 
QoL by PROs. 
Exploratory Endpoints: 
• 
Tumor molecular profiles and correlations with subject outcomes. 
• 
Therapy-induced changes in immune responses and correlations with subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
Phase 2  
Randomized Component 
Primary Endpoint: 
• 
PFS by RECIST Version 1.1. 
Secondary Endpoints: 
• 
PFS by irRC. 
• 
ORR by RECIST Version 1.1 
• 
ORR 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 and 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 subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
Single-Arm Component 
Primary Endpoint: 
• 
ORR by RECIST Version 1.1. 
Secondary Endpoints: 
• 
ORR by irRC. 
• 
PFS by RECIST Version 1.1. 
• 
PFS by irRC. 
• 
OS. 


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• 
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 and 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 subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
In the phase 1b portion of the study, response will be assessed by the Investigator; 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.  
The phase 2 randomized component of the study is initially planned for 120 subjects to be randomized 
1:1 to the NANT CRC vaccine regimen or regorafenib monotherapy. During the trial, 120 subjects are 
expected to accrue 96 PFS events. An interim analysis is planned once 50% of the PFS events have 
accrued (48 events). Based on the interim analysis, the study sample size may be increased to a maximum 
of 240 subjects. 
In the phase 2 single-arm component of the study, 27 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 41 subjects will be enrolled in the second stage, for a total of 68 subjects in the 
phase 2 single-arm component of the study.  
The maximum total enrollment for the study is 332 subjects. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Age ≥ 18 years. 
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or 
Independent Ethics Committee (IEC) guidelines. 
3. Histologically-confirmed recurrent or metastatic CRC previously treated with fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS 
wild-type, an anti-EGFR therapy; or subjects who are ineligible for these therapies. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
5. Have at least 1 measurable lesion of ≥ 1.0 cm. 
6. 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 for 
prospective and exploratory tumor molecular profiling. If an historic specimen is not available, 


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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. 
7. Must be willing to provide blood samples prior to the start of treatment on this study for 
prospective tumor molecular profiling and exploratory analyses. 
8. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of treatment for 
exploratory analyses, if considered safe by the Investigator. 
9. Ability to attend required study visits and return for adequate follow-up, as required by this 
protocol. 
10. 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. 
Phase 2 single-arm component only 
11. Must have progressed on or after regorafenib treatment in the randomized phase 2 portion of the 
study OR progressed or experienced unacceptable toxicity on SoC and regorafenib prior to 
enrollment on the study. 
Exclusion Criteria: 
1. Microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient tumors eligible for, but 
not yet treated with, a PD-1 inhibitor. 
2. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational 
drugs used in this study or that would put the subject at high risk for treatment-related 
complications. 
3. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, 
or autoimmune disease associated with lymphoma).  
4. History of organ transplant requiring immunosuppression.  
5. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). 
6. Inadequate organ function, evidenced by the following laboratory results: 
a. Absolute neutrophil count (ANC) < 1,000 cells/mm3. 
b. Uncorrectable grade 3 anemia (hemoglobin < 8 g/dL). 
c. Platelet count < 75,000 cells/mm3. 
d. Total bilirubin greater than the upper limit of normal (ULN; unless the subject has 
documented Gilbert’s syndrome). 
e. Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) > 2.5 
× ULN (> 5 × ULN in subjects with liver metastases). 
f. Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver 
metastases, or >10 × ULN in subjects with bone metastases). 


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g. Serum creatinine > 2.0 mg/dL or 177 μmol/L. 
h. Serum anion gap > 16 mEq/L or arterial blood with pH < 7.3. 
7. 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. Subjects with uncontrolled hypertension should be medically managed on a stable 
regimen to control hypertension prior to study entry. 
8. Serious myocardial dysfunction defined by echocardiogram (ECHO) as absolute left ventricular 
ejection fraction (LVEF) 10% below the institution’s lower limit of predicted normal. 
9. Dyspnea at rest due to complications of advanced malignancy or other disease requiring 
continuous oxygen therapy. 
10. Positive results of screening test for human immunodeficiency virus (HIV). 
11. 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. 
12. Known hypersensitivity to any component of the study medication(s). 
13. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction 
with any of the study medications. 
14. 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. 
15. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8 inducer 
(rifampin) within 14 days before study day 1. 
16. Participation in an investigational drug study or history of receiving any investigational treatment 
within 30 days prior to screening for this study, except for testosterone-lowering therapy in men 
with prostate cancer. 
17. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the 
protocol. 
18. Concurrent participation in any interventional clinical trial. 
19. Pregnant and nursing women. 
Phase 2 randomized component only 
20. Prior regorafenib treatment. 


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Products, Dosage, and Mode of Administration: 
Investigational Products 
Dosage 
Mode of Administration 
Aldoxorubicin HCl 
80 mg/m2 (induction); 
60 mg/m2 (maintenance) 
IV over 30 minutes 
ALT-803 
10 µg/kg  
SC 
ETBX-011 
1 × 1011 VP/dose  
SC 
ETBX-021 
1 × 1011 VP/dose  
SC 
ETBX-051 
1 × 1011 VP/dose  
SC 
ETBX-061 
1 × 1011 VP/dose  
SC 
GI-4000 
40 YU/dose 
SC 
GI-6207 
40 YU/dose 
SC 
GI-6301 
40 YU/dose 
SC 
haNK  
2 × 109 cells/dose  
IV 
Approved Products 
Dosage 
Mode of Administration 
Avelumab 
10 mg/kg 
IV 
Capecitabine 
650 mg/m2 BID up to a maximum of 
1,000 mg per dose 
PO 
Cetuximab 
250 mg/m2 
IV 
Cyclophosphamide  
25 mg BID (days 1-5) 
25 mg daily (days 8-12) 
PO 
5-FU 
1,500 mg/m2  
85- to 96-hour continuous IV 
infusion 
Leucovorin  
20 mg/m2  
IV bolus 
Nab-paclitaxel  
125 mg (induction);  
100 mg (maintenance) 
IV 
Oxaliplatin 
40 mg/m2 (day 1 of induction); 
20 mg/m2 (day 8 of induction) 
IV 
Regorafenib 
160 mg 
PO 
SBRT 
8 Gy maximum (exact dose to be 
determined by the radiation 
oncologist) 
External beam radiation 
Trastuzumab 
2 mg/kg 
IV 


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Duration of Treatment: 
NANT CRC Vaccine (Experimental Arm) 
• 
Induction phase: 8 weeks (minimum) to 1 year (maximum) 
• 
Maintenance phase: Up to 1 year 
Subjects will be treated for up to 2 years (up to 1 year in each treatment phase), or until they experience 
PD, unacceptable toxicity (not correctable with dose reduction), withdraw consent, or if the Investigator 
feels it is no longer in their best interest to continue treatment. 
Regorafenib (Control Arm) 
Subjects will be treated for up to 2 years, or until they experience PD, unacceptable toxicity (not 
correctable with dose reduction), withdraw consent, or if the Investigator feels it is no longer in their best 
interest to continue treatment. 
Subjects that experience PD on or after treatment with regorafenib in the phase 2 randomized component 
of the study may be subsequently treated with the NANT CRC Vaccine in the phase 2 single-arm 
component of the study. 
Duration of Follow-up:  
Subjects who discontinue study treatment should remain in the study and continue to be followed until 
either death (any cause) or 24 months past administration of the first IP, whichever comes first, as 
follows: 
• 
Resolution of any SAEs attributed to treatment (see Section 7). 
• 
CT, MRI, or PET-CT scan assessment (see Section 6.1.2). 
• 
Vital status: subjects will be followed until either death or for a minimum of 24 months past 
administration of the first dose of chemotherapy to the last subject enrolled in the study, 
whichever comes first. 
Following documented PD, subjects may continue to be followed by the investigational physician or a 
third party by phone or review of medical records approximately every 90 days until withdrawal of 
consent, lost to follow-up, or death (any cause). Additional information from a subject’s medical records 
relevant to this study may be provided to NantKwest as needed to understand the safety and efficacy of 
the regimen tested in this protocol. 
Reference Therapy, Dosage, and Mode of Administration: 
Regorafenib:  
Regorafenib treatment will consist of repeated 4-week cycles for a maximum treatment period of 2 years, 
as follows: 
Days 1-21, every 4 weeks:  
• 
Regorafenib (160 mg PO) 


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Evaluation of Endpoints: 
Safety:  
Safety endpoints include assessments of treatment-emergent AEs, SAEs, and clinically significant 
changes in safety laboratory tests, physical examinations, electrocardiograms (ECGs), echocardiograms 
(ECHOs), and vital signs. All subjects will be evaluable for toxicity from the time of their first study 
treatment. Toxicities will be graded using the NCI CTCAE Version 4.03. 
Efficacy: 
PFS and ORR will be assessed by CT, MRI, or PET-CT of target and non-target lesions every 8 or 
12 weeks until progression occurs regardless of the treatment administered and will be evaluated in 
accordance with RECIST Version 1.1 and irRC. In order to document PD, unscheduled tumor 
assessments may be done if the investigator observes any signs and symptoms of PD. For responding 
subjects (PR or CR), a confirmatory response assessment should be done at 4 weeks after the initial 
response. 
OS, DOR, and DCR will also be assessed. In the phase 1b portion of the study, response will be assessed 
by the Investigator; in the phase 2 portion of the study, the primary assessment of response will be based 
on the BICR. 
An assessment of QoL will be conducted via PROs using the Functional Assessment of Cancer Therapy-
Colorectal Cancer (FACT-C) instrument. Assessments will occur at screening and prior to treatment on 
day 1, every 4 or 12 weeks thereafter, and at the end-of-treatment (EOT) visit.  
Exploratory Analyses: 
Tumor Molecular Profiling: Genomic sequencing of tumor cells from tissue relative to non-tumor cells 
from whole blood will be conducted to identify tumor-specific genomic variances that may contribute to 
disease progression and/or response to treatment. RNA sequencing will be conducted to provide 
expression data and give relevance to DNA mutations. Quantitative proteomics analysis will be 
conducted to determine the absolute amounts of specific proteins, to confirm expression of genes that are 
correlative of disease progression and/or response, and to determine the cutoff values for response. 
Immunologic Analysis: Immune responses to the NANT CRC vaccine regimen and regorafenib 
monotherapy will be evaluated by standard immune assays. Correlations between therapy-induced 
immune changes and subject outcomes will be assessed. 
ctDNA/ctRNA Analysis: ctDNA and ctRNA will be extracted from plasma obtained from whole blood. 
Expression levels of specific tumor- and immune-related analytes will be assessed by quantitative 
real-time polymerase chain reaction (qPCR) and possibly other methods (eg, DNA/RNA sequencing) and 
analyzed for correlations with subject outcomes. 


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Statistical Methods: 
This phase 1b/2 study will evaluate the safety and efficacy of metronomic combination therapy in 
subjects with recurrent or metastatic CRC who have failed SoC therapy. 
Six to 24 subjects will be enrolled in the phase 1b portion of the study. 
In the phase 2 single-arm component of the study, ORR based on RECIST Version 1.1 will be evaluated 
using Simon’s two-stage optimal design.  
The phase 2 randomized component of the study is initially planned for 120 subjects to be randomized 
1:1 to the NANT CRC vaccine regimen or regorafenib monotherapy. A total of 120 subjects are expected 
to accrue 96 PFS events during the trial with a 12-month enrollment period and 12 months of follow-up 
after the last subject is enrolled. Based on median PFS of 2 and 4 months for regorafenib and the NANT 
CRC Vaccine, respectively, a 20% lost-to-follow-up rate, and a 5% type 1 error, 120 subjects with 
96 PFS events has a power of 90% to detect a hazard ratio (HR) of 0.50. 
In the phase 2 randomized component of the study, an interim analysis is planned once 50% of the PFS 
events have accrued (48 events). The Lan DeMets/O’Brien Fleming spending function will be used for 
the interim analysis which allocates a 0.3% and 4.9% type 1 error rate to the interim and final PFS 
analyses, respectively. The trial may be stopped early for strong efficacy if the interim PFS analysis 
shows superiority (ie, p < 0.003). The trial may be stopped early for futility if the interim PFS analysis 
displays a conditional power < 15%. Based on the interim PFS analysis, the study sample size for the 
randomized phase 2 component may be increased to a maximum of 240 subjects using the “Promising 
Zone” methodology for an adaptive sample size increase.  
The interim analysis will be performed by an independent statistician separate from the study team. The 
interim analysis results will not be shared with the study team during the conduct of the study. The 
interim analysis results will be presented to the Independent Data Monitoring Committee (IDMC) who 
will make recommendations to the study team whether to stop the study for efficacy or futility, or 
increase the study sample size. For the NANT CRC Vaccine regimen, safety results will be presented 
separately for the induction and maintenance phases of treatment as well as overall for the entire 
treatment regimen. For the regorafenib treatment, safety results will be presented for the entire treatment 
regimen. Efficacy results will be summarized for the overall treatment regimens. 
Overall safety will be assessed by descriptive analyses using tabulated frequencies of AEs by grade using 
CTCAE version 4.03 in terms of treatment-emergent AEs, SAEs, and clinically significant changes in 
safety laboratory tests, physical examinations, ECGs, ECHOs, and vital signs. 
PFS will be analyzed using Kaplan-Meier methods. The median PFS (and 95% confidence interval [CI]) 
will be summarized. PFS Kaplan-Meier curves will be presented. For the phase 2 randomized component, 
comparison of PFS between the NANT CRC Vaccine regimen and regorafenib monotherapy will be 
based on the stratified log-rank test, stratified by tumor sidedness, performance status, and RAS 
mutational status. PFS assessed by RECIST Version 1.1 will be the primary PFS analysis and PFS 
assessed by irRC will be a secondary analysis. 
OS and DOR will be analyzed in the same manner as PFS. 
ORR (and 95% CI) will be summarized. For the phase 2 randomized component, comparison of ORR 
between the NANT CRC Vaccine regimen and regorafenib monotherapy will be based on the stratified 
Fisher exact test, stratified by tumor sidedness, performance status, and RAS mutational status. ORR 
assessed by RECIST Version 1.1 will be the primary ORR analysis and ORR assessed by irRC will be a 
secondary analysis. 
DCR will be analyzed in the same manner as ORR.  
Descriptive statistics of PROs will be presented. 
Correlations of tumor molecular profiles, therapy-induced changes in immune responses, and molecular 
changes in ctDNA and ctRNA with subject outcomes will be explored. 


