Conditions: Cancer Solid Tumor Ovarian Cancer Peritoneal Cancer Fallopian Tube Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 1
Healthy volunteers: no

Brief summary:
To determine the maximum tolerated dose (MTD) of FT538 monotherapy when administered via intraperitoneal (IP) catheter and in combination with intravenous (IV) enoblituzumab in patients with recurrent ovarian, fallopian tube, and primary peritoneal cancer.

Detailed description:

Arms:
arm 1: Level -1: IP FT538 monotherapy 5 x 10\^7 cells/dose Level 1: IP FT538 monotherapy 1 x 10\^8 cells/dose Level 2: IP FT538 monotherapy 3 x 10\^8 cells/dose Level 3: IP FT538 monotherapy 1 x 10\^9 cells/dose Level 4: IP FT538 monotherapy 1.5 x 10\^9 cells/dose arm 2: Level 5: IP FT538 at the safe dose (MTD-1) + Enoblituzumab Level 6: IP FT538 at the highest dose (MTD) + Enoblituzumab

Interventions: intervention 1: FT538 intervention 2: Enoblituzumab
Intervention descriptions: intervention 1: FT538 IP at assigned dose level on Day 1, Day 8, and Day 15. intervention 2: Enoblituzumab 15 mg/kg IV begin on Day -6 and continuing once every 3 weeks beginning on Day 22 until disease progression or unacceptable toxicity - refer to Section 7.2.1 for timing of the enoblituzumab dose on Day 22 if steroid pre-meds are needed due to an infusion reaction with the 1st enoblituzumab dose as there is a 14 day ban on corticosteroid use after the last dose of FT538

Protocol document:
Prot_SAP_000.pdf: 
Masonic Cancer Center, University of Minnesota 
Cancer Experimental Therapeutics Initiative (CETI) 
 
Intraperitoneal FT538 with Intravenous Enoblituzumab in Recurrent 
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer  
CPRC # 2021LS103 
MT2021-27 
MacroGenics # ECT-MGA271-02 
IND 28294 
 
University of Minnesota 
Principal Investigator/IND Sponsor: 
Melissa A Geller, MD 
Department of Obstetrics and Gynecology 
420 Delaware Street SE MMC 395 
Minneapolis, MN 55455 
Phone: 612 626-3111  
Email: gelle005@umn.edu 
 
 
Collaborators: 
Jeffrey S Miller, MD* 
David H McKenna, Jr., MD* 
*Will not consent patients to enroll on study 
 
 
Biostatistician: 
Qing Cao, MS 
 
 
Version Date: 
September 9, 2022 
Confidential 
 
 
 
 


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Revision History 
 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
 
Mar 4 2022 
Original to FDA 
n/a 
 
May19 2022 
Initial version to the CPRC: 
In response to FDA Clinical Information Request #1: 
 Increase Stage 1 Step 1 patient cohort size from 1 patient to 2, 
increase minimum enroll from 19 to 22 
 Synopsis and Section 5.1: New inclusion criteria:  
o Prior treatment with bevacizumab 
o If BRCA positive, must have failed a prior PARP inhibitor 
 Section 9.2: in risks of drugs similar to enoblituzumab, clarify 
hormone gland problems as hypothyroidism and adrenal insufficiency 
Other edits and clarifications: 
 Expanded the definition (Italic language is new or updated wording) 
of the pre-defined AE as occurring in either of the 2 patients 
(previously 1 patient) and clarified Grade 3 abdominal pain within 28 
days of the 1st dose lasting more than 48 despite treatment with 
standard analgesics or Grade 3 infusion related reaction within 24 
hours after the 1st FT538 infusion or the 1st dose of enoblituzumab 
and symptoms resolved to baseline within 12 hours. 
 Delete pharmacodynamics of peritoneal fluid from correlative 
objectives as could not be performed in previous study.  
 Section 7.4.2 – add product administration guidelines. 
  
yes 
1 
Sep 9 2022 
Prior to patient enrollment: 
 Synopsis and Section 5.1: Clarified the intent of inclusion criterion for 
participants with BRCA mutations to state they must have received 
and not failed a prior PARP inhibitor.  
n/a 
 
 
 
 
 
 


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Table of Contents 
 
Revision History .......................................................................................................................................... 2 
Table of Contents ....................................................................................................................................... 3 
Key Abbreviations ...................................................................................................................................... 7 
Protocol Synopsis....................................................................................................................................... 8 
Study Schema........................................................................................................................................... 10 
1 
Objectives .......................................................................................................................................... 12 
1.1 
Primary Objective ..................................................................................................................... 12 
1.2 
Secondary Objectives .............................................................................................................. 12 
1.3 
Correlative (or Exploratory) Objectives ................................................................................. 12 
2 
Background and Significance ......................................................................................................... 12 
2.1 
Background ............................................................................................................................... 13 
2.2 
Natural Killer (NK) Cells .......................................................................................................... 14 
2.2.1 
Natural Killer Cells as Immunotherapy .......................................................................... 14 
2.2.2 
Experience in Delivery of NK Cell Therapy .................................................................. 15 
2.3 
FT538 ......................................................................................................................................... 16 
2.3.1 
Development of FT538 .................................................................................................... 16 
2.3.2 
Summary of Clinical Data ................................................................................................ 17 
2.3.3 
Summary of Nonclinical Data ......................................................................................... 18 
2.4 
Lymphodepletion with Cyclophosphamide and Fludarabine ............................................. 19 
2.5 
Enoblituzumab .......................................................................................................................... 19 
3 
Study Rationale ................................................................................................................................ 20 
3.1 
The Use of Intraperitoneal Administration in Gynecologic Cancers ................................. 20 
3.2 
Rationale for Using FT538 IP Dosing .................................................................................... 20 
3.3 
Rationale for Lymphodepleting Conditioning ....................................................................... 22 
3.4 
Rationale for Retreatment with FT538 .................................................................................. 22 
3.5 
Rationale for Using Enoblituzumab ....................................................................................... 22 
4 
Study Design ..................................................................................................................................... 23 
5 
Patient Selection ............................................................................................................................... 26 
5.1 
Inclusion Criteria ....................................................................................................................... 26 
5.2 
Exclusion Criteria ..................................................................................................................... 27 
5.3 
Retreatment Criteria ................................................................................................................. 28 