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Figure 1: 
Study Treatment Schema 
 


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Figure 2: 
Induction Phase Treatment Schema for NANT CRC Vaccine 
 


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Figure 3: 
Maintenance Phase Treatment Schema for NANT CRC Vaccine 
 


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Table 18: 
Schedule of Events for NANT CRC Vaccine Induction Phase of Study 
 
Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
General Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusiond 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm availability 
of FFPE tumor 
samplef 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Physical exam: 
height, weightg 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Vital signsh 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
X 
X 
ECOG performance 
status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
12-lead ECGi 
X 
Xj 
Every 4 weeks 
X 
 
ECHO (with 
ejection fraction) 
X 
Xj  
Every 12 weeks 
X 
 
Confirm 
contraceptive 
measures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-C 
Questionnaire 
X 
X 
Every 4 weeks 
X 
 


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Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
Adverse event 
collection 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
X 
X 
Laboratory Assessments 
Chemistry panelk 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
CEA 
X 
X
j 
Every 4 weeks 
X 
 
Hematologyl 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Pregnancy test m 
X 
X
j 
Every 4 weeks 
X 
 
Serum virology 
(HIV)n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine HER2 
expression and RAS 
mutational statuso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect whole blood 
for tumor molecular 
profilingp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect whole blood 
for immunology 
analysisq 
X 
Every 4 weeks during routine blood draws 
X 
 
Collect whole blood 
for ctDNA/ctRNA 
analysisq 
X 
Every 4 weeks during routine blood draws 
X 
 
Collect historic 
tumor biopsy 
specimen for tumor 
X 
 
 
 


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Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
molecular profilingr 
Tumor biopsyr 
X 
8 weeks after the start of treatment 
 
 
Additional tumor 
biopsy 
 
May be collected at any time point, as clinically indicated at the Investigator’s discretion. 
 
 
Tumor Imaging and Assessments 
CT, MRI, or PET-
CTs
 
X 
Every 8 weeks 
X 
 
a Subjects will remain in the induction phase of the study for up to 1 year. Treatment will continue in the induction phase until the subject experiences PD or 
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. Those who have a CR in the induction phase will enter the maintenance phase of the study. Subjects who experience ongoing SD or an ongoing PR at 
1 year may enter the maintenance phase at the Investigator’s and Sponsor’s discretion. Any required laboratory sample collection (eg, blood draws, urinalysis) 
may be performed within a 3-day window of the time indicated. Subjects crossing over to treatment with the NANT CRC Vaccine in the single-arm phase 2 
component of the study following disease progression on or after discontinuing regorafenib in the randomized phase 2 component of the study will have a 
minimum 14-day washout period between last regorafenib treatment and first NANT CRC Vaccine treatment. Patients who crossover will begin at day 1 of the 
above schedule, except that relevant new medical history will be collected. Tumor imaging does not need to be performed on day 1 for crossover patients if they 
have had an imaging assessment within the last 28 days. 
b End-of-treatment visit must be performed 30 (±5 days) after the last study treatment. 
c Additional assessments performed during an unscheduled visit are at the discretion of the Investigator or treating physician and must be recorded in the 
subject’s source documents and on the Unscheduled Visit eCRF. 
d Inclusion/exclusion criteria will also be evaluated at enrollment. 
e Medical history will also be evaluated at enrollment. 
f Subject’s FFPE tumor tissue sample must be obtained following the conclusion of the most recent anticancer treatment and prior to first study treatment. If not 
available, a fresh tumor biopsy must be performed, if considered safe by the Investigator. In the event a fresh biopsy needs to be scheduled, the site may 
consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to the first dose of any study 
drug. 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. 
g Height required at screening visit only. Weight on day 1 of each treatment cycle should be used to calculate drug doses. 
h Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes and within 30 minutes prior to the start of any infusional study treatment. For visits where a subject is 
receiving an infusion of any study compounds, vital signs will be collected at the following time points in relation to the start of first infusion of the day: prior 


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to infusion, 15 minutes post, 30 minutes post, and hourly until the subject is discharged. Temperature will be documented each visit at the first pre-infusion 
assessment of vital signs and subsequently if clinically indicated. 
i 12-lead ECG to be performed in triplicate at screening. 
j Day 1 assessments can be skipped if the screening assessment was performed within 1 week prior to the start of treatment. 
k Chemistry panel to include laboratory assessments noted in Table 17. 
l Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
m Serum pregnancy tests for females of child-bearing potential 
n HIV status to be determined by an approved test. 
o Assessment of HER2 expression to determine whether ETBX-021 and trastuzumab will be administered to the subject and assessment of RAS mutational status 
to determine whether GI-4000 will be administered to the subject, as described in Section 3.1.1. RAS status will also be used as a stratification factor in the 
Phase 2 randomized portion of the study. 
p Whole blood for tumor molecular profiling will be collected during the screening period for subjects who have been enrolled in the study. 
q Whole blood for immunology and ctDNA/ctRNA analyses will be collected during the screening period for subjects who have been enrolled in the study, every 
4 weeks in the induction phase during routine blood draws, and at the EOT visit. 
r Historic tumor biopsy specimen for tumor molecular profiling is required to determine eligibility for participation in the study. If an historic specimen is not 
available, a fresh tumor biopsy must be performed, 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. In the event a fresh biopsy needs to be 
scheduled, the site may consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to 
the first dose of any study medications. A tumor biopsy is also required 8 weeks after the start of treatment, if considered safe by the Investigator. 
s Tumor imaging by CT scan, MRI, or PET-CT will be performed at screening and every 8 weeks during the induction phase, as described in Section 6.1.2. All 
screening tumor imaging assessments should be performed based on the subject's qualifying scan obtained within 28 days prior to the start of treatment. 
RECIST and irRC documentation are to be completed at each assessment period. 
 


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Table 19: 
Schedule of Events for NANT CRC Vaccine Maintenance Phase of Study 
 
Maintenance Phase Treatment (repeats every 2 weeks, except where noted)a 
 
 
Study Week 
1 
2 
EOT Visitb 
Unscheduled 
Visitc 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical exam, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signsd 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
Every 12 weeks 
X 
 
ECHO (with ejection 
fraction) 
X 
Every 12 weeks 
X 
 
Confirm contraceptive 
measures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event collection 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
FACT-C questionnaire 
X 
Every 12 weeks 
X 
 
Laboratory Assessments 
Chemistry panele 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA 
X 
Every 12 weeks 
X 
 
Hematologyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testg 
X 
Every 12 weeks 
X 
 
Collect whole blood for 
immunology analysish 
X 
Every 8 weeks during routine blood draws 
X 
 
Collect whole blood for 
ctDNA/ctRNA analysish 
X 
Every 8 weeks during routine blood draws 
X 
 


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Maintenance Phase Treatment (repeats every 2 weeks, except where noted)a 
 
 
Study Week 
1 
2 
EOT Visitb 
Unscheduled 
Visitc 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
Additional tumor biopsy 
May be collected at any time point, as clinically indicated at the Investigator’s discretion 
Tumor Imaging and Assessments 
 CT, MRI, or PET-CTi 
X 
Every 12 weeks 
X 
 
a Subjects will remain in 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 correctable with dose reduction), withdraws consent, or if the Investigator feels it is no longer in the subject’s best interest to 
continue treatment. Any required laboratory sample collection (eg, blood draws, urinalysis) may be performed within a 3-day window of the time indicated. 
b EOT visit must be performed 30 (±5 days) after the last study treatment. 
c Additional assessments performed during an unscheduled visit are at the discretion of the PI or treating physician and must be recorded in the subject’s source 
documents and on the Unscheduled Visit eCRF. 
d Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes. For visits where a subject is receiving an infusion of any study compounds, vital signs will be collected at the 
following time points in relation to the start of first infusion of the day: prior to infusion, 15 minutes post, 30 minutes post, and hourly until the subject is 
discharged. Temperature will be documented each visit at the first pre-infusion assessment of vital signs and subsequently if clinically indicated. 
e Chemistry panel to include laboratory assessments noted in Table 17. 
f Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
g Serum pregnancy test for females of child-bearing potential. 
h Blood collection for exploratory immunology and ctDNA/ctRNA analyses will be performed every 8 weeks in the maintenance phase during routine blood 
draws and at the end-of-treatment visit.  
i Tumor imaging by CT scan, MRI, or PET-CT will continue to be performed every 12 weeks during the maintenance phase of treatment, as described in 
Section 6.1.2. RECIST and irRC documentation to be completed at each assessment period. 
 


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Table 20: 
Regorafenib Treatment Arm – Schedule of Events 
 
Screening  
(days -28 to -1) 
On day 1 of each weeka 
EOT Visitb 
Unscheduled 
Visitc 
Weeks 1 - 8 
Weeks 12-52  
Weeks 53 – 104  
 
 
Frequency of Assessment 
 
 
General Assessments 
 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusiond 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
Confirm availability of FFPE tumor 
samplee 
X 
 
 
 
 
 
Confirm contraceptive measures 
X 
 
 
 
 
 
Concomitant medications 
X 
Weekly 
Every 4 weeks 
X 
X 
Physical exam: heightf, weight 
X 
Weekly 
Every 4 weeks 
X 
X 
Vital signsg 
X 
Weekly 
Every 4 weeks 
X 
X 
Adverse event collection 
 
Weekly 
Every 4 weeks 
X 
X 
ECOG performance status 
X 
Weekly 
Every 4 weeks 
X 
 
12-lead ECGh 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
FACT-C Questionnaire 
X 
Every 4 weeks 
Every 12 weeks 
X 
 
Laboratory Assessments 
Serum virology (HIV)j 
X 
 
 
 
 
 
Determine RAS mutational statusk 
X 
 
 
 
 
 
Collect whole blood for tumor molecular 
profilingl 
X 
 
 
 
 
 
Collect historic tumor biopsy specimen 
for tumor molecular profilingm 
X 
 
 
 
 
 


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Screening  
(days -28 to -1) 
On day 1 of each weeka 
EOT Visitb 
Unscheduled 
Visitc 
Weeks 1 - 8 
Weeks 12-52  
Weeks 53 – 104  
Chemistry paneln 
X 
Weeklyi 
Every 4 weeks 
X 
 
Hematologyo 
X 
Weeklyi 
Every 4 weeks 
X 
 
Urinalysis 
X 
Weeklyi 
Every 4 weeks 
X 
 
Pregnancy testp 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
CEA 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
Collect whole blood for immunology 
analysis (during routine blood draws) 
X 
Every 4 weeks  
Every 8 weeks 
X 
 
Collect whole blood for ctDNA/ctRNA 
analysis (during routine blood draws) 
X 
Every 4 weeks 
Every 8 weeks 
X 
 
Tumor biopsym 
X 
8 weeks after 
the start of 
treatment 
 
 
 
 
Additional tumor biopsy 
 
May be collected at any time point, as clinically 
indicated at the Investigator’s discretion. 
 
 
Tumor Imaging and Assessments 
CT, MRI, or PET-CTq 
X 
Every 8 weeks 
Every 12 weeks 
X 
 
a Treatment will continue until the subject experiences PD or 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. Those subjects who have a CR in the first year will move to the schedule of events for 
year 2. Any required laboratory sample collection listed below (eg, blood draws, urinalysis) may be performed within a 3-day window of the time indicated. 
b End-of-treatment visit must be performed 30 (±5 days) after the last study treatment. Subjects crossing over to treatment with the NANT CRC Vaccine in the 
single-arm phase 2 component of the study following disease progression on or after discontinuing regorafenib in the randomized phase 2 component of the 
study do not need to have an EOT visit as long as they commence treatment with the NANT CRC Vaccine within 30 (± 5 days) of their last regorafenib 
treatment, at which time they will be assessed according to the schedule of events described in Table 18. Crossover patients do not need to undergo screening 
assessments described in Table 18, except for providing any relevant new medical history occurring after enrollment in the trial.  
c Additional assessments performed during an unscheduled visit are at the discretion of the Investigator or treating physician and must be recorded in the 
subject’s source documents and on the Unscheduled Visit eCRF. 
d Also evaluated at enrollment. 
e Subject’s FFPE tumor tissue sample must be obtained following the conclusion of the most recent anticancer treatment and prior to first study treatment. If not 
available, a fresh tumor biopsy must be performed, if considered safe by the Investigator. In the event a fresh biopsy needs to be scheduled, the site may 
consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to the first dose of any study 


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drug. 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. 
f Height required at screening visit only.  
g Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes. 
h 12-lead ECG to be performed in triplicate at screening. 
i Day 1 of week 1 assessments can be skipped if the screening assessment was performed within 1 week prior to the start of treatment. 
j HIV status to be determined by an approved test. 
k Assessment of RAS mutational status to allow stratification of subjects during randomization. 
l Whole blood for tumor molecular profiling will be collected during the screening period for subjects who have been enrolled in the study. 
m Historic tumor biopsy specimen for tumor molecular profiling is required to determine eligibility for participation in the study. If an historic specimen is not 
available, a fresh tumor biopsy must be performed, 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. In the event a fresh biopsy needs to be 
scheduled, the site may consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to 
the first dose of any study medications. A tumor biopsy is also required 8 weeks after the start of treatment, if considered safe by the Investigator. 
n Chemistry panel to include laboratory assessments noted in Table 17. 
o Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
p Serum pregnancy tests for females of child-bearing potential  
q All screening tumor imaging assessments should be performed based on the subject's qualifying scan obtained within 28 days prior to the start of treatment. 
RECIST and irRC documentation are to be completed at each assessment period. 
 