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6 
Patient Screening and Study Enrollment ...................................................................................... 29 
6.1 
Consent and Study Screening Registration ......................................................................... 29 
6.2 
Patient Enrollment and Cohort Assignment ......................................................................... 29 
6.3 
Optional 2nd Treatment Course with FT538 (Retreatment) ................................................ 30 
6.4 
Inability to Begin Study Treatment ......................................................................................... 30 
7 
Treatment Plan ................................................................................................................................. 30 
7.1 
Peritoneal Port/Intraperitoneal Catheter Placement (Day – 6 or earlier) ......................... 30 
7.2 
Enoblituzumab (Day -6 then Day 22 and every 3 weeks thereafter) - Cohort 5 and 6 
only 
32 
7.2.1 
Enoblituzumab Pre-Medications and Prophylaxis Guidelines ................................... 32 
7.2.2 
Monitoring During the Enoblituzumab Infusion Period ............................................... 33 
7.2.3 
Management of Enoblituzumab Infusion Related Reactions ..................................... 33 
7.3 
Preparative Regimen (Day -5 and Day -4) ........................................................................... 36 
7.4 
FT538 (Day 1, Day 8, and Day 15) ........................................................................................ 37 
7.4.1 
Decision to Treat on Day of Planned FT538 ................................................................ 37 
7.4.2 
FT538 Intraperitoneal Infusion Guidelines ................................................................... 37 
7.4.3 
Monitoring During and Post-Infusion ............................................................................. 38 
7.4.4 
Potential Risks Associated with FT538 ......................................................................... 39 
7.5 
Monitoring for Dose Limiting Toxicities and Excessive Toxicity ........................................ 42 
7.6 
Supportive Care ........................................................................................................................ 43 
7.7 
Cautionary and Prohibited Therapy ....................................................................................... 43 
7.8 
Duration of FT538 Treatment and Possible Retreatment .................................................. 44 
7.9 
Duration of Enoblituzumab (COHORT 5 or 6 ONLY) ......................................................... 44 
7.10 
Duration of Study Participation ............................................................................................... 44 
8 
Management of Adverse Events Related to FT538 .................................................................... 45 
8.1 
Management Guidelines for Specific FT538 Adverse Events ........................................... 45 
8.1.1 
Acute Allergic/Infusion Reactions .................................................................................. 45 
8.1.2 
Cytokine Release Syndrome or CRS-Like Syndrome ................................................ 47 
8.1.3 
Neurotoxicity ..................................................................................................................... 49 
8.1.4 
Graft versus Host Disease .............................................................................................. 51 
9 
Management of Selected Expected Toxicities Associated with Enoblituzumab (Dose Cohort 
5 and 6) ...................................................................................................................................................... 52 
9.1 
Known Infusion Related Reaction (IRR) to Enoblituzumab ............................................... 52 
9.2 
Most Common Side Effects of Single Agent Enoblituzumab ............................................. 52 


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10 
Schedule of Patient Activities ..................................................................................................... 53 
10.1 
Required Standard of Care Activities Refer to the introduction in Section 10 regarding 
timing of treatment. .............................................................................................................................. 55 
10.2 
Research Related Evaluations ............................................................................................... 57 
10.2.1 
Intraperitoneal (IP) Fluid Collection ............................................................................... 58 
10.2.2 
Tumor Biopsies ................................................................................................................. 59 
10.3 
Retreatment Required Clinical Care and Research Related Evaluations ....................... 59 
11 
Event Monitoring, Documentation, and Reporting .................................................................. 61 
11.1 
Event Terminology ................................................................................................................... 61 
11.2 
Event Monitoring and Documentation Requirements ......................................................... 62 
11.3 
Dose Limiting Toxicity Event/Stopping Rule Documentation and Reporting .................. 63 
11.3.1 
During Fast-Track Enrollment Only ............................................................................... 64 
11.3.2 
Dose Limiting Toxicity (All Patients) .............................................................................. 64 
11.3.3 
Excessive Toxicity (All Patients) .................................................................................... 65 
11.4 
SAE and Death Documentation ............................................................................................. 65 
11.5 
Expedited Reporting Requirements ...................................................................................... 66 
12 
Investigational Product Description, Supply and Potential Toxicities ................................... 66 
12.1 
Enoblituzumab .......................................................................................................................... 66 
12.1.1 
Availability .......................................................................................................................... 67 
12.1.2 
Dosage Forms and Strength .......................................................................................... 67 
12.1.3 
Storage ............................................................................................................................... 67 
12.1.4 
Preparation ........................................................................................................................ 67 
12.1.5 
Warnings and Precautions .............................................................................................. 67 
12.1.6 
Potential Toxicities ........................................................................................................... 68 
12.2 
FT538 ......................................................................................................................................... 69 
12.2.1 
Availability and Storage ................................................................................................... 69 
12.2.2 
Product Labeling ............................................................................................................... 70 
12.2.3 
Route of Administration ................................................................................................... 70 
12.2.4 
FT538 Product Resupply ................................................................................................ 71 
12.2.5 
Potential Risks Associated with FT538 ......................................................................... 71 
13 
Study Data Collection and Monitoring ....................................................................................... 71 
13.1 
Data Management .................................................................................................................... 71 
13.2 
Case Report Forms .................................................................................................................. 71 


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13.3 
Data and Safety Monitoring Plan ........................................................................................... 72 
13.4 
Regular Team Meetings to Review Safety ........................................................................... 72 
13.5 
Record Retention ..................................................................................................................... 73 
14 
Statistical Considerations ............................................................................................................ 73 
14.1 
Study Design, Objectives and Endpoints ............................................................................. 73 
14.2 
Sample Size .............................................................................................................................. 75 
14.3 
Statistical Analysis ................................................................................................................... 75 
14.4 
Monitoring Guidelines (Early Study Stopping Rules) .......................................................... 76 
15 
Conduct of the Study ................................................................................................................... 76 
15.1 
Good Clinical Practice ............................................................................................................. 76 
15.2 
Ethical Considerations ............................................................................................................. 77 
15.3 
Informed Consent ..................................................................................................................... 77 
16 
References .................................................................................................................................... 77 
Appendix I – GOG PS Scale and NYHA Classification ...................................................................... 82 
Appendix II - Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference (CTEP)
 .................................................................................................................................................................... 83 
Appendix III – Risks Associated with Cyclophosphamide and Fludarabine ........................................ 87 
Appendix IV – Management of Clinical Neurotoxicity ......................................................................... 89 
 
 
 


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Key Abbreviations 
Abbreviation 
Definition 
ABW 
actual body weight 
ADCC 
antibody dependent cell-mediated cytotoxicity 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse events of special interest 
ASTCT 
American Society for Transplantation and Cellular Therapy 
CAR 
chimeric antigen receptor 
CFR 
Code of Federal Regulations 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CNS 
central nervous system 
CRM 
continual reassessment method 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
CY/FLU 
cyclophosphamide/fludarabine 
DC 
dose cohort 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DLT 
dose limiting toxicity 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GvHD 
graft-versus-host disease 
IB 
Investigator’s Brochure 
ICANS 
Immune Effector Cell-Associated Neurotoxicity Syndrome 
ICE 
Immune Effector Cell-Associated Encephalopathy 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
IRR 
Infusion related reaction 
IRR/CRS 
infusion related reaction/cytokine release syndrome 
IV 
intravenous 
LTFU 
long-term follow-up 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer 
NYHA 
New York Heart Association 
OS 
overall survival 
PARP 
Poly (ADR-Ribose) Polymerase 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease or disease progression 
PFS 
progression free survival 
PFT 
pulmonary function test 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
standard of care 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TRM  
treatment related mortality 
ULN 
upper limit of normal 
USPI 
United States Prescribing Information 
 


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Protocol Synopsis 
Intraperitoneal FT538 with Intravenous Enoblituzumab in Recurrent Ovarian, Fallopian Tube, and 
Primary Peritoneal Cancer  
Study Design: 
This is a single center Phase I clinical trial of FT538 administered intraperitoneally (IP) once a week for 3 consecutive weeks 
for the treatment of recurrent gynecologic cancers. As this is an early 1st in human study and the 1st intraperitoneal (IP) 
infusion of FT538, the safety of FT538 is confirmed prior to the addition of intravenous (IV) enoblituzumab. Enoblituzumab 
is given on Day-6 prior to the 1st dose of FT538 and every 3 weeks beginning on Day 22 until disease progression or 
unacceptable toxicity. A short course of outpatient lymphodepleting chemotherapy is given before the 1st dose of FT538, 
but after the 1st enoblituzumab infusion for patients assigned to Dose Cohort 5 or Dose Cohort 6. 
 
FT538 is an allogeneic natural killer (NK)-cell immunotherapy produced from a clonal master human-induced pluripotent 
stem cell (iPSC) line with the following engineered elements: a) deletion of the gene encoding CD38 (i.e., CD38 knockout); 
b) high-affinity, non-cleavable CD16 receptor and c) interleukin (IL)-15/IL-15 receptor alpha fusion protein. Enoblituzumab 
is an Fc-optimized monoclonal antibody that targets B7-H3 which is highly expressed on ovarian cancer. 
 