NANT Colorectal Cancer Vaccine 
Clinical Trial Protocol: QUILT-3.071 
APPENDIX 1. SPONSOR SIGNATURE 
NantKwest, Inc. 
Study Title: 
NANT Colorectal Cancer (CRC) Vaccine: A phase 1 b/2 trial of 
the NANT CRC vaccine vs. regorafenib in subjects with metastatic 
CRC who have been previously treated with standard-of-care 
(SoC) therapy 
Study Number: 
QUILT-3.071 
Version Number: 
1 
Final Date: 
24 April 2018 
This clinical trial protocol was subject to critical review and has been approved by NantKwest. 
The following personnel contributed to writing and/or approving this protocol: 
Vice President Adult Medical Affairs, 
NantKwest Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Email: John.Lee@NantKwest.com 
Cell Phone:+ 1-605-610-6391 
Confidential and Proprietary 
173 


NANT Colorectal Cancer Vaccine 
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1 
 TITLE PAGE 
NANT COLORECTAL CANCER (CRC) VACCINE: A 
PHASE 1b/2 TRIAL OF THE NANT CRC VACCINE VS 
REGORAFENIB IN SUBJECTS WITH METASTATIC 
CRC WHO HAVE BEEN PREVIOUSLY TREATED 
WITH STANDARD-OF-CARE (SOC) THERAPY 
 
Study Number: 
QUILT-3.071 
IND Sponsor: 
NantKwest, Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Sponsor Contact:  
(For medical questions/emergencies) 
John H. Lee, MD 
Senior Vice President Adult Medical Affairs, 
NantKwest Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Email: John.Lee@NantKwest.com 
Cell Phone: +1-605-610-6391 
 
Protocol Version 
Date 
Version 1 
24 April 2018 
Version 2 
10 August 2018 


NANT Colorectal Cancer Vaccine 
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Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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2 
STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with Good Clinical Practice (GCP) as described in the 
International Conference on Harmonization Guideline E6 (ICH E6) and in accordance with 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) and the general ethical 
principles outlined in the Declaration of Helsinki. The study will receive approval from an 
Institutional Review Board (IRB) prior to commencement. The Principal Investigator will assure 
that no deviation from or changes to the protocol will take place without prior agreement from 
NantKwest and documented approval from the IRB, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
Principal Investigator:  
 
Signed: _____________________________________ Date: ______________ 
 


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Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
NantKwest, Inc. 
Name of Investigational Products: 
1. Aldoxorubicin hydrochloride (HCl) 
2. ALT-803 (recombinant human superagonist interleukin-15 (IL-15) complex [also known as IL-
15N72D:IL-15RαSu/IgG1 Fc complex]) 
3. ETBX-011 (adenovirus serotype-5 [Ad5] [E1-, E2b-]-carcinoembryonic antigen [CEA] vaccine) 
4. ETBX-021 (Ad5 [E1-, E2b-]-human epidermal growth factor receptor 2 [HER2] vaccine) 
5. ETBX-051 (Ad5 [E1-, E2b-]-Brachyury vaccine) 
6. ETBX-061 (Ad5 [E1-, E2b-]-mucin 1 [MUC1] vaccine)  
7. GI-4000 (RAS yeast vaccine) 
8. GI-6207 (CEA yeast vaccine) 
9. GI-6301 (Brachyury yeast vaccine)  
10. haNK™, NK-92 [CD16.158V, ER IL-2], Suspension for Infusion (haNK™ for Infusion) 
Name of Approved Products: 
11. Avelumab (BAVENCIO® injection, for intravenous [IV] use) 
12. Capecitabine (XELODA® tablets, for oral use) 
13. Cetuximab (ERBITUX® injection, for IV infusion) 
14. Cyclophosphamide (Cyclophosphamide Capsules, for oral use; or Cyclophosphamide Tablets, 
USP) 
15. 5-Fluorouracil (5-FU; Fluorouracil Injection, for IV use only) 
16. Leucovorin (LEUCOVORIN Calcium for Injection, for IV or intramuscular [IM] use) 
17. Nab-paclitaxel (ABRAXANE® for Injectable Suspension [paclitaxel protein-bound particles for 
injectable suspension] [albumin-bound]) 
18. Oxaliplatin (ELOXATIN® injection for IV use) 
19. Regorafenib (STIVARGA® tablets, for oral use) 
20. Stereotactic body radiation therapy (SBRT) 


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Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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Name of Active Ingredients: 
Investigational Products  
1. Aldoxorubicin HCl 
2. ALT-803, recombinant human superagonist interleukin-15 (IL-15) complex (also known as 
IL-15N72D:IL-15RαSu/IgG1 Fc complex)  
3. Ad5 [E1-, E2b-]-CEA 
4. Ad5 [E1-, E2b-]-HER2 
5. Ad5 [E1-, E2b-]-Brachyury 
6. Ad5 [E1-, E2b-]-MUC1  
7. GI-4014 expressing mutations in RAS at codon 12 (G12V), and codon 61 (Q61R and Q61L); 
GI-4015 expressing mutations in RAS at codon 12 (G12C), and codon 61 (Q61R and Q61L); 
GI-4016 expressing mutations in RAS at codon 12 (G12D) and codon 61 (Q61R and Q61L) and 
GI-4020 expressing mutations in RAS at codon 12 (G12R) and codon 61 (Q61L and Q61H) 
8. Recombinant yeast based vaccine expressing the full length human carcinoembryonic antigen 
(CEA), with a modified gene coding sequence to code for a single amino acid substitution 
(asparagine to aspartic acid) at the native protein amino acid position 610 
9. Recombinant yeast based vaccine expressing the human Brachyury oncoprotein  
10. NK-92 [CD16.158V, ER IL2] cells 
Approved Products 
11. Avelumab 
12. Capecitabine 
13. Cetuximab 
14. Cyclophosphamide (anhydrous) 
15. Fluorouracil, USP 
16. Leucovorin (calcium salt) 
17. Paclitaxel, USP 
18. Oxaliplatin, USP 
19. Regorafenib 
20. Radiation 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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Title of Study: 
NANT Colorectal Cancer (CRC) Vaccine: A phase 1b/2 trial of the NANT CRC Vaccine vs. regorafenib 
in subjects with metastatic CRC who have been previously treated with standard-of-care (SoC) therapy 
Study Number: 
QUILT-3.071 
Study Phase: 
Phase 1b/Phase 2 (randomized and single-arm [using Simon’s two-stage optimal design]) 
Study Objectives: 
Phase 1b 
• 
The primary objective is to evaluate the overall safety profile of the NANT CRC Vaccine 
regimen in subjects with recurrent or metastatic CRC who have been previously treated with 
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 responses, and 
molecular changes in circulating tumor DNA (ctDNA) and RNA (ctRNA); and their 
correlations with subject outcomes. 
Phase 2  
Randomized component – The randomized component of the phase 2 portion of the study will compare 
the NANT CRC Vaccine regimen (experimental arm) to regorafenib monotherapy (control arm) in 
subjects with recurrent or metastatic CRC who have previously been treated with SoC therapy that did 
not include regorafenib. 
• The primary objective is to compare efficacy as assessed by PFS using Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 based on Blinded Independent Central 
Review (BICR). 
• 
Secondary objectives are to compare safety and additional measures of efficacy (PFS by 
immune-related response criteria (irRC), ORR, 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 
correlations with subject outcomes. 
Single-arm component – The single-arm component of the phase 2 portion of the study will evaluate the 
NANT CRC Vaccine regimen in subjects with recurrent or metastatic CRC who have previously been 
treated with SoC therapy that included regorafenib. 
• 
The primary objective is to evaluate the efficacy of the NANT CRC Vaccine regimen as 
assessed by ORR using RECIST Version 1.1 based on BICR. 
 


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• 
Secondary objectives are to evaluate safety and additional measures of efficacy (ORR by 
irRC, 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 
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 recurrent or metastatic CRC who have previously received SoC therapy. The phase 2 
portion of the study will consist of both a single-arm component and a randomized component. 
In phase 1b, the NANT CRC Vaccine will be assessed for safety. 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 NANT CRC Vaccine 
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. In total, 6 to 24 subjects will be enrolled in the phase 1b portion of the study. 
In the randomized component of the phase 2 portion, subjects who have received SoC therapy that did not 
include regorafenib for recurrent or metastatic CRC will be randomized to receive either the NANT CRC 
Vaccine (experimental arm) or regorafenib monotherapy (control arm). Randomization will be stratified 
by tumor sidedness (left vs right) and performance status (ECOG 0 vs 1). For the control arm of the 
randomized portion, subjects who progress on or after discontinuing regorafenib may be enrolled in the 
single-arm component described below after a 14-day washout period.  
The single-arm component of the phase 2 portion will enroll subjects who have progressed or experienced 
unacceptable toxicity on SoC that included regorafenib, and subjects who have progressed on or after 
regorafenib treatment in the randomized phase 2 portion of this study.  
The NANT CRC Vaccine regimen will be administered in 2 phases, an induction and a maintenance 
phase, as described below. Subjects will continue induction treatment for up to 1 year. 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 and Sponsor’s discretion. Subjects may remain in the 
maintenance phase of the study for up to 1 year. 
In the randomized component of the phase 2 portion of the study, the control arm will self-administer 
regorafenib every day for the first 21 days of every 28-day treatment cycle.  
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. Subjects receiving treatment in the 
control arm may cross over to treatment in the induction phase of the experimental arm after experiencing 
PD. Subjects receiving treatment in the experimental arm with an initial assessment of PD per RECIST 
Version 1.1 may, at the discretion of the Investigator, continue to receive study treatment until PD is 
confirmed as detailed in Section 6.1.2. The maximum time on study treatment is 2 years. 
Subjects who withdraw from the trial for reasons other than progression are encouraged not to initiate 
another anticancer treatment unless/until progression has been documented at a follow-up visit. 
For all subjects, 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 treatment 
periods (depending on response), as described in Section 6.4.1. Separate blood tubes will be collected 
every 4 weeks (induction phase for experimental arm and year 1 or until CR for control arm) or 8 weeks 
(maintenance phase for experimental arm and year 2 or post-CR for control arm) during routine blood 


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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 for all subjects. Tumor response will be assessed every 8 weeks 
(induction phase for experimental arm and year 1 or until CR for control arm) or 12 weeks (maintenance 
phase for experimental arm and year 2 or post-CR for control arm) until progression occurs, regardless of 
the treatment administered, by computed tomography (CT) or magnetic resonance imaging (MRI) of 
target and non-target lesions in accordance with RECIST Version 1.1 and irRC. The same mode(s) of 
assessment used to identify/evaluate lesions at screening should be used throughout the course of the 
study unless subject safety necessitates a change (eg, allergic reaction to contrast media). Unscheduled 
tumor assessments should be carried out if the investigator observes any signs or symptoms of PD. When 
disease progression per RECIST Version 1.1 is initially observed for a subject in the experimental arm, 
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 for a subject 
in the experimental arm, 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 subjects exhibiting a 
response (PR or CR), a confirmatory imaging assessment should be done 4–6 weeks after the initial 
response. 
Prospective Tumor Molecular Profiling 
Prospective tumor molecular profiling will be conducted on tumor samples from all subjects receiving the 
NANT CRC Vaccine to inform HER2 expression and RAS mutational status, and will be used to 
determine whether the Ad5-based vaccine ETBX-021 (HER2), cetuximab, and the yeast-based vaccine 
GI-4000 (RAS) will be administered. Subjects will receive ETBX-021 (HER2) if their tumor is 
HER2-positive (IHC 3+ or FISH positive), as determined by FDA-approved diagnostic tests. Subjects 
will receive cetuximab if their tumor is RAS wild-type as determined by whole genome sequencing. 
Subjects will receive GI-4000 (RAS) if their tumor is positive for specific RAS mutations, as determined 
by whole genome sequencing. ETBX-021 (HER2), cetuximab, and GI-4000 (RAS) administration will be 
initiated as soon as results from tumor molecular profiling are available. All other agents in the 
NANT CRC Vaccine regimen will be administered regardless of 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 blood is described in Section 6.4.1.2 and is similar to the collection of samples for 
the exploratory tumor molecular profiling.  
NANT CRC Vaccine: Induction Phase 
Treatment in the induction phase will consist of repeated 3-week cycles for a maximum treatment period 
of 1 year, as follows: 
Day 1, every 3 weeks:  
• 
Leucovorin (20 mg/m2 IV bolus) 
• 
Oxaliplatin (40 mg/m2 IV) 
• 
Nab-paclitaxel (125 mg 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]) 


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Day 5 (± 1 day), every 3 weeks for 3 cycles then every 9 weeks thereafter:  
• 
Ad5-based vaccines: ETBX-011 (CEA), ETBX-021 (HER2), ETBX-051 (Brachyury), and 
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 ETBX-021 (HER2) and GI-
4000 (RAS) will be administered, as described above. 
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 
≤ 4 cycles) 
Days 8–12, every 3 weeks: 
• 
Cyclophosphamide (25 mg PO daily) 
Day 9, every 3 weeks: 
• 
ALT-803 (15 μg/kg SC) 
• 
haNK (2 × 109 cells/dose IV) 
• 
Avelumab (10 mg/kg IV) 
Day 11, every 3 weeks:  
• 
haNK (2 × 109 cells/dose IV) 
Day 15, every 3 weeks: 
• 
SBRT (not to exceed 8 Gy, exact dose to be determined by the radiation oncologist; for 
≤ 4 cycles) 
• 
Nab-paclitaxel (100 mg IV) 
Day 16, every 3 weeks:  
• 
haNK (2 × 109 cells/dose IV) 
• 
Cetuximab (250 mg/m2 IV) 
Prospective tumor molecular profiling will determine whether cetuximab will be 
administered, as described above. 
NANT CRC Vaccine: 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, as follows: 
Day 1, every 2 weeks:  
• 
Aldoxorubicin HCl (60 mg/m2 IV) 
• 
Nab-paclitaxel (100 mg IV) 


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Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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Days 1, 3, and 5, every 2 weeks: 
• 
Capecitabine (650 mg/m2 PO BID, up to a maximum of 1000 mg per dose) 
Days 1–5, every 2 weeks: 
• 
Cyclophosphamide (25 mg BID) 
Day 2, every 2 weeks:  
• 
ALT-803 (15 µg/kg SC) 
• 
haNK (2 × 109 cells/dose IV) 
• 
Avelumab (10 mg/kg IV) 
• 
Cetuximab (250 mg/m2 IV) 
Prospective tumor molecular profiling will determine whether cetuximab will be 
administered, as described above. 
Day 5 (± 1 day), every 8 weeks thereafter: 
• 
Ad5-based vaccines: ETBX-011 (CEA), ETBX-021 (HER2), ETBX-051 (Brachyury), and 
ETBX-061 (MUC1) (1 × 1011 VP/vaccine/dose SC) 
• 
Yeast-based vaccines: GI-4000 (RAS), GI-6207 (CEA), and GI-6301 (Brachyury)  
(40 YU/vaccine/dose SC) 
Prospective tumor molecular profiling will determine whether ETBX-021 (HER2) and  
GI-4000 (RAS) will be administered, as described above. 
Days 8-12, every 2 weeks 
• 
Cyclophosphamide (25 mg PO daily) 
Study Endpoints 
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. 
 
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. 
• 
ORR by irRC. 
• 
PFS by RECIST Version 1.1. 
• 
PFS by irRC. 


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Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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• 
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. 
Exploratory Endpoints: 
• 
Tumor molecular profiles and correlations with subject outcomes. 
• 
Therapy-induced changes in immune responses and correlations with subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
Phase 2  
Randomized Component 
Primary Endpoint: 
• 
PFS by RECIST Version 1.1. 
Secondary Endpoints: 
• 
PFS by irRC. 
• 
ORR by RECIST Version 1.1 
• 
ORR 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 and 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 subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
Single-Arm Component 
Primary Endpoint: 
• 
ORR by RECIST Version 1.1. 
 
 
 


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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 and 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 subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
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.  
The phase 2 randomized component of the study is initially planned for 120 subjects to be randomized 
1:1 to the NANT CRC Vaccine regimen or regorafenib monotherapy. During the trial, 120 subjects are 
expected to accrue 96 PFS events. An interim analysis is planned once 50% of the PFS events have 
accrued (48 events). Based on the interim analysis, the study sample size may be increased to a maximum 
of 240 subjects. 
In the phase 2 single-arm component of the study, 27 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 41 subjects will be enrolled in the second stage, for a total of 68 subjects in the 
phase 2 single-arm component of the study.  
The maximum total enrollment for the study is 332 subjects. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Age ≥ 18 years. 
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or 
Independent Ethics Committee (IEC) guidelines. 
3. Histologically-confirmed recurrent or metastatic CRC previously treated with fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapy. These chemotherapy regimens may or may not 
have included an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. 
Subjects who are ineligible or have declined these therapies may also be enrolled. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 


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5. Have at least 1 measurable lesion of ≥ 1.0 cm. 
6. 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 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. 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. 
7. Must be willing to provide blood samples prior to the start of treatment on this study for 
prospective tumor molecular profiling and exploratory analyses. 
8. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of treatment for 
exploratory analyses, if considered safe by the Investigator. 
9. Ability to attend required study visits and return for adequate follow-up, as required by this 
protocol. 
10. 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. 
Phase 2 single-arm component only 
11. Must have progressed on or after regorafenib treatment in the randomized phase 2 portion of the 
study OR progressed or experienced unacceptable toxicity on SoC and regorafenib prior to 
enrollment on the study. 
Exclusion Criteria: 
1. Microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient tumors eligible for, but 
not yet treated with, a PD-1 inhibitor. 
2. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational 
drugs used in this study or that would put the subject at high risk for treatment-related 
complications. 
3. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, 
or autoimmune disease associated with lymphoma).  
4. History of organ transplant requiring immunosuppression.  
5. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). 
6. Inadequate organ function, evidenced by the following laboratory results: 
a. Absolute neutrophil count (ANC) < 1,000 cells/mm3. 
b. Uncorrectable grade 3 anemia (hemoglobin < 8 g/dL). 
c. Platelet count < 75,000 cells/mm3. 
 


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d. Total bilirubin greater than the upper limit of normal (ULN; unless the subject has 
documented Gilbert’s syndrome). 
e. Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) 
> 2.5 × ULN (> 5 × ULN in subjects with liver metastases). 
f. Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver 
metastases, or >10 × ULN in subjects with bone metastases). 
g. Serum creatinine > 2.0 mg/dL or 177 μmol/L. 
h. Serum anion gap > 16 mEq/L or arterial blood with pH < 7.3. 
7. 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. Subjects with uncontrolled hypertension should be medically managed on a stable 
regimen to control hypertension prior to study entry. 
8. Serious myocardial dysfunction defined by echocardiogram (ECHO) as absolute left ventricular 
ejection fraction (LVEF) 10% below the institution’s lower limit of predicted normal. 
9. Dyspnea at rest due to complications of advanced malignancy or other disease requiring 
continuous oxygen therapy. 
10. Positive results of screening test for human immunodeficiency virus (HIV). 
11. 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. 
12. Known hypersensitivity to any component of the study medication(s). 
13. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction 
with any of the study medications. 
14. 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. 
15. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8 inducer 
(rifampin) within 14 days before study day 1. 
16. Participation in an investigational drug study or history of receiving any investigational treatment 
within 30 days prior to screening for this study, except for testosterone-lowering therapy in men 
with prostate cancer. 
17. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the 
protocol. 
18. Concurrent participation in any interventional clinical trial. 
19. Pregnant and nursing women. 


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Phase 2 randomized component only 
20. Prior regorafenib treatment. 
Products, Dosage, and Mode of Administration: 
Investigational Products 
Dosage 
Mode of Administration 
Aldoxorubicin HCl 
100 mg/m2 (induction); 
60 mg/m2 (maintenance) 
IV 
ALT-803 
15 µg/kg  
SC 
ETBX-011 (CEA) 
1 × 1011 VP/dose  
SC 
ETBX-021 (HER2) 
1 × 1011 VP/dose  
SC 
ETBX-051 (Brachyury) 
1 × 1011 VP/dose  
SC 
ETBX-061 (MUC1) 
1 × 1011 VP/dose  
SC 
GI-4000 (RAS) 
40 YU/dose 
SC 
GI-6207 (CEA) 
40 YU/dose 
SC 
GI-6301 (Brachyury) 
40 YU/dose 
SC 
haNK  
2 × 109 cells/dose  
IV 
Approved Products 
Dosage 
Mode of Administration 
Avelumab 
10 mg/kg 
IV 
Capecitabine 
650 mg/m2 BID up to a maximum of 
1000 mg per dose 
PO 
Cetuximab 
250 mg/m2 
IV 
Cyclophosphamide  
25 mg BID (days 1-5) 
25 mg daily (days 8-12) 
PO 
5-FU 
1500 mg/m2  
85- to 96-hour continuous IV 
infusion 
Leucovorin  
20 mg/m2  
IV bolus 
Nab-paclitaxel  
125 mg (day 1 of induction);  
100 mg (day 15 of induction and day 
1 of maintenance) 
IV 
Oxaliplatin 
40 mg/m2 
IV 
Regorafenib 
160 mg 
PO 
SBRT 
8 Gy maximum (exact dose to be 
determined by the radiation 
oncologist) 
External beam radiation 


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Duration of Treatment: 
NANT CRC Vaccine (Experimental Arm) 
• 
Induction phase: 8 weeks (minimum) to 1 year (maximum) 
• 
Maintenance phase: Up to 1 year 
Subjects will be treated for up to 2 years (up to 1 year in each treatment phase), or until they experience 
confirmed PD or unacceptable toxicity (not correctable with dose reduction), withdraw consent, or if the 
Investigator feels it is no longer in their best interest to continue treatment. 
Regorafenib (Control Arm) 
Subjects will be treated for up to 2 years, or until they experience PD or unacceptable toxicity 
(not correctable with dose reduction), withdraw consent, or if the Investigator feels it is no longer in their 
best interest to continue treatment. 
Subjects that experience PD on or after treatment with regorafenib in the phase 2 randomized component 
of the study may be subsequently treated with the NANT CRC Vaccine in the phase 2 single-arm 
component of the study. 
Duration of Follow-up:  
Subjects who discontinue study treatment should remain in the study and continue to be followed for: 
• 
CT or MRI imaging and response assessments (see Section 6.1.2). 
• 
Collection of vital status every 90 days (± 14 days). 
Subjects should be followed until either death (any cause) or for a minimum of 24 months past 
administration of the first dose of study drug. 
Reference Therapy, Dosage, and Mode of Administration: 
Regorafenib:  
Regorafenib treatment will consist of repeated 4-week cycles for a maximum treatment period of 2 years, 
as follows: 
Days 1-21, every 4 weeks:  
• 
Regorafenib (160 mg PO) 


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Evaluation of Endpoints: 
Safety:  
Safety endpoints include assessments of treatment-emergent AEs, SAEs, and clinically significant 
changes in safety laboratory tests, physical examinations, electrocardiograms (ECGs), echocardiograms 
(ECHOs), and vital signs. All subjects will be evaluable for toxicity from the time of their first study 
treatment. Toxicities will be graded using the NCI CTCAE Version 4.03. 
Efficacy: 
PFS and ORR will be assessed by CT or MRI of target and non-target lesions every 8 or 12 weeks until 
progression occurs regardless of the treatment administered and will be evaluated in accordance with 
RECIST Version 1.1 and irRC. In order to document PD, unscheduled tumor assessments may be done if 
the investigator observes any signs and symptoms of PD. For responding subjects (PR or CR), a 
confirmatory response assessment should be done at 4–6 weeks after the initial response. 
OS, DOR, and DCR will also be assessed. 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 the BICR. 
An assessment of QoL will be conducted via PROs using the Functional Assessment of Cancer 
Therapy-Colorectal Cancer (FACT-C) instrument. Assessments will occur at screening and prior to 
treatment on day 1, every 4 or 12 weeks thereafter, and at the end-of-treatment (EOT) visit.  
Exploratory Analyses: 
Tumor Molecular Profiling: Genomic sequencing of tumor cells from tissue relative to non-tumor cells 
from whole blood will be conducted to identify tumor-specific genomic variances that may contribute to 
disease progression and/or response to treatment. RNA sequencing will be conducted to provide 
expression data and give relevance to DNA mutations. Quantitative proteomics analysis will be 
conducted to determine the absolute amounts of specific proteins, to confirm expression of genes that are 
correlative of disease progression and/or response, and to determine the cutoff values for response. 
Immunologic Analysis: Immune responses to the NANT CRC Vaccine regimen and regorafenib 
monotherapy will be evaluated by standard immune assays. Correlations between therapy-induced 
immune changes and subject outcomes will be assessed. 
ctDNA/ctRNA Analysis: ctDNA and ctRNA will be extracted from plasma obtained from whole blood. 
Expression levels of specific tumor- and immune-related analytes will be assessed by quantitative 
real-time polymerase chain reaction (qPCR) and possibly other methods (eg, DNA/RNA sequencing) and 
analyzed for correlations with subject outcomes. 


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Statistical Methods: 
This phase 1b/2 study will evaluate the safety and efficacy of metronomic combination therapy in 
subjects with recurrent or metastatic CRC who have failed SoC therapy. 
Six to 24 subjects will be enrolled in the phase 1b portion of the study. 
In the phase 2 single-arm component of the study, ORR based on RECIST Version 1.1 will be evaluated 
using Simon’s two-stage optimal design.  
The phase 2 randomized component of the study is initially planned for 120 subjects to be randomized 
1:1 to the NANT CRC vaccine regimen or regorafenib monotherapy. A total of 120 subjects are expected 
to accrue 96 PFS events during the trial with a 12-month enrollment period and 12 months of follow-up 
after the last subject is enrolled. Based on median PFS of 2 and 4 months for regorafenib and the 
NANT CRC Vaccine, respectively, a 20% lost-to-follow-up rate, and a 5% type 1 error, 120 subjects with 
96 PFS events has a power of 90% to detect a hazard ratio (HR) of 0.50. 
In the phase 2 randomized component of the study, an interim analysis is planned once 50% of the PFS 
events have accrued (48 events). The Lan DeMets/O’Brien Fleming spending function will be used for 
the interim analysis which allocates a 0.3% and 4.9% type 1 error rate to the interim and final PFS 
analyses, respectively. The trial may be stopped early for strong efficacy if the interim PFS analysis 
shows superiority (ie, p < 0.003). The trial may be stopped early for futility if the interim PFS analysis 
displays a conditional power < 15%. Based on the interim PFS analysis, the study sample size for the 
randomized phase 2 component may be increased to a maximum of 240 subjects using the “Promising 
Zone” methodology for an adaptive sample size increase.  
The interim analysis will be performed by an independent statistician separate from the study team. The 
interim analysis results will not be shared with the study team during the conduct of the study. The 
interim analysis results will be presented to the Independent Data Monitoring Committee (IDMC) who 
will make recommendations to the study team whether to stop the study for efficacy or futility, or 
increase the study sample size. For the NANT CRC Vaccine regimen, safety results will be presented 
separately for the induction and maintenance phases of treatment as well as overall for the entire 
treatment regimen. For the regorafenib treatment, safety results will be presented for the entire treatment 
regimen. Efficacy results will be summarized for the overall treatment regimens. 
Overall safety will be assessed by descriptive analyses using tabulated frequencies of AEs by grade using 
CTCAE version 4.03 in terms of treatment-emergent AEs, SAEs, and clinically significant changes in 
safety laboratory tests, physical examinations, ECGs, ECHOs, and vital signs. 
PFS will be analyzed using Kaplan-Meier methods. The median PFS (and 95% confidence interval [CI]) 
will be summarized. PFS Kaplan-Meier curves will be presented. For the phase 2 randomized component, 
comparison of PFS between the NANT CRC Vaccine regimen and the control treatment will be based on 
the stratified log-rank test, stratified by tumor sidedness and performance status. PFS assessed by 
RECIST Version 1.1 will be the primary PFS analysis and PFS assessed by irRC will be a secondary 
analysis. 
OS and DOR will be analyzed in the same manner as PFS. 
ORR (and 95% CI) will be summarized. For the phase 2 randomized component, comparison of ORR 
between the NANT CRC Vaccine regimen and the control treatment will be based on the stratified Fisher 
exact test, stratified by tumor sidedness and performance status. ORR assessed by RECIST Version 1.1 
will be the primary ORR analysis and ORR assessed by irRC will be a secondary analysis. 
DCR will be analyzed in the same manner as ORR.  
Descriptive statistics of PROs will be presented. 
Correlations of tumor molecular profiles, therapy-induced changes in immune responses, and molecular 
changes in ctDNA and ctRNA with subject outcomes will be explored. 