This study is conducted based on the following Dose Cohorts:  
Dose Cohort (DC) 
Treatment Plan 
-1 
IP FT538 monotherapy 5 x 10^7 cells/dose on Day 1, Day 8, and Day 15 
1 (start) 
IP FT538 monotherapy 1 x 10^8 cells/dose on Day 1, Day 8, and Day 15 
2 
IP FT538 monotherapy 3 x 10^8 cells/dose on Day 1, Day 8, and Day 15 
3 
IP FT538 monotherapy 1 x 10^9 cells/dose on Day 1, Day 8, and Day 15 
4 
IP FT538 monotherapy 1.5 x 10^9 cells/dose on Day 1, Day 8, and Day 15 
5 
IP FT538 at the safe dose (MTD-1) from the 1st 4 dose cohorts on Day 1, Day 8, 
and Day 15 plus IV enoblituzumab on Day -6, Day 22, then every 3 weeks until PD  
6 
IP FT538 at the highest dose (MTD) from the 1st 4 dose cohorts on Day 1, Day 8, 
and Day 15 plus IV enoblituzumab on Day -6, Day 22, then every 3 weeks until PD 
For study endpoints, follow-up continues until disease progression and then for survival only for 1 year from the 1st dose of 
FT538.  
Enrollment 
Plan: 
A minimum of 28 days must separate each Dose Cohort. A minimum of 14 days must separate the 1st and 2nd patient. All 
patients are assessed for Dose Limiting Toxicity (DLT) as defined in the Schema and in Section 7.5. 
STAGE 1 STEP 1 Fast-track design (2 patients per dose cohort) 
Start at Dose Cohort 1, enroll 2 patients per dose cohort separated by a minimum of 14 days until:  
 The 1st occurrence of a pre-defined adverse event in either patient defined as one of the following treatment emergent 
events: Grade 3 abdominal pain, not attributable to the cancer, within 28 days after the 1st FT538 infusion lasting more 
than 48 hours despite treatment with standard analgesics or a Grade 3 infusion related reaction within 24 hours after 
the 1st FT538 infusion in any dose cohort or 1st enoblituzumab infusion in DC 5 or DC 6 and symptoms resolve to 
baseline within 12 hours. 
  and both patients complete the 28 day DLT period with no DLT- Activate Stage 1 Step 2 
OR  
 1st DLT event in either patient within 28 days after the 1st dose of FT538 as defined in the Schema and in Section 
7.5 - Activate Stage 2 (Stage 1 Step 2 is not used)  
OR 
 10 patients are treated in Dose Cohort 6 (This completes enrollment; Stage 1 Step 2 and Stage 2 are not used.) 
STAGE 1 STEP 2 Expand current Dose Cohort and subsequent Dose Cohorts to 3 patients 
The cohort size increases from 2 to 3 patients with 1 additional patient added to the current cohort. At least 14 days 
must separate the 1st and 2nd patients in a 3 patient cohort and a minimum of 28 days separate each 3 patient cohort. 
Continue dose escalation until: 
 1st DLT event as defined in the Schema and Section 7.5 - Activate Stage 2 
OR  
 10 patients are treated in Dose Cohort 6 (This completes enrollment and Stage 2 is not used.) 
STAGE 2 Continual Reassessment Method (CRM) at 1st DLT event 
The study design changes to an application of the CRM. Enrollment occurs in cohorts of 3 with a minimum of 14 days 
between the 1st and 2nd patient in a cohort. Each new cohort of 3 patients is sequentially assigned to the most appropriate 
FT538 dose level by the study statistician based on the updated toxicity probabilities once the 3rd patient in a cohort 
completes the 28 day DLT period. The MTD is identified by the minimum of the following criteria: (1) the total sample size 
of 33 is exhausted or (2) 10 consecutive patients are enrolled in the same Dose Cohort.  


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Investigational 
Product (IP): 
 FT538 provided by Fate Therapeutics 
 Enoblituzumab provided by MacroGenics, Inc. (Cohort 5 and Cohort 6 only) 
Study Agents: 
Lymphodepleting chemotherapy (fludarabine and cyclophosphamide) 
Long-Term 
Follow-Up: 
The FDA recommends a 15-year safety follow-up from the 1st dose of a genetically modified cell therapy. Data collection is 
achieved through a separate long-term follow-up (LTFU) study. Consent to the LTFU study is done at the time of enrollment 
into the treatment study.  
Primary 
Objective: 
To determine the maximum tolerated dose (MTD) of FT538 monotherapy when administered via intraperitoneal (IP) catheter 
and in combination with intravenous (IV) enoblituzumab in patients with recurrent ovarian, fallopian tube, and primary 
peritoneal cancer.  
Secondary 
Objectives: 
 To characterize the toxicities associated with IP FT538 when administered as monotherapy and after IV enoblituzumab.  
 To estimate progression-free survival (PFS) and overall survival (OS) at 6 months and 12 months from the 1st dose of 
FT538. 
 To gain preliminary efficacy information based on RECIST 1.1 of this treatment combination. 
Correlative 
Objectives: 
Blood and ascites and/or intraperitoneal washings including:  
 To characterize the pharmacokinetics (PK) of FT538 monotherapy and in combination with enoblituzumab in the 
peritoneal fluid, peripheral blood, and tumor biopsy samples.  
 To assess the association of PK of FT538 monotherapy and in combination with enoblituzumab in the peritoneal fluid in 
this patient population with safety and anti-tumor activity. 
Tumor biopsies including: 
 To assess tumor microenvironment. 
Key Inclusion 
Criteria: 
 Recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer meeting one of the following minimal 
prior treatment requirement (no maximum number of prior treatments): 
platinum resistant: FT538 may be given as 2nd line (first salvage therapy) 
platinum sensitive: FT538 may be give as 3rd line therapy (second salvage therapy) 
 Must have received prior bevacizumab. 
 In the presence of a BRCA mutation, must have received a prior PARP inhibitor.  
 Must have measurable disease per RECIST1.1 within the abdomen and pelvis as assessed within 42 days prior to the 
1st FT538 infusion.   
 Extra-peritoneal disease is permitted; however each lesion must be <5 cm in diameter.   
 Agrees to the placement of an intraperitoneal catheter before the 1st dose of study directed therapy (chemotherapy or 
for Cohorts 5 and 6, enoblituzumab) and remains in place through around Day 36 or the decision not to re-treat is made.  
 ≥ 18 years of age at time of consent signing, GOG performance status ≤ 2. 
 Patient weight of ≥ 50 kg due to FT538 fixed cell dosing and FT538 product pre-dosed packaging. 
 Adequate organ function within 14 days (28 days for cardiac and pulmonary) of study treatment start as defined in Section 
5.1.7 of the protocol. 
 Provides written consent to the companion LTFU study.  
 Voluntary written consent for this study. 
Key Exclusion 
Criteria: 
 Pregnant or planning to become pregnant in the next 6 months. 
 Known allergy to the following FT538 components: albumin (human) or DMSO 
 Currently receiving or likely to require systemic immunosuppressive therapy (e.g., prednisone >5 mg daily) for any reason 
from Day -5 to 14 days after the last dose of FT538 (Day 29) with the exception of corticosteroids as a pre-medication 
per institutional standard of care – inhaled and topical steroids are permitted.  
 Prior enoblituzumab 
 Receipt of any investigational agent within 28 days prior to the first dose of FT538 (or enoblituzumab)  
 Known seropositive for HIV or known active Hepatitis B or C infection with detectable viral load by PCR 
Enrollment Goal Enrollment will most likely include 22 patients, or it could be as high as 33 patients if DLTs are encountered early. 
Accrual Plan: 
Accrual should range from 10-12 patients per year - study accrual is expected to be completed within 24-36 months. 


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Study Schema 
 
 
 
 
 
 
 
             
  
 
 
     FT538 IP Dosing  
           End of 
 
         disease reassessement per SOC 
 
        CY/FLU     #1 
      #2   
#3 
 
       DLT       repeat CT               and survival 
screening and 
IP catheter placement
      
 
 
 
 
 
 
 
 
 
 
 
 
Continue 
on LTFU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
     -6   -5   -4       1 
         8 
  15 
        22 
    29             36  
    43 and   3 mon  6 mon   9 mon   12 mon 
IP washing    x# 
 
            x 
    x 
         x   
    x 
       x 
  x# 
  every 3 weeks 
 
# biopsy if feasible, at time of catheter placement and removal  
              remove IP catheter at any time once it is determined no retreatment 
  Refer to Section 6.4 for off-study procedures if IP catheter cannot be placed by interventional radiology 
    
      Enoblituzumab (Cohort 5 and Cohort 6 only) Enoblituzumab 15 mg/kg IV begin on Day -6 and continuing once every 3 weeks beginning on Day 22 until disease 
progression or unacceptable toxicity – refer to Section 7.2.1 for timing of the enoblituzumab dose on Day 22 if steroid pre-meds are needed due to an infusion 
reaction with the 1st enoblituzumab dose as there is a 14 day ban on corticosteroid use after the last dose of FT538 
 
CY/FLU Lymphodepleting Chemotherapy: Fludarabine 25 mg/m2 IV followed by CY 300 mg/m2 IV) given on 2 consecutive days (Day -5 and Day-4)  
Refer to Section 7 for allowable treatment windows. 
 
FT538 IP at assigned dose level on Day 1, Day 8, and Day 15  
Dose Cohort (DC) 
FT538 Dose IP (cells per dose) 
-1 
IP FT538 monotherapy 5 x 10^7 cells/dose 
1 (start) 
IP FT538 monotherapy 1 x 10^8 cells/dose 
2 
IP FT538 monotherapy 3 x 10^8 cells/dose  
3 
IP FT538 monotherapy 1 x 10^9 cells/dose  
4 
IP FT538 monotherapy 1.5 x 10^9 cells/dose  
5 
Safe dose (MTD-1) from 1st 4 dose cohorts + IV enoblituzumab  
6 
Highest dose (MTD) from 1st 4 dose cohorts + IV enoblituzumab  
 
Day 22: Cohort 5 and 6 enoblituzumab is given on Day -6, Day 22 and every 3 weeks thereafter per Section 7.2) 
Day 29: Assessment at the end of the 28 day DLT period 
Day 36: Disease reassessment with CT of chest/abd/pelvis – remove catheter if no retreatment or if retreatment is planned. 
Follow-up for 1 year from the 1st dose of FT538: for disease response per standard of care until disease progression, and then survival only.  
 




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1 Objectives 
1.1 Primary Objective 
The primary objective of the study is to determine the maximum tolerated dose 
(MTD) of FT538 monotherapy when administered via intraperitoneal (IP) catheter 
and in combination with intravenous (IV) enoblituzumab in patients with recurrent 
ovarian, fallopian tube, and primary peritoneal cancer. 
1.2 Secondary Objectives  
Secondary objectives of this protocol are: 
 To characterize the toxicities associated with IP FT538 when administered as 
monotherapy and after IV enoblituzumab.  
 To estimate progression-free survival (PFS) and overall survival (OS) at 6 
months and 12 months from the 1st dose of FT538. 
 To gain preliminary efficacy information based on RECIST 1.1 of this treatment 
combination. 
1.3 Correlative (or Exploratory) Objectives 
Blood and ascites and/or intraperitoneal washings are collected for study related 
analysis including: 
 To characterize the pharmacokinetics (PK) of FT538 monotherapy and in 
combination with enoblituzumab in the peritoneal fluid, peripheral blood and 
tumor biopsy samples.  
 To assess the association of PK in the peritoneal fluid of FT538 monotherapy 
and in combination with enoblituzumab in patient population with safety and anti-
tumor activity. 
 
Tumor biopsies (if feasible) at the time of catheter placement and catheter removal 
for study related analysis including: 
 To assess tumor microenvironment.  
2 Background and Significance 
Ovarian cancer is the most lethal gynecologic malignancy. The estimated 5-year survival 
is 48% for all stages of ovarian cancer, and 29% for distant disease. Notably, 59% of 
women with ovarian cancer present with Stage III or IV disease, the rate of recurrence is 
70 to 90% for Stage III and 90 to 95% for Stage IV (SEERS). Women who recur cannot 
be cured with current therapies. Our long term objective is to exploit the innate immune 
system to treat ovarian cancer and substantially improve survival rates. 
 
 


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2.1 Background 
Dr. Jeffrey Miller and collaborators from the University of Minnesota pioneered the 
development of allogeneic haplo-identical natural killer (NK) cell cancer 
immunotherapy beginning in the year 2000. While previous clinical trials of 
methods to induce autologous NK cell activity demonstrated safety, such as 
prolonged treatment with low-dose subcutaneous IL-2, higher doses of IV IL-2 and 
infusions of ex vivo IL-2 activated NK cells, these methods failed to demonstrate 
clinical efficacy. As the concept of “missing self” and the rules of NK cell 
alloreactivity emerged, interest in the use of haplo-identical NK cells to increase 
anti-tumor activity was established. It was believed that effector NK cells educated 
in haplo-identical healthy donors could induce stronger graft-versus-leukemia 
effects since these cells were not exposed to immunosuppressive mechanisms 
found in cancer patients. Additionally, it was further hypothesized that haplo-
identical donors would provide a higher frequency of alloreactive NK cells (i.e., NK 
cells with attenuated inhibitory receptor signaling due to the major 
histocompatibility complex class I mismatch between the haplo-identical NK cells 
and the patient’s tumor cells). 
We established the safety and success of adoptive transfer of allogeneic NK cell 
products in a trial using haplotype mismatched, related-donor NK cell products  
(mean NK cell dose of 2 (range 1-6.2) x107 cells/kg from a single donor apheresis), 
followed by subcutaneous IL-2 to induce in vivo NK survival and expansion (Miller 
2005). Importantly, successful expansion of the allogeneic NK cells was achieved 
after a lympho-depleting regimen of high dose cyclophosphamide (Cy) and 
fludarabine (Flu). This chemotherapy regimen, delivered prior to NK cell transfer, 
transiently prevents patient T cells from rejecting adoptively transferred NK cells 
creating an environment conducive to NK cell expansion. Complete remissions in 
AML correlated with in vivo NK expansion and higher proportions of circulating 
(and functional) NK cells. This treatment approach leads to potent anti-tumor 
killing. To date, we have treated over 150 patients with refractory AML and other 
cancers, including ovarian, with adoptively transferred NK cells (INDs 8847, 13659, 
and 14448) utilizing our standard platform of Cy/Flu, followed by delivery of 
exogenous IL-2 or IL-15 to promote in vivo NK cell activation and expansion. 
Although these results are an improvement over standard salvage therapy for 
patients with refractory leukemia (expected CR rate of 30% with NK therapy vs 
10% with current SOC), they suggest that adoptive cell therapy in its current form 
requires additional anti-tumor activity. (Bachanova 2014) 
 
 