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Figure 1: 
Study Treatment Schema 
 


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Figure 2: 
Induction Phase Treatment Schema for NANT CRC Vaccine 
 


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Figure 3: 
Maintenance Phase Treatment Schema for NANT CRC Vaccine 
 


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Table 18: 
Schedule of Events for NANT CRC Vaccine Induction Phase of Study 
 
Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
General Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusiond 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm availability 
of FFPE tumor 
samplef 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Physical exam: 
height, weightg 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Vital signsh 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
ECOG performance 
status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12-lead ECGi 
X 
Xj 
Every 4 weeks 
X 
 
ECHO (with 
ejection fraction) 
X 
Xj  
Every 12 weeks 
X 
 
Confirm 
contraceptive 
measures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-C 
Questionnaire 
X 
X 
Every 4 weeks 
X 
 
Adverse event 
collection 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
X 


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Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
Laboratory Assessments 
Chemistry panelk 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CEA 
X 
X
j 
Every 4 weeks 
X 
 
Hematologyl 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Pregnancy test m 
X 
X
j 
Every 4 weeks 
X 
 
Serum virology 
(HIV)n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine HER2 
expression and RAS 
mutational statuso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect whole blood 
for tumor molecular 
profilingp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect whole blood 
for immunology 
analysisq 
X 
Every 4 weeks during routine blood draws 
X 
 
Collect whole blood 
for ctDNA/ctRNA 
analysisq 
X 
Every 4 weeks during routine blood draws 
X 
 
Collect historic 
tumor biopsy 
specimen for tumor 
molecular profilingr 
X 
 
 
 
Tumor biopsyr 
X 
8 weeks after the start of treatment 
 
 
Additional tumor 
biopsy 
 
May be collected at any time point, as clinically indicated at the Investigator’s discretion. 
 
 
Tumor Imaging and Assessments 
CT or MRIs 
X 
Every 8 weeks 
X 
 


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a Subjects will remain in the induction phase of the study for up to 1 year. Treatment will continue in the induction phase until the subject experiences confirmed 
PD or 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. Those who have a CR in the induction phase will enter the maintenance phase of the study. Subjects who experience ongoing SD or an 
ongoing PR at 1 year may enter the maintenance phase at the Investigator’s and Sponsor’s discretion. Any required laboratory sample collection 
(eg, blood draws, urinalysis) may be performed within a 3-day window of the time indicated. Subjects crossing over to treatment with the NANT CRC Vaccine 
in the single-arm phase 2 component of the study following disease progression on or after discontinuing regorafenib in the randomized phase 2 component of 
the study will have a minimum 14-day washout period between the last regorafenib treatment and the first NANT CRC Vaccine treatment. Patients who 
crossover will begin at day 1 of the above schedule, except that relevant new medical history will be collected. Tumor imaging does not need to be performed on 
day 1 for crossover patients if they have had an imaging assessment within the last 28 days. 
b End-of-treatment visit must be performed 30 (±5 days) after the last study treatment. 
c Additional assessments performed during an unscheduled visit are at the discretion of the Investigator or treating physician and must be recorded in the 
subject’s source documents and on the Unscheduled Visit eCRF. 
d Inclusion/exclusion criteria will also be evaluated at enrollment. 
e Medical history will also be evaluated at enrollment. 
f Subject’s FFPE tumor tissue sample must be obtained following the conclusion of the most recent anticancer treatment and prior to first study treatment. If not 
available, a fresh tumor biopsy must be performed, if considered safe by the Investigator. In the event a fresh biopsy needs to be scheduled, the site may 
consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to the first dose of any study 
drug. 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. 
g Height required at screening visit only. Weight on day 1 of each treatment cycle should be used to calculate drug doses. 
h Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes and within 30 minutes prior to the start of any infusional study treatment. For visits where a subject is 
receiving an infusion of any study compounds, vital signs will be collected at the following time points in relation to the start of first infusion of the day: prior 
to infusion, 15 minutes post, 30 minutes post, and hourly until the subject is discharged. Temperature will be documented each visit at the first pre-infusion 
assessment of vital signs and subsequently if clinically indicated. 
i 12-lead ECG to be performed in triplicate at screening. 
j Day 1 of week 1 assessments can be skipped if the screening assessment was performed within 1 week prior to the start of treatment. 
k Chemistry panel to include laboratory assessments noted in Table 17. 
l Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
m Serum pregnancy tests for females of child-bearing potential. 
n HIV status to be determined by an approved test. 
o Assessment of HER2 expression to determine whether ETBX-021 (HER2) will be administered to the subject and assessment of RAS mutational status to 
determine whether GI-4000 (RAS) or cetuximab will be administered to the subject, as described in Section 3.1.1. 
p Whole blood for tumor molecular profiling will be collected during the screening period for subjects who have been enrolled in the study. 
q Whole blood for immunology and ctDNA/ctRNA analyses will be collected during the screening period for subjects who have been enrolled in the study, every 
4 weeks in the induction phase during routine blood draws, and at the EOT visit. 
r Historic tumor biopsy specimen for tumor molecular profiling is required to determine eligibility for participation in the study. If an historic specimen is not 
available, a fresh tumor biopsy must be performed, 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. In the event a fresh biopsy needs to be 


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scheduled, the site may consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to 
the first dose of any study medications. A tumor biopsy is also required 8 weeks after the start of treatment, if considered safe by the Investigator. 
s Tumor imaging by CT or MRI will be performed at screening and every 8 weeks during the induction phase, as described in Section 6.1.2. All screening tumor 
imaging assessments should be performed based on the subject's qualifying scan obtained within 28 days prior to the start of treatment. RECIST and irRC 
documentation are to be completed at each assessment period. 
 


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Table 19: 
Schedule of Events for NANT CRC Vaccine Maintenance Phase of Study 
 
Maintenance Phase Treatment (repeats every 2 weeks, except where noted)
a 
 
 
Study Week 
1 
2 
EOT Visit
b 
Unscheduled 
Visit
c 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical exam, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signs
d 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
Every 12 weeks 
X 
 
ECHO (with ejection 
fraction) 
X 
Every 12 weeks 
X 
 
Confirm contraceptive 
measures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event collection 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
FACT-C questionnaire 
X 
Every 12 weeks 
X 
 
Laboratory Assessments 
Chemistry panel
e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA 
X 
Every 12 weeks 
X 
 
Hematology
f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test
g 
X 
Every 12 weeks 
X 
 
Collect whole blood for 
immunology analysis
h 
X 
Every 8 weeks during routine blood draws 
X 
 
Collect whole blood for 
ctDNA/ctRNA analysish 
X 
Every 8 weeks during routine blood draws 
X 
 
Additional tumor biopsy 
May be collected at any time point, as clinically indicated at the Investigator’s discretion 
Tumor Imaging and Assessments 
 CT or MRI
i 
X 
Every 12 weeks 
X 
 
a Subjects will remain in the maintenance phase of the study for up to 1 year. Treatment will continue in the maintenance phase until the subject experiences 
confirmed PD or unacceptable toxicity (not correctable with dose reduction), withdraws consent, or if the Investigator feels it is no longer in the subject’s best 


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interest to continue treatment. Any required laboratory sample collection (eg, blood draws, urinalysis) may be performed within a 3-day window of the time 
indicated. 
b EOT visit must be performed 30 (±5 days) after the last study treatment. 
c Additional assessments performed during an unscheduled visit are at the discretion of the PI or treating physician and must be recorded in the subject’s source 
documents and on the Unscheduled Visit eCRF. 
d Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes. For visits where a subject is receiving an infusion of any study compounds, vital signs will be collected at the 
following time points in relation to the start of first infusion of the day: prior to infusion, 15 minutes post, 30 minutes post, and hourly until the subject is 
discharged. Temperature will be documented each visit at the first pre-infusion assessment of vital signs and subsequently if clinically indicated. 
e Chemistry panel to include laboratory assessments noted in Table 17. 
f Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
g Serum pregnancy test for females of child-bearing potential. 
h Blood collection for exploratory immunology and ctDNA/ctRNA analyses will be performed every 8 weeks in the maintenance phase during routine blood 
draws and at the end-of-treatment visit.  
i Tumor imaging by CT or MRI will continue to be performed every 12 weeks during the maintenance phase of treatment, as described in Section 6.1.2. RECIST 
and irRC documentation to be completed at each assessment period. 
 


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Table 20: 
Regorafenib Control Arm – Schedule of Events 
 
Screening  
(days -28 to -1) 
On day 1 of each weeka 
EOT Visitb 
Unscheduled 
Visitc 
Weeks 1-8 
Weeks 13-52  
Weeks 53-104  
 
 
Frequency of Assessment 
 
 
General Assessments 
 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusiond 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
Confirm availability of FFPE tumor 
samplee 
X 
 
 
 
 
 
Confirm contraceptive measures 
X 
 
 
 
 
 
Concomitant medications 
X 
Weekly 
Every 4 weeks 
X 
X 
Physical exam: heightf, weight 
X 
Weekly 
Every 4 weeks 
X 
X 
Vital signsg 
X 
Weekly 
Every 4 weeks 
X 
X 
Adverse event collection 
 
Weekly 
Every 4 weeks 
X 
X 
ECOG performance status 
X 
Weekly 
Every 4 weeks 
X 
 
12-lead ECGh 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
FACT-C Questionnaire 
X 
Every 4 weeks 
Every 12 weeks 
X 
 
Laboratory Assessments 
Serum virology (HIV)j 
X 
 
 
 
 
 
Collect whole blood for tumor molecular 
profilingk 
X 
 
 
 
 
 
Collect historic tumor biopsy specimen for 
tumor molecular profilingl 
X 
 
 
 
 
 
Chemistry panelm 
X 
Weeklyi 
Every 4 weeks 
X 
 


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Screening  
(days -28 to -1) 
On day 1 of each weeka 
EOT Visitb 
Unscheduled 
Visitc 
Weeks 1-8 
Weeks 13-52  
Weeks 53-104  
Hematologyn 
X 
Weeklyi 
Every 4 weeks 
X 
 
Urinalysis 
X 
Weeklyi 
Every 4 weeks 
X 
 
Pregnancy testo 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
CEA 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
Collect whole blood for immunology 
analysisp 
X 
Every 4 weeks  
Every 8 weeks 
X 
 
Collect whole blood for ctDNA/ctRNA 
analysis (during routine blood draws)p 
X 
Every 4 weeks 
Every 8 weeks 
X 
 
Tumor biopsyl 
X 
8 weeks after 
the start of 
treatment 
 
 
 
 
Additional tumor biopsy 
 
May be collected at any time point, as clinically 
indicated at the Investigator’s discretion. 
 
 
Tumor Imaging and Assessments 
CT or MRIq 
X 
Every 8 weeks 
Every 12 weeks 
X 
 
a Treatment will continue until the subject experiences PD or 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. Those subjects who have a CR in the first year will move to the schedule of events for 
year 2. Any required laboratory sample collection listed below (eg, blood draws, urinalysis) may be performed within a 3-day window of the time indicated. 
b End-of-treatment visit must be performed 30 (±5 days) after the last study treatment. Subjects crossing over to treatment with the NANT CRC Vaccine in the 
single-arm phase 2 component of the study following disease progression on or after discontinuing regorafenib in the randomized phase 2 component of the 
study do not need to have an EOT visit as long as they commence treatment with the NANT CRC Vaccine within 30 (± 5 days) of their last regorafenib 
treatment, at which time they will be assessed according to the schedule of events described in Table 18. Crossover patients do not need to undergo screening 
assessments described in Table 18, except for providing any relevant new medical history occurring after enrollment in the trial.  
c Additional assessments performed during an unscheduled visit are at the discretion of the Investigator or treating physician and must be recorded in the 
subject’s source documents and on the Unscheduled Visit eCRF. 
d Also evaluated at enrollment. 


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Clinical Trial Protocol: QUILT-3.071 Amendment 1 
 
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e Subject’s FFPE tumor tissue sample must be obtained following the conclusion of the most recent anticancer treatment and prior to first study treatment. If not 
available, a fresh tumor biopsy must be performed, if considered safe by the Investigator. In the event a fresh biopsy needs to be scheduled, the site may 
consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to the first dose of any study 
drug. 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. 
f Height required at screening visit only.  
g Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes. 
h 12-lead ECG to be performed in triplicate at screening. 
i Day 1 of week 1 assessments can be skipped if the screening assessment was performed within 1 week prior to the start of treatment. 
j HIV status to be determined by an approved test. 
k Whole blood for tumor molecular profiling will be collected during the screening period for subjects who have been enrolled in the study. 
l Historic tumor biopsy specimen for tumor molecular profiling is required to determine eligibility for participation in the study. If an historic specimen is not 
available, a fresh tumor biopsy must be performed, 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. In the event a fresh biopsy needs to be 
scheduled, the site may consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to 
the first dose of any study medications. A tumor biopsy is also required 8 weeks after the start of treatment, if considered safe by the Investigator. 
m Chemistry panel to include laboratory assessments noted in Table 17. 
n Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
o Serum pregnancy tests for females of child-bearing potential  
p Blood collection for exploratory immunology and ctDNA/ctRNA analyses will be performed every 4 weeks (year 1or prior to CR) or 8 (year 2 or after CR) 
weeks during routine blood draws and at the end-of-treatment visit.  
q All screening tumor imaging assessments should be performed based on the subject's qualifying scan obtained within 28 days prior to the start of treatment. 
RECIST and irRC documentation are to be completed at each assessment period. 
 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 1 
APPENDIX 1. 
SPONSOR SIGNATURE 
Study Title: 
NANT Colorectal Cancer (CRC) Vaccine: A phase 1 b/2 trial of 
the NANT CRC vaccine vs. regorafenib in subjects with metastatic 
CRC who have been previously treated with standard-of-care 
(SoC) therapy 
Study Number: 
QUILT-3.071 
Version Number: 
2 
Final Date: 
10 August 2018 
This clinical trial protocol was subject to critical review and has been approved by NantKwest. 
The following personnel contributed to writing and/or approving this protocol: 
SigneO: 
Jo 
H. Lee, MD 
, enior Vice President Adult Medical Affairs, 
NantKwest Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Email: John.Lee@NantKwest.com 
Cell Phone: + 1-60 5-610-63 91 
Confidential and Proprietary 
174 
Date: 
(0- f[S 


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Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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1 
 TITLE PAGE 
NANT COLORECTAL CANCER (CRC) VACCINE: 
A PHASE 1b/2 TRIAL OF THE NANT CRC VACCINE VS 
REGORAFENIB IN SUBJECTS WITH METASTATIC 
CRC WHO HAVE BEEN PREVIOUSLY TREATED 
WITH STANDARD-OF-CARE (SOC) THERAPY 
 