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2.2 Natural Killer (NK) Cells 
2.2.1 Natural Killer Cells as Immunotherapy 
Cancer immunotherapy is a rapidly evolving field that has transformed the 
treatment of many tumor types including solid tumors. However, despite important 
advances, the majority of patients will either not respond or eventually experience 
disease relapse. Particularly in solid tumors, the mechanisms of tumor resistance 
to cancer immunotherapies are diverse and include the ability of tumors to form 
physical and immunologic barriers to immune effector cells such as T cells and 
NK cells (Melero 2014). Further understanding of the biology that enables these 
cells to enter tumors and retain anti-tumor cytotoxic activity is important in order to 
maximize their clinical benefit for patients. 
NK cells are so named for their “natural” ability to kill cancer cells without prior 
sensitization (Kiessling 1975). NK cells kill cancer cells by multiple mechanisms 
including direct cytotoxicity, cytokine secretion, and antibody dependent cell-
mediated cytotoxicity (ADCC): 
 Direct cytotoxicity through the targeted release of perforins and granzymes. 
Importantly, while MHC-I deficient cells evade CD8 T-cell recognition, they are 
preferential targets for NK cells and are highly susceptible to NK cell-mediated 
killing (Malmberg 2017). 
 Cytokines, including interferon-gamma (IFNγ) and tumor necrosis factor-alpha 
(TNFα) promote direct tumor cell killing (Wang R 2012). 
 ADCC, which occurs when an antibody binds to a tumor cell and the antibody’s 
Fc region binds to the CD16 receptor on NK cells, triggering a cytotoxic 
response towards the tumor cell (Waldhauer 2008; Wang, W 2015). 
In addition to direct effects on tumor cells, NK cells can interact with the adaptive 
immune system to generate and maintain adaptive immune responses against 
cancer cells: 
 Killing of tumor cells by NK cells results in the release of tumor antigens for 
recognition by the adaptive immune system (Dahlberg 2015). 
 NK cells upon activation secrete cytokines that recruit and activate endogenous 
T cells. Importantly, activated NK cells are potent producers of chemokines 
such as CXCL10, CCL4, and CCL5, which are known recruitment factors for T 
cells. Cytokines secreted by NK cells also induce maturation of dendritic cells, 
which serve as antigen-presenting cells to mediate adaptive immune 
responses (Smyth 2002). 


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2.2.2 Experience in Delivery of NK Cell Therapy 
In clinical investigations, allogeneic NK-cell therapies have been well-tolerated 
with documented anti-tumor activity. More than 500 patients across 30 completed 
clinical studies have received allogeneic NK cells (Veluchamy 2017). Notably, and 
unlike allogeneic T cell therapies, allogeneic NK cells have not been associated 
with graft-vs-host disease (GvHD). Furthermore, with a single exception (Cooley 
2019), allogeneic NK cell therapies have not been associated with cytokine release 
syndrome (CRS) or neurotoxicity, common complications observed with CAR-T 
cell therapies. Complete remission rates ranging from 21% to 53% have been 
observed following a single administration of allogeneic NK cells in subjects with 
relapsed/refractory acute myelogenous leukemia (AML) (Miller 2005; Bachanova 
2014; Romee 2016), and in subjects with poor prognosis refractory non Hodgkin 
lymphoma (Bachanova 2018). Clinical responses have also been reported in 
subjects with solid tumors including non-small cell lung cancer (Iliopoulou 2010; 
Tonn 2013), as well as in subjects with platinum-resistant ovarian cancer 
(Geller 2011), melanoma (Arai 2008), and renal cell carcinoma (Arai 2008).  
Most recently we have treated three patients with advanced, recurrent ovarian 
cancer with FT516 on a single-center, phase I clinical trial entitled “Intraperitoneal 
FATE FT516 and Interleukin-2 (IL-2) with Intravenous Enoblituzumab in Recurrent 
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer”. FT516 is an allogeneic 
natural killer (NK) cell immunotherapy derived from a clonal human-induced 
pluripotent stem cell (iPSC) line, engineered to express a high affinity, non-
cleavable CD16 (hnCD16) Fc receptor. The engineered features of FT516 were 
designed to result in increased activity against target tumor cells as monotherapy 
and when combined with monoclonal antibodies (mAbs) that can mediate antibody 
dependent cell cytotoxicity (ADCC). In Patient #3 on this clinical trial, we found by 
flow cytometry, that on Day 8 following IP infusion of FT516 and IL-2 IP delivery, 
65% of the NK cells were HLA-A3 negative (DONOR), however by Day 15, only 
1% of NK cells in IP washings were Donor cells. Based on our findings and on 
convincing and evolving preclinical data, we have made the decision to transition 
from the FT516 product to the FT538 product proposed in this protocol. Following 
review of the pre-clinical data, and our recent experience with our first 3 patients 
in the FT516 trial, we believe that making this change is the next logical step in our 
research. The functional modifications of FT538 include a novel high-affinity 158V, 
non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to augment 
ADCC; an IL-15 receptor fusion (IL-15RF) that promotes enhanced NK cell activity; 
and the elimination of CD38 expression to mitigate the potential for NK cell 
fratricide. Together, these features are intended to augment ADCC, enhance cell 
persistence and prevent anti-CD38 monoclonal antibody-induced fratricide. With 


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the enhanced capabilities of this cell product in combination with enoblituzumab 
we believe we can improve upon persistence within the peritoneal cavity. 
2.3 FT538 
2.3.1 Development of FT538 
FT538 is an allogeneic natural killer (NK)-cell immunotherapy produced from a 
clonal master human-induced pluripotent stem cell (iPSC) line with the following 
engineered elements: a) deletion of the gene encoding CD38 (i.e., CD38 knockout 
[KO]; Bjordahl et al. 2019; Cichocki et al. 2019); b) high-affinity, non-cleavable 
CD16 receptor (hnCD16; Jing et al. 2015; Zhu et al. 2020); and c) interleukin (IL)-
15/IL-15 receptor alpha fusion protein (IL-15RF; Rubinstein et al. 2006; Stoklasek 
et al. 2006). The clonal master cell bank (MCB) used for the production of FT538 
was generated by selecting and expanding a single well-characterized iPSC clone 
in which a single IL-15RF/hnCD16 expression cassette was inserted into the CD38 
gene locus through non-viral-mediated targeted transgene integration. The use of 
a clonal MCB as the starting material for routine current Good Manufacturing 
Practices (cGMP) production of FT538 is intended to directly address many of the 
limitations associated with patient- and donor-specific cell therapies. Notably, 
many doses of FT538 drug product can be uniformly produced in a single 
manufacturing campaign. These doses of drug product are homogeneous and are: 
(i) tested to assure compliance with a pre-defined quality specification, (ii) 
cryopreserved in an infusion medium, and (iii) stored to maintain a sustainable 
inventory. As such, FT538 in the clinical setting has off-the-shelf availability for use 
in multi-dose regimens, which may prove critical for driving long-term durable 
responses in patients with progressing disease. The engineered features of FT538 
are designed to result in increased activity against target tumor cells as 
monotherapy and when combined with monoclonal antibodies (mAbs) that can 
mediate antibody-dependent cellular cytotoxicity (ADCC). Important functional 
attributes of FT538 include the following:  
• 
FT538 is expected to have superior effector function compared to patients’ 
endogenous NK cells, which are typically diminished in number and function 
due to prior treatment regimens (e.g., chemotherapy) and tumor-suppressive 
mechanisms. FT538 mediates “innate cytotoxicity” that is potent and specific 
to transformed cells.  
• 
The CD38 gene KO in FT538 is intended to prevent anti-CD38 antibody-
mediated NK-cell fratricide and consequently enhance ADCC when FT538 is 
administered with concurrent anti-CD38 mAb therapy (Bjordahl et al. 2019). In 
addition, NK cells with CD38 KO have been shown to be more resistant to 
oxidative stress and exhibit enhanced effector function (Cichocki et al. 2019).  


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• 
FT538 expresses an hnCD16 Fc receptor. The high-affinity CD16 variant 
arising from a naturally occurring 158V polymorphism has demonstrated 
enhanced ADCC when combined with therapeutic mAbs in nonclinical studies. 
In clinical studies evaluating patients whose endogenous NK cells express the 
high-affinity CD16 Fc receptor variant, higher objective response rates and 
increased progression-free survival (PFS) were observed with treatment with 
rituximab, cetuximab, and trastuzumab (Bibeau et al. 2009; Cartron et al. 2002; 
Musolino et al. 2008). In addition, hnCD16 contains the genetic alteration 
(S179P) that prevents cleavage of CD16 by the metalloproteinase ADAM17 
(Jing et al. 2015; Lajoie et al. 2014), a mechanism in the regulation and 
attenuation of NK-cell activity by the tumor microenvironment (Romee et al. 
2013).  
• 
FT538 expresses IL-15RF, designed to provide an endogenous activation and 
proliferation signal, reducing the dependence on exogenous cytokine 
administration such as IL-2 and IL-15, both of which have been associated with 
significant toxicities that may limit clinical usage when incorporated into clinical 
studies of peripheral blood NK cells (Cooley et al. 2019).  
2.3.2 Summary of Clinical Data 
FT538 is currently being evaluated in a Phase I study FT538-101, A Phase I, 
Open-Label, Multicenter Study of FT538 as Monotherapy in Relapsed/Refractory 
Acute Myelogenous Leukemia and in Combination with Monoclonal Antibodies in 
Relapsed/Refractory 
Multiple 
Myeloma 
(ClinicalTrials.gov 
identifier 
NCT04614636) in subjects with advanced hematologic malignancies on either 
Regimen A (acute myelogenous leukemia [AML]; monotherapy) or Regimen B 
(multiple myeloma; FT538 + daratumumab). As of the data cutoff date of 
01 December 2021, a total of 15 patients have been treated with FT538: 13 in 
Regimen A and 2 in Regimen B. Nine patients remain on study (7 patients with 
AML in Regimen A, all of whom have completed the initial treatment cycle and are 
either awaiting potential retreatment with another cycle of FT538 or are in the post-
treatment/long-term follow-up period; and 2 patients with multiple myeloma in 
Regimen B). Six patients with AML in Regimen A discontinued from the study for 
the following reasons: death (n=2), Primary Investigator decision (n=2), withdrawal 
of consent (n=1), and “other” (n=1).  The 3 patients who discontinued due to death 
and “other” all had progressive disease. 
The most common treatment emergent adverse events (TEAEs) occurring in 3 or 
more patients include sepsis, hypokalemia, pneumonia, nausea, vomiting, 
diarrhea, febrile neutropenia, hypophosphatemia, headache, and anxiety. The 
most common Grade ³3 TEAEs occurring in 2 or more patients include sepsis, 


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pneumonia, febrile neutropenia, lymphocyte count decreased, and platelet count 
decreased. Serious TEAEs occurring in 2 or more patients include sepsis, 
pneumonia, and febrile neutropenia.  No DLTs or serious adverse events (SAEs) 
assessed as possibly or probably related to FT538 have been observed to date in 
any patient. No cytokine release syndrome (CRS), neurotoxicity related to FT538, 
or GvHD were observed. One event of Grade 3 TLS assessed as not related to 
FT538 was reported. 
Based on protocol-defined dose-escalation rules, the FT538 dose of 1  108 did 
not exceed the maximum tolerated dose, and therefore dose escalation to the 
3  108 dose level could proceed. Enrollment is ongoing at a dose level of 
3 × 108 cells for this regimen as of 01 December 2021. To date, 3 AML subjects 
have been treated at a dose of 3 × 108 cells with 2 of the 3 subjects completing the 
DLT assessment period. One subject received all three planned doses of FT538; 
but did not complete the DLT assessment period due to early progressive disease 
and began a new anti-cancer regimen on Study Day 19. None of the 3 subjects 
experienced a DLT, nor were any episodes of CRS, ICANS or acute GVHD 
observed. 
Evaluation of the multiple myeloma cohort of Regimen B (FT538 + daratumumab) 
is ongoing at the first dose level of 1 × 108 cells. 
Overall, based on the available aggregate safety data, FT538 appears to be 
tolerable at the doses tested to date, up to 3 × 108 cells, without evidence of 
unexpected FT538-related toxicities in this preliminary evaluation. Observed 
toxicities are consistent with those expected with the conditioning chemotherapies 
in the setting of advanced relapsed/refractory disease and extensive prior 
therapies, with no evidence of new or unexpected toxicity signals to date. There 
have been no observations of acute GvHD in any of the 15 patients treated with 
FT538.  
Refer to the FT538 Investigator’s Brochure for additional details. 
2.3.3 Summary of Nonclinical Data 
Nonclinical data of FT538 activity was generated with FT538-R, the non-Good 
Manufacturing Practice (non-GMP), research-use equivalent of FT538, and 
include the following:  
• 
The combination of FT538-R and ADCC-inducing mAbs, including 
daratumumab, resulted in enhanced anti-tumor activity as compared to mAb 
alone, peripheral blood NK cells alone, or FT538 alone.  


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• 
No safety concerns have been observed. A 3-month Good Laboratory 
Practice (GLP) toxicology study revealed no FT538-R−related serologic or 
histologic evidence of toxicity, and no evidence of tumorigenicity was 
identified. •  
• 
Biodistribution and persistence of FT538-R cells in immunodeficient NOD-
SCID-IL2rγnull (NSG) mice was evaluated following three intravenous (IV) 
injections at 3 × 106 cells/mouse or 1.2 × 107 cells/mouse administered 7 
days apart on day of study 1, day of study 8, and day of study 15. The data 
demonstrate that FT538-R is detected in most tissues and that their 
persistence generally decreases over time to a level approaching or below 
the lower limit of detection by day of study 67.  
 
Additional information on nonclinical studies with FT538 is provided in the FT538 
Investigator’s Brochure.  
2.4 Lymphodepletion with Cyclophosphamide and Fludarabine  
The importance of lymphodepleting chemotherapy has been well demonstrated in 
mouse experiments and was first proposed by the National Cancer Institute (NCI) 
in the context of melanoma specific CTL by Rosenberg and colleagues. (Dudley 
2002) Lymphodepleting conditioning prior to adoptive transfer of lymphocytes is 
thought to promote persistence of adoptively transferred lymphocytes by creating 
"immunologic space” and providing a pool of homeostatic cytokines such as IL-15. 
The use of Cy/Flu-mediated lymphodepletion at the proposed doses and schedule 
is consistent with our previous human experience. (Miller 2005, Bachanova 2014) 
2.5 Enoblituzumab 
MGA271 (enoblituzumab, also known as RES242) is a humanized immunoglobulin 
(Ig) G1/kappa monoclonal antibody (mAb) that binds B7 homolog 3 (B7-H3), also 
referred to as CD276, a member of the B7 family of ligands that bind to receptors 
on lymphocytes and regulate immune responses. This agent is being developed 
by MacroGenics, Inc. B7-H3 is overexpressed on a number of tumor types and the 
primary mechanism of action for MGA271 is thought to be via antibody-dependent 
cellular cytotoxicity (ADCC). MGA271 comprises an engineered human IgG1 
fragment crystallizable (Fc) domain that imparts increased affinity for the human 
activating Fc-gamma receptor (FcγR) IIIA (CD16A) and decreased affinity for the 
human inhibitory FcγRIIB (CD32B). (Enoblituzumab IB). 
 