Study Number: 
QUILT-3.071 
IND Sponsor: 
NantKwest, Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Sponsor Contact:  
(For medical questions/emergencies) 
John H. Lee, MD 
Senior Vice President Adult Medical Affairs, 
NantKwest Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Email: John.Lee@NantKwest.com 
Cell Phone: +1-605-610-6391 
 
Protocol Version 
Date 
Version 1 
24 April 2018 
Version 2 
10 August 2018 
Version 3 
28 September 2018 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with Good Clinical Practice (GCP) as described in the 
International Conference on Harmonization Guideline E6 (ICH E6) and in accordance with 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) and the general ethical 
principles outlined in the Declaration of Helsinki. The study will receive approval from an 
Institutional Review Board (IRB) prior to commencement. The Principal Investigator will assure 
that no deviation from or changes to the protocol will take place without prior agreement from 
NantKwest and documented approval from the IRB, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
Principal Investigator:  
 
Signed: _____________________________________ Date: ______________ 
 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
NantKwest, Inc. 
Name of Investigational Products: 
1. Aldoxorubicin hydrochloride (HCl) 
2. ETBX-011 (adenovirus serotype-5 [Ad5] [E1-, E2b-]-carcinoembryonic antigen [CEA] vaccine) 
3. ETBX-021 (Ad5 [E1-, E2b-]-human epidermal growth factor receptor 2 [HER2] vaccine) 
4. ETBX-051 (Ad5 [E1-, E2b-]-Brachyury vaccine) 
5. ETBX-061 (Ad5 [E1-, E2b-]-mucin 1 [MUC1] vaccine)  
6. GI-4000 (RAS yeast vaccine) 
7. GI-6207 (CEA yeast vaccine) 
8. GI-6301 (Brachyury yeast vaccine)  
9. haNK™, NK-92 [CD16.158V, ER IL-2], Suspension for Infusion (haNK™ for Infusion) 
10. N-803 (also known as ALT-803; recombinant human superagonist interleukin-15 (IL-15) 
complex [also known as IL-15N72D:IL-15RαSu/IgG1 Fc complex]) 
Name of Approved Products: 
11. Avelumab (BAVENCIO® injection, for intravenous [IV] use) 
12. Capecitabine (XELODA® tablets, for oral use) 
13. Cetuximab (ERBITUX® injection, for IV infusion) 
14. Cyclophosphamide (Cyclophosphamide Capsules, for oral use; or Cyclophosphamide Tablets, 
USP) 
15. 5-Fluorouracil (5-FU; Fluorouracil Injection, for IV use only) 
16. Leucovorin (LEUCOVORIN Calcium for Injection, for IV or intramuscular [IM] use) 
17. Nab-paclitaxel (ABRAXANE® for Injectable Suspension [paclitaxel protein-bound particles for 
injectable suspension] [albumin-bound]) 
18. Oxaliplatin (ELOXATIN® injection for IV use) 
19. Regorafenib (STIVARGA® tablets, for oral use) 
20. Stereotactic body radiation therapy (SBRT) 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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Name of Active Ingredients: 
Investigational Products  
1. Aldoxorubicin HCl 
2. Ad5 [E1-, E2b-]-CEA 
3. Ad5 [E1-, E2b-]-HER2 
4. Ad5 [E1-, E2b-]-Brachyury 
5. Ad5 [E1-, E2b-]-MUC1  
6. GI-4014 expressing mutations in RAS at codon 12 (G12V), and codon 61 (Q61R and Q61L); 
GI-4015 expressing mutations in RAS at codon 12 (G12C), and codon 61 (Q61R and Q61L); 
GI-4016 expressing mutations in RAS at codon 12 (G12D) and codon 61 (Q61R and Q61L) and 
GI-4020 expressing mutations in RAS at codon 12 (G12R) and codon 61 (Q61L and Q61H) 
7. Recombinant yeast based vaccine expressing the full length human carcinoembryonic antigen 
(CEA), with a modified gene coding sequence to code for a single amino acid substitution 
(asparagine to aspartic acid) at the native protein amino acid position 610 
8. Recombinant yeast based vaccine expressing the human Brachyury oncoprotein  
9. NK-92 [CD16.158V, ER IL2] cells 
10. N-803, recombinant human superagonist interleukin-15 (IL-15) complex (also known as 
IL-15N72D:IL-15RαSu/IgG1 Fc complex)  
Approved Products 
11. Avelumab 
12. Capecitabine 
13. Cetuximab 
14. Cyclophosphamide (anhydrous) 
15. Fluorouracil, USP 
16. Leucovorin (calcium salt) 
17. Paclitaxel, USP 
18. Oxaliplatin, USP 
19. Regorafenib 
20. Radiation 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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Title of Study: 
NANT Colorectal Cancer (CRC) Vaccine: A phase 1b/2 trial of the NANT CRC Vaccine vs. regorafenib 
in subjects with metastatic CRC who have been previously treated with standard-of-care (SoC) therapy 
Study Number: 
QUILT-3.071 
Study Phase: 
Phase 1b/Phase 2 (randomized and single-arm [using Simon’s two-stage optimal design]) 
Study Objectives: 
Phase 1b 
• 
The primary objective is to evaluate the overall safety profile of the NANT CRC Vaccine 
regimen in subjects with recurrent or metastatic CRC who have been previously treated with 
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 responses, and 
molecular changes in circulating tumor DNA (ctDNA) and RNA (ctRNA); and their 
correlations with subject outcomes. 
Phase 2  
Randomized component – The randomized component of the phase 2 portion of the study will compare 
the NANT CRC Vaccine regimen (experimental arm) to regorafenib monotherapy (control arm) in 
subjects with recurrent or metastatic CRC who have previously been treated with SoC therapy that did 
not include regorafenib. 
• The primary objective is to compare efficacy as assessed by PFS using Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 based on Blinded Independent Central 
Review (BICR). 
• 
Secondary objectives are to compare safety and additional measures of efficacy (PFS by 
immune-related response criteria (irRC), ORR, 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 
correlations with subject outcomes. 
Single-arm component – The single-arm component of the phase 2 portion of the study will evaluate the 
NANT CRC Vaccine regimen in subjects with recurrent or metastatic CRC who have previously been 
treated with SoC therapy that included regorafenib. 
• 
The primary objective is to evaluate the efficacy of the NANT CRC Vaccine regimen as 
assessed by ORR using RECIST Version 1.1 based on BICR. 
 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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• 
Secondary objectives are to evaluate safety and additional measures of efficacy (ORR by 
irRC, 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 
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 recurrent or metastatic CRC who have previously received SoC therapy. The phase 2 
portion of the study will consist of both a single-arm component and a randomized component. 
In phase 1b, the NANT CRC Vaccine will be assessed for safety. 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 NANT CRC Vaccine 
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. In total, 6 to 24 subjects will be enrolled in the phase 1b portion of the study. 
In the randomized component of the phase 2 portion, subjects who have received SoC therapy that did not 
include regorafenib for recurrent or metastatic CRC will be randomized to receive either the NANT CRC 
Vaccine (experimental arm) or regorafenib monotherapy (control arm). Randomization will be stratified 
by tumor sidedness (left vs right) and performance status (Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 vs 1). For the control arm of the randomized portion, subjects who progress on or 
after discontinuing regorafenib may be enrolled in the single-arm component described below after a 14-
day washout period.  
The single-arm component of the phase 2 portion will enroll subjects who have progressed or experienced 
unacceptable toxicity on SoC that included regorafenib, and subjects who have progressed on or after 
regorafenib treatment in the randomized phase 2 portion of this study.  
The NANT CRC Vaccine regimen will be administered in 2 phases, an induction and a maintenance 
phase, as described below. Subjects will continue induction treatment for up to 1 year. 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 and Sponsor’s discretion. Subjects may remain in the 
maintenance phase of the study for up to 1 year. 
In the randomized component of the phase 2 portion of the study, the control arm will self-administer 
regorafenib every day for the first 21 days of every 28-day treatment cycle.  
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. Subjects receiving treatment in the 
control arm may cross over to treatment in the induction phase of the experimental arm after experiencing 
PD. Subjects receiving treatment in the experimental arm with an initial assessment of PD per RECIST 
Version 1.1 may, at the discretion of the Investigator, continue to receive study treatment until PD is 
confirmed as detailed in Section 6.1.2. The maximum time on study treatment is 2 years. 
Subjects who withdraw from the trial for reasons other than progression are encouraged not to initiate 
another anticancer treatment unless/until progression has been documented at a follow-up visit. 
For all subjects, 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 treatment 
periods (depending on response), as described in Section 6.4.1. Separate blood tubes will be collected 
every 4 weeks (induction phase for experimental arm and year 1 or until CR for control arm) or 8 weeks 


NANT Colorectal Cancer Vaccine 
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Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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(maintenance phase for experimental arm and year 2 or post-CR for control arm) 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 for all subjects. Tumor response will be assessed every 8 weeks 
(induction phase for experimental arm and year 1 or until CR for control arm) or 12 weeks (maintenance 
phase for experimental arm and year 2 or post-CR for control arm) until progression occurs, regardless of 
the treatment administered, by computed tomography (CT) or magnetic resonance imaging (MRI) of 
target and non-target lesions in accordance with RECIST Version 1.1 and irRC. The same mode(s) of 
assessment used to identify/evaluate lesions at screening should be used throughout the course of the 
study unless subject safety necessitates a change (eg, allergic reaction to contrast media). Unscheduled 
tumor assessments should be carried out if the investigator observes any signs or symptoms of PD. When 
disease progression per RECIST Version 1.1 is initially observed for a subject in the experimental arm, 
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 for a subject 
in the experimental arm, 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 subjects exhibiting a 
response (PR or CR), a confirmatory imaging assessment should be done 4–6 weeks after the initial 
response. 
Prospective Tumor Molecular Profiling 
Prospective tumor molecular profiling will be conducted on tumor samples from all subjects receiving the 
NANT CRC Vaccine to inform RAS mutational status, and will be used to determine whether cetuximab 
and the yeast-based vaccine GI-4000 (RAS) will be administered. Subjects will receive cetuximab if their 
tumor is RAS wild-type as determined by whole genome sequencing. Subjects will receive GI-4000 
(RAS) if their tumor is positive for specific RAS mutations, as determined by whole genome sequencing. 
Cetuximab and GI-4000 (RAS) administration will be initiated as soon as results from tumor molecular 
profiling are available. All other agents in the NANT CRC Vaccine regimen will be administered 
regardless of 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 blood is described in Section 6.4.1.2 and is similar to the collection of samples for 
the exploratory tumor molecular profiling.  
NANT CRC Vaccine: Induction Phase 
Treatment in the induction phase will consist of repeated 3-week cycles for a maximum treatment period 
of 1 year, as follows: 
Day 1, every 3 weeks:  
• 
Leucovorin (20 mg/m2 IV bolus) 
• 
Nab-paclitaxel (125 mg IV) 
• 
Oxaliplatin (40 mg/m2 IV) 
Days 1–5, every 3 weeks: 
• 
Cyclophosphamide (25 mg by mouth [PO] twice a day [BID]) 
• 
5-FU (1500 mg/m2 continuous IV infusion over 85–96 hours) 
• 
 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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Day 5 (± 1 day), every 3 weeks for 3 cycles then every 9 weeks thereafter:  
• 
Ad5-based vaccines: ETBX-011 (CEA), ETBX-021 (HER2), ETBX-051 (Brachyury), and 
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 (RAS) will be 
administered, as described above. 
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 
≤ 4 cycles) 
Days 8–12, every 3 weeks: 
• 
Cyclophosphamide (25 mg PO daily) 
Day 9, every 3 weeks: 
• 
Avelumab (10 mg/kg IV) 
• 
haNK (2 × 109 cells/dose IV) 
• 
N-803 (15 μg/kg SC) 
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 
≤ 4 cycles) 
Day 16, every 3 weeks:  
• 
Cetuximab (250 mg/m2 IV) 
Prospective tumor molecular profiling will determine whether cetuximab will be 
administered, as described above. 
• 
haNK (2 × 109 cells/dose IV) 
NANT CRC Vaccine: 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, as follows: 
Day 1, every 2 weeks:  
• 
Aldoxorubicin HCl (60 mg/m2 IV) 
• 
Nab-paclitaxel (100 mg IV) 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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Days 1, 3, and 5, every 2 weeks: 
• 
Capecitabine (650 mg/m2 PO BID, up to a maximum of 1,000 mg per dose) 
Days 1–5, every 2 weeks: 
• 
Cyclophosphamide (25 mg PO BID) 
Day 2, every 2 weeks:  
• 
Avelumab (10 mg/kg IV) 
• 
Cetuximab (250 mg/m2 IV) 
Prospective tumor molecular profiling will determine whether cetuximab will be 
administered, as described above. 
• 
haNK (2 × 109 cells/dose IV) 
• 
N-803 (15 µg/kg SC) 
Day 5 (± 1 day), every 8 weeks thereafter: 
• 
Ad5-based vaccines: ETBX-011 (CEA), ETBX-021 (HER2), ETBX-051 (Brachyury), and 
ETBX-061 (MUC1) (1 × 1011 VP/vaccine/dose SC) 
• 
Yeast-based vaccines: GI-4000 (RAS), GI-6207 (CEA), and GI-6301 (Brachyury)  
(40 YU/vaccine/dose SC) 
Prospective tumor molecular profiling will determine whether GI-4000 (RAS) will be 
administered, as described above. 
Days 8-12, every 2 weeks 
• 
Cyclophosphamide (25 mg PO daily) 
Study Endpoints 
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. 
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. 
• 
ORR by irRC. 
• 
PFS by RECIST Version 1.1. 
• 
PFS by irRC. 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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• 
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. 
Exploratory Endpoints: 
• 
Tumor molecular profiles and correlations with subject outcomes. 
• 
Therapy-induced changes in immune responses and correlations with subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
Phase 2  
Randomized Component 
Primary Endpoint: 
• 
PFS by RECIST Version 1.1. 
Secondary Endpoints: 
• 
PFS by irRC. 
• 
ORR by RECIST Version 1.1 
• 
ORR 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 and 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 subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
Single-Arm Component 
Primary Endpoint: 
• 
ORR by RECIST Version 1.1. 
Secondary Endpoints: 
• 
ORR by irRC. 