 


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3 Study Rationale 
3.1 The Use of Intraperitoneal Administration in Gynecologic Cancers  
Ovarian, primary peritoneal and fallopian tube cancers are diseases that spread 
locally within the peritoneal cavity. Ovarian cancer is an intraperitoneal disease, 
rarely metastasizing beyond the abdominal cavity, so the goal is to deliver therapy 
directly to the tumor site to potentially maximize efficacy.  It is for this reason and 
based on our preclinical data, which demonstrated better anti-tumor effects with IP 
delivery than systemic delivery, that we have elected to deliver the FT538 within 
the peritoneal cavity. (Geller 2013, Uppendahl 2019) I 
3.2 Rationale for Using FT538 IP Dosing 
Based on our published in vivo mouse data (Hermanson 2016) our current platform 
for NK cell therapy in ovarian cancer delivers NK cells IP as we have seen 
significant inhibition of ovarian cancer growth using this delivery. As ovarian cancer 
is an intraperitoneal disease, rarely metastasizing beyond the abdominal cavity, 
therapy delivered directly to the tumor site makes intuitive sense. Recent studies 
conducted by our collaborators defined the lymphocyte population within the 
peritoneal fluid (PF) of women with high-grade serous ovarian cancer (Figure 1). 
They found that women with ovarian cancer had a significantly lower percentage 
of NK cells in the PF compared to women with benign disease. Importantly, the 
ovarian cancer patients with lower number of NK cells had significantly lower 
survival.  
 
This data provides the rationale for delivering the FT538 product directly within the 
peritoneal cavity. In addition, we recently completed a clinical trial where we 
developed a 7-day culture process using a GSK3 inhibitor and IL-15 to 
manufacture 
modulated 
adaptive 
NK 
cells 
(FATE-NK100) 
from 
CMV+ haploidentical donors for adoptive transfer. The phase I Apollo trial tested 
the maximum tolerated dose/maximum feasible dose (MTD/MFD) of FATE-NK100 
administered intraperitoneally (IP) to treat platinum-sensitive or -resistant recurrent 
ovarian, fallopian tube, and primary peritoneal cancer. FATE-NK100 via IP port 
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was tested using 3 dose cohorts ([DC]; 1 × 107 cells/kg; >1 × 107 cells/kg to ≤3 × 
107 cells/kg; or >3 × 107 to ≤10 × 107 cells/kg) after lympho-conditioning with 
fludarabine 25 mg/m2 IV and cyclophosphamide 300 mg/m2 IV on days −6 and −5. 
After FATE-NK100 infusion on day 0, rhIL-2 at 6 million IU was given IP 3 times a 
week for 6 doses for in vivo NK activation. Nine patients were treated with no dose-
limiting toxicities (DLTs). Retreatment based on clinical benefit was performed on 
3 patients (33%), 2 following stable disease (DC 2) and 1 with partial remission 
(48% tumor reduction, DC 3). We found that the allogeneic product cells persist 
and have enhanced function compared to patient NK cells for up to 21 days, even 
after retreatment (our unpublished data). 
We anticipate that the novel FT538 cell product will overcome the limitations of our 
current NK cell product, specifically by displaying better activity associated with 
longer survival after infusion into the peritoneal cavity. We have data showing that 
within the peritoneal microenvironment, the surface expression of CD16a on NK 
cells is significantly decreased presumed from ADAM17 mediated cleavage. This 
is one possible reason for decreased NK cell cytotoxicity in ovarian cancer that 
can be overcome with the use of the non-cleavable FT516 cell product. CD16a cell 
surface levels are tightly regulated by ADAM17 (Wu 2019, Romee 2013, Wang Y 
2013, Jing 2015). We were the first to report that ADAM17 mediates this process 
by cleaving CD16a in a cis manner at a specific location proximal to the cell 
membrane. (Jing 2015) Though this is a normal process of immune homeostasis, 
it has been reported that NK cells in the tumor tissues of ovarian cancer patients 
have significantly reduced levels of CD16a (Figure 2) and impaired anti-tumor 
effector functions (Lai 1996, Patankar 2005, Belisle 2007, Felices 2017). 
 
Figure 2. Percentage of CD16+ NK cells are significantly reduced in the peritoneal cavity compared 
to NK cells in the peripheral blood of ovarian cancer patients and in healthy patients. 
ASCITES
OV. PATIENT PBMC
NORMAL PBMC
0
20
40
60
80
100
CD16+ NK Cells %
ASCITES
OV. PATIENT PBMC
NORMAL PBMC
0
2000
4000
6000
8000
10000
CD16 MFI of NK Cells


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3.3 Rationale for Lymphodepleting Conditioning 
The purpose of conditioning prior to the administration of FT538 is to create an 
immune environment amenable to FT538 persistence and expansion. This is 
accomplished by promoting homeostatic proliferation of FT538 as well as 
eliminating regulatory immune cells and other competing elements of the immune 
system that compete for homeostatic cytokines (Klebanoff 2005). Conditioning 
with CY and FLU has been established with CD19 CAR T-cell therapies (Kymriah® 
USPI; Yescarta® USPI) and was shown to improve CAR-T expansion and 
persistence associated with clinical benefit (Turtle et. al. 2016). The doses and 
schedules of CY and FLU conditioning used in this study are identical to those 
administered as conditioning prior to infusion of axicabtagene ciloleucel (Yescarta 
USPI). 
In addition to the generation of “immunologic space” to support FT538, reasons for 
administering lymphodepleting chemotherapy prior to the first IP dose of FT538 
include:  
1) Cyclophosphamide is used as a standard chemotherapy agent in the treatment 
of recurrent ovarian cancer (Chura 2007) and  
2) We know that immunosuppression dominates the IP cavity in women with 
ovarian cancer (Lukesova 2015, Felices 2017). Additionally, we have data 
showing that the IP tumor microenvironment is highly suppressive and causes 
significant downregulation of CD16 (the low-affinity Fc receptor utilized by NK 
cells to mediate ADCC).  We believe that the proposed low dose 
lymphodepleting regimen is still necessary to enhance FT538 anti-tumor 
activity.  
3.4 Rationale for Retreatment with FT538 
A second course of FT538 may be offered to those who experience clinical benefit 
at the 1st disease reassessment around Day 36. Clinical benefit is defined as stable 
disease or better without a decrease performance status from baseline. Advanced 
ovarian, primary peritoneal and fallopian tube cancers cannot be cured with current 
available therapies therefore, if the patient has achieved stable disease (SD) or 
better, it is reasonable to offer retreatment with FT538.   
3.5 Rationale for Using Enoblituzumab 
Clinical experience and trials have not identified an effective cancer antibody for 
ovarian cancer compared to others solid tumors responding to HER2 and EGFR 
targeted antibodies. Enoblituzumab is an Fc optimized humanized IgG1 
monoclonal antibody that binds to B7-H3 (CD276). B7-H3 is widely expressed by 
a number of different tumor types, including a majority of ovarian cancers and 