NANT Colorectal Cancer Vaccine 
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Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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• 
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 and 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 subject outcomes. 
• 
Molecular changes in ctDNA and ctRNA and correlations with subject outcomes. 
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.  
The phase 2 randomized component of the study is initially planned for 120 subjects to be randomized 
1:1 to the NANT CRC Vaccine regimen or regorafenib monotherapy. During the trial, 120 subjects are 
expected to accrue 96 PFS events. An interim analysis is planned once 50% of the PFS events have 
accrued (48 events). Based on the interim analysis, the study sample size may be increased to a maximum 
of 240 subjects. 
In the phase 2 single-arm component of the study, 27 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 41 subjects will be enrolled in the second stage, for a total of 68 subjects in the 
phase 2 single-arm component of the study.  
The maximum total enrollment for the study is 332 subjects. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Age ≥ 18 years. 
2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or 
Independent Ethics Committee (IEC) guidelines. 
3. Histologically-confirmed recurrent or metastatic CRC previously treated with fluoropyrimidine-, 
oxaliplatin- and irinotecan-based chemotherapy. These chemotherapy regimens may or may not 
have included an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. 
Subjects who are ineligible or have declined these therapies may also be enrolled. 
4. ECOG performance status of 0 or 1. 
5. Have at least 1 measurable lesion of ≥ 1.0 cm. 
6. Must have a recent formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimen following 


NANT Colorectal Cancer Vaccine 
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Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
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the conclusion of the most recent anticancer treatment 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. 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. 
7. Must be willing to provide blood samples prior to the start of treatment on this study for 
prospective tumor molecular profiling and exploratory analyses. 
8. Must be willing to provide a tumor biopsy specimen 8 weeks after the start of treatment for 
exploratory analyses, if considered safe by the Investigator. 
9. Ability to attend required study visits and return for adequate follow-up, as required by this 
protocol. 
10. 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. 
Phase 2 single-arm component only 
11. Must have progressed on or after regorafenib treatment in the randomized phase 2 portion of the 
study OR progressed or experienced unacceptable toxicity on SoC and regorafenib prior to 
enrollment on the study. 
Exclusion Criteria: 
1. Microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient tumors eligible for, but 
not yet treated with, a PD-1 inhibitor. 
2. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational 
drugs used in this study or that would put the subject at high risk for treatment-related 
complications. 
3. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, 
or autoimmune disease associated with lymphoma).  
4. History of organ transplant requiring immunosuppression.  
5. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). 
6. Inadequate organ function, evidenced by the following laboratory results: 
a. Absolute neutrophil count (ANC) < 1,000 cells/mm3. 
b. Uncorrectable grade 3 anemia (hemoglobin < 8 g/dL). 
c. Platelet count < 75,000 cells/mm3. 
d. Total bilirubin greater than the upper limit of normal (ULN; unless the subject has 
documented Gilbert’s syndrome). 
e. Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) 
> 2.5 × ULN (> 5 × ULN in subjects with liver metastases). 


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f. Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver 
metastases, or >10 × ULN in subjects with bone metastases). 
g. Serum creatinine > 2.0 mg/dL or 177 μmol/L. 
h. Serum anion gap > 16 mEq/L or arterial blood with pH < 7.3. 
7. 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. Subjects with uncontrolled hypertension should be medically managed on a stable 
regimen to control hypertension prior to study entry. 
8. Serious myocardial dysfunction defined by echocardiogram (ECHO) as absolute left ventricular 
ejection fraction (LVEF) 10% below the institution’s lower limit of predicted normal. 
9. Dyspnea at rest due to complications of advanced malignancy or other disease requiring 
continuous oxygen therapy. 
10. Positive results of screening test for human immunodeficiency virus (HIV). 
11. 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. 
12. Known hypersensitivity to any component of the study medication(s). 
13. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction 
with any of the study medications. 
14. 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. 
15. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8 inducer 
(rifampin) within 14 days before study day 1. 
16. Participation in an investigational drug study or history of receiving any investigational treatment 
within 30 days prior to screening for this study, except for testosterone-lowering therapy in men 
with prostate cancer. 
17. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the 
protocol. 
18. Concurrent participation in any interventional clinical trial. 
19. Pregnant and nursing women. 
Phase 2 randomized component only 
20. Prior regorafenib treatment. 


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Products, Dosage, and Mode of Administration: 
Investigational Products 
Dosage 
Mode of Administration 
Aldoxorubicin HCl 
100 mg/m2 (induction); 
60 mg/m2 (maintenance) 
IV 
ETBX-011 (CEA) 
1 × 1011 VP/dose  
SC 
ETBX-021 (HER2) 
1 × 1011 VP/dose  
SC 
ETBX-051 (Brachyury) 
1 × 1011 VP/dose  
SC 
ETBX-061 (MUC1) 
1 × 1011 VP/dose  
SC 
GI-4000 (RAS) 
40 YU/dose 
SC 
GI-6207 (CEA) 
40 YU/dose 
SC 
GI-6301 (Brachyury) 
40 YU/dose 
SC 
haNK  
2 × 109 cells/dose  
IV 
N-803 
15 µg/kg  
SC 
Approved Products 
Dosage 
Mode of Administration 
Avelumab 
10 mg/kg 
IV 
Capecitabine 
650 mg/m2 BID up to a maximum of 
1000 mg per dose 
PO 
Cetuximab 
250 mg/m2 
IV 
Cyclophosphamide  
25 mg BID (days 1-5) 
25 mg daily (days 8-12) 
PO 
5-FU 
1500 mg/m2  
85- to 96-hour continuous IV 
infusion 
Leucovorin  
20 mg/m2  
IV bolus 
Nab-paclitaxel  
125 mg (day 1 of induction);  
100 mg (day 15 of induction and day 
1 of maintenance) 
IV 
Oxaliplatin 
40 mg/m2 
IV 
Regorafenib 
160 mg 
PO 
SBRT 
8 Gy maximum (exact dose to be 
determined by the radiation 
oncologist) 
External beam radiation 


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Duration of Treatment: 
NANT CRC Vaccine (Experimental Arm) 
• 
Induction phase: 8 weeks (minimum) to 1 year (maximum) 
• 
Maintenance phase: Up to 1 year 
Subjects will be treated for up to 2 years (up to 1 year in each treatment phase), or until they experience 
confirmed PD or unacceptable toxicity (not correctable with dose reduction), withdraw consent, or if the 
Investigator feels it is no longer in their best interest to continue treatment. 
Regorafenib (Control Arm) 
Subjects will be treated for up to 2 years, or until they experience PD or unacceptable toxicity 
(not correctable with dose reduction), withdraw consent, or if the Investigator feels it is no longer in their 
best interest to continue treatment. 
Subjects that experience PD on or after treatment with regorafenib in the phase 2 randomized component 
of the study may be subsequently treated with the NANT CRC Vaccine in the phase 2 single-arm 
component of the study. 
Duration of Follow-up:  
Subjects who discontinue study treatment should remain in the study and continue to be followed for: 
• 
CT or MRI imaging and response assessments (see Section 6.1.2). 
• 
Collection of vital status every 90 days (± 14 days). 
Subjects should be followed until either death (any cause) or for a minimum of 24 months past 
administration of the first dose of study drug. 
Reference Therapy, Dosage, and Mode of Administration: 
Regorafenib:  
Regorafenib treatment will consist of repeated 4-week cycles for a maximum treatment period of 2 years, 
as follows: 
Days 1-21, every 4 weeks:  
• 
Regorafenib (160 mg PO) 


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Evaluation of Endpoints: 
Safety:  
Safety endpoints include assessments of treatment-emergent AEs, SAEs, and clinically significant 
changes in safety laboratory tests, physical examinations, electrocardiograms (ECGs), echocardiograms 
(ECHOs), and vital signs. All subjects will be evaluable for toxicity from the time of their first study 
treatment. Toxicities will be graded using the NCI CTCAE Version 4.03. 
Efficacy: 
PFS and ORR will be assessed by CT or MRI of target and non-target lesions every 8 or 12 weeks until 
progression occurs regardless of the treatment administered and will be evaluated in accordance with 
RECIST Version 1.1 and irRC. In order to document PD, unscheduled tumor assessments may be done if 
the investigator observes any signs and symptoms of PD. For responding subjects (PR or CR), a 
confirmatory response assessment should be done at 4–6 weeks after the initial response. 
OS, DOR, and DCR will also be assessed. 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. 
An assessment of QoL will be conducted via PROs using the Functional Assessment of Cancer 
Therapy-Colorectal Cancer (FACT-C) instrument. Assessments will occur at screening and prior to 
treatment on day 1, every 4 or 12 weeks thereafter, and at the end-of-treatment (EOT) visit.  
Exploratory Analyses: 
Tumor Molecular Profiling: Genomic sequencing of tumor cells from tissue relative to non-tumor cells 
from whole blood will be conducted to identify tumor-specific genomic variances that may contribute to 
disease progression and/or response to treatment. RNA sequencing will be conducted to provide 
expression data and give relevance to DNA mutations. Quantitative proteomics analysis will be 
conducted to determine the absolute amounts of specific proteins, to confirm expression of genes that are 
correlative of disease progression and/or response, and to determine the cutoff values for response. 
Immunologic Analysis: Immune responses to the NANT CRC Vaccine regimen and regorafenib 
monotherapy will be evaluated by standard immune assays. Correlations between therapy-induced 
immune changes and subject outcomes will be assessed. 
ctDNA/ctRNA Analysis: ctDNA and ctRNA will be extracted from plasma obtained from whole blood. 
Expression levels of specific tumor- and immune-related analytes will be assessed by quantitative 
real-time polymerase chain reaction (qPCR) and possibly other methods (eg, DNA/RNA sequencing) and 
analyzed for correlations with subject outcomes. 


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Statistical Methods: 
This phase 1b/2 study will evaluate the safety and efficacy of metronomic combination therapy in 
subjects with recurrent or metastatic CRC who have failed SoC therapy. 
Six to 24 subjects will be enrolled in the phase 1b portion of the study. 
In the phase 2 single-arm component of the study, ORR based on RECIST Version 1.1 will be evaluated 
using Simon’s two-stage optimal design.  
The phase 2 randomized component of the study is initially planned for 120 subjects to be randomized 
1:1 to the NANT CRC vaccine regimen or regorafenib monotherapy. A total of 120 subjects are expected 
to accrue 96 PFS events during the trial with a 12-month enrollment period and 12 months of follow-up 
after the last subject is enrolled. Based on median PFS of 2 and 4 months for regorafenib and the 
NANT CRC Vaccine, respectively, a 20% lost-to-follow-up rate, and a 5% type 1 error, 120 subjects with 
96 PFS events has a power of 90% to detect a hazard ratio (HR) of 0.50. 
In the phase 2 randomized component of the study, an interim analysis is planned once 50% of the PFS 
events have accrued (48 events). The Lan DeMets/O’Brien Fleming spending function will be used for 
the interim analysis which allocates a 0.3% and 4.9% type 1 error rate to the interim and final PFS 
analyses, respectively. The trial may be stopped early for strong efficacy if the interim PFS analysis 
shows superiority (ie, p < 0.003). The trial may be stopped early for futility if the interim PFS analysis 
displays a conditional power < 15%. Based on the interim PFS analysis, the study sample size for the 
randomized phase 2 component may be increased to a maximum of 240 subjects using the “Promising 
Zone” methodology for an adaptive sample size increase.  
The interim analysis will be performed by an independent statistician separate from the study team. The 
interim analysis results will not be shared with the study team during the conduct of the study. The 
interim analysis results will be presented to the Independent Data Monitoring Committee (IDMC) who 
will make recommendations to the study team whether to stop the study for efficacy or futility, or 
increase the study sample size. For the NANT CRC Vaccine regimen, safety results will be presented 
separately for the induction and maintenance phases of treatment as well as overall for the entire 
treatment regimen. For the regorafenib treatment, safety results will be presented for the entire treatment 
regimen. Efficacy results will be summarized for the overall treatment regimens. 
Overall safety will be assessed by descriptive analyses using tabulated frequencies of AEs by grade using 
CTCAE version 4.03 in terms of treatment-emergent AEs, SAEs, and clinically significant changes in 
safety laboratory tests, physical examinations, ECGs, ECHOs, and vital signs. 
PFS will be analyzed using Kaplan-Meier methods. The median PFS (and 95% confidence interval [CI]) 
will be summarized. PFS Kaplan-Meier curves will be presented. For the phase 2 randomized component, 
comparison of PFS between the NANT CRC Vaccine regimen and the control treatment will be based on 
the stratified log-rank test, stratified by tumor sidedness and performance status. PFS assessed by 
RECIST Version 1.1 will be the primary PFS analysis and PFS assessed by irRC will be a secondary 
analysis. 
OS and DOR will be analyzed in the same manner as PFS. 
ORR (and 95% CI) will be summarized. For the phase 2 randomized component, comparison of ORR 
between the NANT CRC Vaccine regimen and the control treatment will be based on the stratified Fisher 
exact test, stratified by tumor sidedness and performance status. ORR assessed by RECIST Version 1.1 
will be the primary ORR analysis and ORR assessed by irRC will be a secondary analysis. 
DCR will be analyzed in the same manner as ORR.  
Descriptive statistics of PROs will be presented. 
Correlations of tumor molecular profiles, therapy-induced changes in immune responses, and molecular 
changes in ctDNA and ctRNA with subject outcomes will be explored. 


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Figure 1: 
Study Treatment Schema 
 


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Figure 2: 
Induction Phase Treatment Schema for NANT CRC Vaccine 
 


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Figure 3: 
Maintenance Phase Treatment Schema for NANT CRC Vaccine 
 


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Table 18: 
Schedule of Events for NANT CRC Vaccine Induction Phase of Study 
 
Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
General Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusiond 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm availability 
of FFPE tumor 
samplef 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Physical exam: 
height, weightg 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Vital signsh 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
ECOG performance 
status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
12-lead ECGi 
X 
Xj 
Every 4 weeks 
X 
 
ECHO (with 
ejection fraction) 
X 
Xj  
Every 12 weeks 
X 
 
Confirm 
contraceptive 
measures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-C 
Questionnaire 
X 
X 
Every 4 weeks 
X 
 
Adverse event 
collection 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
X 


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Screening 
Induction Phase Treatment (repeats every 3 weeks, except where noted)a 
 
 
Study Week 
 
1 
2 
3 
EOT 
Visitb 
Unscheduled 
Visitc 
Study Day 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
 
 
Laboratory Assessments 
Chemistry panelk 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CEA 
X 
X
j 
Every 4 weeks 
X 
 
Hematologyl 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis 
X 
X
j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Pregnancy test m 
X 
X
j 
Every 4 weeks 
X 
 
Serum virology 
(HIV)n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine HER2 
expression and RAS 
mutational statuso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect whole blood 
for tumor molecular 
profilingp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect whole blood 
for immunology 
analysisq 
X 
Every 4 weeks during routine blood draws 
X 
 
Collect whole blood 
for ctDNA/ctRNA 
analysisq 
X 
Every 4 weeks during routine blood draws 
X 
 
Collect historic 
tumor biopsy 
specimen for tumor 
molecular profilingr 
X 
 
 
 
Tumor biopsyr 
X 
8 weeks after the start of treatment 
 
 
Additional tumor 
biopsy 
 
May be collected at any time point, as clinically indicated at the Investigator’s discretion. 
 
 
Tumor Imaging and Assessments 
CT or MRIs
 
X 
Every 8 weeks 
X 
 


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a Subjects will remain in the induction phase of the study for up to 1 year. Treatment will continue in the induction phase until the subject experiences confirmed 
PD or 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. Those who have a CR in the induction phase will enter the maintenance phase of the study. Subjects who experience ongoing SD or an 
ongoing PR at 1 year may enter the maintenance phase at the Investigator’s and Sponsor’s discretion. Any required laboratory sample collection 
(eg, blood draws, urinalysis) may be performed within a 3-day window of the time indicated. Subjects crossing over to treatment with the NANT CRC Vaccine 
in the single-arm phase 2 component of the study following disease progression on or after discontinuing regorafenib in the randomized phase 2 component of 
the study will have a minimum 14-day washout period between the last regorafenib treatment and the first NANT CRC Vaccine treatment. Patients who 
crossover will begin at day 1 of the above schedule, except that relevant new medical history will be collected. Tumor imaging does not need to be performed on 
day 1 for crossover patients if they have had an imaging assessment within the last 28 days. 
b End-of-treatment visit must be performed 30 (±5 days) after the last study treatment. 
c Additional assessments performed during an unscheduled visit are at the discretion of the Investigator or treating physician and must be recorded in the 
subject’s source documents and on the Unscheduled Visit eCRF. 
d Inclusion/exclusion criteria will also be evaluated at enrollment. 
e Medical history will also be evaluated at enrollment. 
f Subject’s FFPE tumor tissue sample must be obtained following the conclusion of the most recent anticancer treatment and prior to first study treatment. If not 
available, a fresh tumor biopsy must be performed, if considered safe by the Investigator. In the event a fresh biopsy needs to be scheduled, the site may 
consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to the first dose of any study 
drug. 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. 
g Height required at screening visit only. Weight on day 1 of each treatment cycle should be used to calculate drug doses. 
h Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes and within 30 minutes prior to the start of any infusional study treatment. For visits where a subject is 
receiving an infusion of any study compounds, vital signs will be collected at the following time points in relation to the start of first infusion of the day: prior 
to infusion, 15 minutes post, 30 minutes post, and hourly until the subject is discharged. Temperature will be documented each visit at the first pre-infusion 
assessment of vital signs and subsequently if clinically indicated. Assessment of vital signs and AEs on day 15 is required only if study treatment is 
administered on that day. 
i 12-lead ECG to be performed in triplicate at screening. 
j Day 1 assessments can be skipped if the screening assessment was performed within 1 week prior to the start of treatment. For ECG and ECHO assessments 
only, day 1 assessments can be skipped if the screening assessment was performed within 28 days prior to the start of treatment. 
k Chemistry panel to include laboratory assessments noted in Table 17. 
l Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
m Serum pregnancy tests for females of child-bearing potential. 
n HIV status to be determined by an approved test. 
o Assessment of RAS mutational status to determine whether GI-4000 (RAS) will be administered to the subject, as described in Section 3.1.1. Assessment of
HER2 positivity may be conducted as soon as tumor tissue is available, and results from this assessment will not affect the drug regimen administered to
subjects in this study.
p Whole blood for tumor molecular profiling will be collected during the screening period for subjects who have been enrolled in the study. 
q Whole blood for immunology and ctDNA/ctRNA analyses will be collected during the screening period for subjects who have been enrolled in the study, every 
4 weeks in the induction phase during routine blood draws, and at the EOT visit. 


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r Historic tumor biopsy specimen for tumor molecular profiling is required to determine eligibility for participation in the study. If an historic specimen is not 
available, a fresh tumor biopsy must be performed, 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. In the event a fresh biopsy needs to be 
scheduled, the site may consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to 
the first dose of any study medications. A tumor biopsy is also required 8 weeks after the start of treatment, if considered safe by the Investigator. 
s Tumor imaging by CT or MRI will be performed at screening and every 8 weeks during the induction phase, as described in Section 6.1.2. All screening tumor 
imaging assessments should be performed based on the subject's qualifying scan obtained within 28 days prior to the start of treatment. RECIST and irRC 
documentation are to be completed at each assessment period. 
 


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Table 19: 
Schedule of Events for NANT CRC Vaccine Maintenance Phase of Study 
 
Maintenance Phase Treatment (repeats every 2 weeks, except where noted)a 
 
 
Study Week 
1 
2 
EOT Visitb 
Unscheduled 
Visitc 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Physical exam, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital signsd 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
X 
Every 12 weeks 
X 
 
ECHO (with ejection 
fraction) 
X 
Every 12 weeks 
X 
 
Confirm contraceptive 
measures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event collection 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
FACT-C questionnaire 
X 
Every 12 weeks 
X 
 
Laboratory Assessments 
Chemistry panele 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CEA 
X 
Every 12 weeks 
X 
 
Hematologyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testg 
X 
Every 12 weeks 
X 
 
Collect whole blood for 
immunology analysish 
X 
Every 8 weeks during routine blood draws 
X 
 
Collect whole blood for 
ctDNA/ctRNA analysish 
X 
Every 8 weeks during routine blood draws 
X 
 
Additional tumor biopsy 
May be collected at any time point, as clinically indicated at the Investigator’s discretion 
Tumor Imaging and Assessments 
 CT or MRIi 
X 
Every 12 weeks 
X 
 


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a Subjects will remain in the maintenance phase of the study for up to 1 year. Treatment will continue in the maintenance phase until the subject experiences 
confirmed PD or 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. Any required laboratory sample collection (eg, blood draws, urinalysis) may be performed within a 3-day window of the time 
indicated. 
b EOT visit must be performed 30 (±5 days) after the last study treatment. 
c Additional assessments performed during an unscheduled visit are at the discretion of the PI or treating physician and must be recorded in the subject’s source 
documents and on the Unscheduled Visit eCRF. 
d Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes. For visits where a subject is receiving an infusion of any study compounds, vital signs will be collected at the 
following time points in relation to the start of first infusion of the day: prior to infusion, 15 minutes post, 30 minutes post, and hourly until the subject is 
discharged. Temperature will be documented each visit at the first pre-infusion assessment of vital signs and subsequently if clinically indicated. 
e Chemistry panel to include laboratory assessments noted in Table 17. 
f Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
g Serum pregnancy test for females of child-bearing potential. 
h Blood collection for exploratory immunology and ctDNA/ctRNA analyses will be performed every 8 weeks in the maintenance phase during routine blood 
draws and at the end-of-treatment visit.  
i Tumor imaging by CT or MRI will continue to be performed every 12 weeks during the maintenance phase of treatment, as described in Section 6.1.2. RECIST 
and irRC documentation to be completed at each assessment period. 
 


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Table 20: 
Regorafenib Control Arm – Schedule of Events 
 
Screening  
(days -28 to -1) 
On day 1 of each weeka 
EOT Visitb 
Unscheduled 
Visitc 
Weeks 1-8 
Weeks 13-52  
Weeks 53-104  
 
 
Frequency of Assessment 
 
 
General Assessments 
 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusiond 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical historyd 
X 
 
 
 
 
 
Confirm availability of FFPE tumor 
samplee 
X 
 
 
 
 
 
Confirm contraceptive measures 
X 
 
 
 
 
 
Concomitant medications 
X 
Weekly 
Every 4 weeks 
X 
X 
Physical exam: heightf, weight 
X 
Weekly 
Every 4 weeks 
X 
X 
Vital signsg 
X 
Weekly 
Every 4 weeks 
X 
X 
Adverse event collection 
 
Weekly 
Every 4 weeks 
X 
X 
ECOG performance status 
X 
Weekly 
Every 4 weeks 
X 
 
12-lead ECGh 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
FACT-C Questionnaire 
X 
Every 4 weeks 
Every 12 weeks 
X 
 
Laboratory Assessments 
Serum virology (HIV)j 
X 
 
 
 
 
 
Collect whole blood for tumor molecular 
profilingk 
X 
 
 
 
 
 
Collect historic tumor biopsy specimen for 
tumor molecular profilingl 
X 
 
 
 
 
 
Chemistry panelm 
X 
Weeklyi 
Every 4 weeks 
X 
 


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Screening  
(days -28 to -1) 
On day 1 of each weeka 
EOT Visitb 
Unscheduled 
Visitc 
Weeks 1-8 
Weeks 13-52  
Weeks 53-104  
Hematologyn 
X 
Weeklyi 
Every 4 weeks 
X 
 
Urinalysis 
X 
Weeklyi 
Every 4 weeks 
X 
 
Pregnancy testo 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
CEA 
X 
Every 4 weeksi 
Every 12 weeks 
X 
 
Collect whole blood for immunology 
analysisp 
X 
Every 4 weeks  
Every 8 weeks 
X 
 
Collect whole blood for ctDNA/ctRNA 
analysis (during routine blood draws)p 
X 
Every 4 weeks 
Every 8 weeks 
X 
 
Tumor biopsyl 
X 
8 weeks after 
the start of 
treatment 
 
 
 
 
Additional tumor biopsy 
 
May be collected at any time point, as clinically 
indicated at the Investigator’s discretion. 
 
 
Tumor Imaging and Assessments 
CT or MRIq 
X 
Every 8 weeks 
Every 12 weeks 
X 
 
a Treatment will continue until the subject experiences PD or 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. Those subjects who have a CR in the first year will move to the schedule of events for 
year 2. Any required laboratory sample collection listed below (eg, blood draws, urinalysis) may be performed within a 3-day window of the time indicated. 
b End-of-treatment visit must be performed 30 (±5 days) after the last study treatment. Subjects crossing over to treatment with the NANT CRC Vaccine in the 
single-arm phase 2 component of the study following disease progression on or after discontinuing regorafenib in the randomized phase 2 component of the 
study do not need to have an EOT visit as long as they commence treatment with the NANT CRC Vaccine within 30 (± 5 days) of their last regorafenib 
treatment, at which time they will be assessed according to the schedule of events described in Table 18. Crossover patients do not need to undergo screening 
assessments described in Table 18, except for providing any relevant new medical history occurring after enrollment in the trial.  
c Additional assessments performed during an unscheduled visit are at the discretion of the Investigator or treating physician and must be recorded in the 
subject’s source documents and on the Unscheduled Visit eCRF. 
d Also evaluated at enrollment. 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071 Amendment 2 
 
Confidential and Proprietary 
137 
e Subject’s FFPE tumor tissue sample must be obtained following the conclusion of the most recent anticancer treatment and prior to first study treatment. If not 
available, a fresh tumor biopsy must be performed, if considered safe by the Investigator. In the event a fresh biopsy needs to be scheduled, the site may 
consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to the first dose of any study 
drug. 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. 
f Height required at screening visit only.  
g Vital signs of temperature, heart rate, blood pressure, and respiratory rate will be assessed at every visit. Vital signs are to be obtained after the subject has been 
in a seated resting position for at least 5 minutes. 
h 12-lead ECG to be performed in triplicate at screening. 
i Day 1 assessments can be skipped if the screening assessment was performed within 1 week prior to the start of treatment. For ECG only, day 1 assessment can 
be skipped if the screening assessment was performed within 28 days prior to the start of treatment. 
j HIV status to be determined by an approved test. 
k Whole blood for tumor molecular profiling will be collected during the screening period for subjects who have been enrolled in the study. 
l Historic tumor biopsy specimen for tumor molecular profiling is required to determine eligibility for participation in the study. If an historic specimen is not 
available, a fresh tumor biopsy must be performed, 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. In the event a fresh biopsy needs to be 
scheduled, the site may consent the subject and schedule the screening visit assessments to be performed such that all assessments fall within 28 days prior to 
the first dose of any study medications. A tumor biopsy is also required 8 weeks after the start of treatment, if considered safe by the Investigator. 
m Chemistry panel to include laboratory assessments noted in Table 17. 
n Hematology to include CBC with differential (5 part) and platelets with hemoglobin and hematocrit. 
o Serum pregnancy tests for females of child-bearing potential  
p Blood collection for exploratory immunology and ctDNA/ctRNA analyses will be performed every 4 weeks (year 1or prior to CR) or 8 (year 2 or after CR) 
weeks during routine blood draws and at the end-of-treatment visit.  
q All screening tumor imaging assessments should be performed based on the subject's qualifying scan obtained within 28 days prior to the start of treatment. 
RECIST and irRC documentation are to be completed at each assessment period. 
 


NANT Colorectal Cancer Vaccine 
NantKwest, Inc. 
Clinical Trial Protocol: QUILT-3.071Amendment2 
APPENDIX 1. 
SPONSOR SIGNATURE 
Study Title: 
NANT Colorectal Cancer (CRC) Vaccine: A phase lb/2 trial of 
the NANT CRC vaccine vs. regorafenib in subjects with metastatic 
CRC who have been previously 
with standard-of-care 
(SoC) therapy 
Study Number: 
QUILT-3.071 
Version Number: 
3 
Final Date: 
28 September 2018 
This clinical trial protocol was subject to critical review and has been approved by NantKwest. 
The following personnel contributed to writing and/or approving this protocol: 
. Lee, MD 
nior Vice President Adult Medical Affairs, 
NantKwest Inc. 
9920 Jefferson Blvd 
Culver City, CA 90232 
Email: John.Lee@NantKwest.com 
Cell Phone: + 1-605-610-6391 
Confidential and Proprietary 
172 
Date: Cf-)g- tB