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ovarian cancer stroma (MacGregor 2019), and may play a key role in regulating 
the immune response.  
The rationale for instituting enoblituzumab into this trial is based on preclinical data 
showing that B7H3 expression is prevalent in the majority of ovarian cancers. 
Additionally, in a study by Zang and colleagues (Zang X 2010); B7-H3 was found 
to be expressed on 78% of the endothelium of tumor-associated vasculature from 
patients with Stage III and IV ovarian cancer. This suggests that targeting B7-H3 
in advanced ovarian cancer may serve to target both tumor cells and cells critical 
for the generation and support of the tumor microenvironment. The engineered 
features of FT538 are designed to result in increased activity against target tumor 
cells as monotherapy and when combined with monoclonal antibodies (mAbs) that 
can mediate antibody-dependent cellular cytotoxicity (ADCC) mediated by NK 
cells. Enoblituzumab is a humanized immunoglobulin (Ig) G1/kappa monoclonal 
antibody (mAb) that when combined with FT538 is designed to enhance ADCC as 
well as direct NK-mediated cytotoxicity to B7-H3 expressing cells. The combination 
of FT538 and enoblituzumab has stronger mechanistic rationale which is why we 
have selected this combination. 
4 Study Design 
This is a single center Phase I clinical trial of FT538 administered intraperitoneally (IP) 
once a week for 3 consecutive weeks for the treatment of recurrent gynecologic cancers. 
As this is an early first in human study and the first intraperitoneal infusion of FT538, the 
safety of FT538 is confirmed prior to introducing enoblituzumab in combination with 
FT538. Once a safe does of FT538 is identified, enoblituzumab is added as an 
intravenous infusion on Day -6 and every 3 weeks beginning on Day 22 (1 week after the 
last dose of FT538) until disease progression or unacceptable side effects. A short course 
of outpatient lymphodepleting chemotherapy is given prior to the first dose of FT538. 
FT538 is an allogeneic natural killer (NK)-cell immunotherapy produced from a clonal 
master human-induced pluripotent stem cell (iPSC) line with the following engineered 
elements: a) deletion of the gene encoding CD38 (i.e., CD38 knockout; b) high-affinity, 
non-cleavable CD16 receptor and c) interleukin (IL)-15/IL-15 receptor alpha fusion 
protein. Enoblituzumab is an Fc-optimized monoclonal antibody that targets B7-H3 which 
is highly expressed on ovarian cancer. 
 
 


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This study is conducted based on the following Dose Cohorts:  
Dose Cohort 
(DC) 
Treatment Plan 
-1 
IP FT538 monotherapy 5 x 10^7 cells/dose on Day 1, Day 8, and Day 15 
1 (start) 
IP FT538 monotherapy 1 x 10^8 cells/dose on Day 1, Day 8, and Day 15 
2 
IP FT538 monotherapy 3 x 10^8 cells/dose on Day 1, Day 8, and Day 15 
3 
IP FT538 monotherapy 1 x 10^9 cells/dose on Day 1, Day 8, and Day 15 
4 
IP FT538 monotherapy 1.5 x 10^9 cells/dose on Day 1, Day 8, and Day 15 
5 
IP FT538 at the safe dose (MTD-1) from the 1st 4 dose cohorts on Day 1, Day 8, 
and Day 15 plus IV enoblituzumab on Day -6, Day 22, then every 3 weeks until 
disease progression  
6 
IP FT538 at the highest dose (MTD) from the 1st 4 dose cohorts on Day 1, Day 8, 
and Day 15 plus IV enoblituzumab on Day -6, Day 22, then every 3 weeks until 
disease progression 
A minimum of 28 days must separate each Dose Cohort. Within a Dose Cohort, a 
minimum of 14 days must separate the 1st and 2nd patient. All patients are assessed for 
Dose Limiting Toxicity (DLT) as defined in the Schema and in Section 7.5. 
STAGE 1 STEP 1 Fast-track design (2 patients per Dose Cohort) 
Start at Dose Cohort 1 (DC 1), enroll 2 patients per dose cohort separated by a 
minimum of 14 days until the:  
 The 1st occurrence of a pre-defined adverse event in either patient in a DC 
defined as one of the following treatment emergent events:  
o Grade 3 abdominal pain, not attributable to the cancer, within 28 days after the 
1st FT538 infusion lasting more than 48 hours despite treatment with standard 
analgesics  
or  
o Grade 3 infusion related reaction within 24 hours after the 1st FT538 infusion in 
any Dose Cohort or 1st enoblituzumab infusion in DC 5 or DC 6 and symptoms 
resolve to baseline within 12 hours 
  and both patients complete the 28 day DLT period with no DLT- Activate Stage 1 
Step 2 
OR  
 1st DLT event within 28 days after the 1st dose of FT538 as defined in the Schema 
and in Section 7.5 - Activate Stage 2 (Stage 1 Step 2 is not used)  
OR 


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 10 patients are treated at the Dose Cohort 6 (This completes enrollment - Stage 1 
Step 2 and Stage 2 are not used) 
 
STAGE 1 STEP 2 Expand current Dose Cohort and subsequent DCs to 3 patients 
The cohort size increases from 2 to 3 patients with 1 additional patient added to the 
current dose cohort. At least 14 days must and a minimum of 28 days separate each 
3 patient cohort. Continue dose escalation until: 
 1st DLT event as defined in the Schema and Section 7.5 - Activate Stage 2 
OR  
 10 patients are treated at the Dose Cohort 6 (This completes enrollment; Stage 2 
is not used.) 
 
STAGE 2 Continual Reassessment Method (CRM) at the 1st DLT 
The study design changes to an application of the continual reassessment method 
(CRM). Enrollment occurs in cohorts of three with a minimum of 14 days between the 1st 
and 2nd patient in a cohort. Each new cohort of three patients are sequentially assigned 
to the most appropriate dose by the study statistician based on the updated toxicity 
probabilities once the 3rd patient in a cohort completes the 28 day DLT period. The 
maximum tolerated dose (MTD) will be identified by the minimum of the following criteria: 
(1) the total sample size of 33 is exhausted or (2) 10 consecutive patients are enrolled in 
the same Dose Cohort. 
If a patient experiences clinical benefit (defined as stable disease or better and no decline 
in baseline performance status) after the initial treatment course, they may be offered the 
opportunity of retreatment using the same FT538 Dose Cohort. Refer to Section 5.3 and 
Section 7.8 for additional details. 
For study endpoints, follow-up continues for disease response per standard of care until 
disease progression, and then for survival only for 1 year after the 1st dose of FT538. 
After 1 year, follow-up continues on the long-term follow-up (LTFU) study to adhere to 
FDA’s recommended 15 year follow-up after treatment with a genetically modified cell 
therapy. A separate consent is required for the LTFU study.  
 
 


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5 Patient Selection 
Study entry is open to persons regardless of race or ethnic background. While there will 
be every effort to seek out and include minority patients, the patient population is expected 
to be no different than that of other gynecological cancer studies at the University of 
Minnesota. 
A potential participant must meet all of the inclusion and none of the exclusion criteria to 
be considered eligible for study participation. 
5.1 Inclusion Criteria 
5.1.1 Recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal 
cancer meeting one of the following minimal prior treatment requirements 
(no limit to the maximum number of prior treatments). 
 Platinum Resistant: may receive FT538 as 2nd line (as 1st salvage 
therapy). Platinum resistant is defined as disease that has responded to 
initial chemotherapy but demonstrates recurrence within a relatively short 
period of time (< 6 months) following the completion of treatment. 
 Platinum Sensitive: may receive FT538 as 3rd line therapy (as 2nd 
salvage therapy). Platinum sensitive is defined as the recurrence of active 
disease in a patient who has achieved a documented response to initial 
platinum-based treatment and has been off therapy for an extended 
period of time (≥ 6 months). 
5.1.2 
Must have received prior bevacizumab. 
5.1.3 In the presence of a BRCA mutation, must have received a prior PARP 
inhibitor.  
5.1.4 Measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 
(RECIST - refer to Appendix II) within the abdomen and pelvis assessed 
within 42 days of the 1st FT538 infusion. Extra-peritoneal disease is 
permitted; however each lesion must be < 5 cm at the largest diameter. 
5.1.5 At least 18 years of age at the time of consent. 
5.1.6 GOG Performance Status 0, 1, or 2 (refer to Appendix I). 
5.1.7 Adequate organ function within 14 days (28 days for pulmonary and 
cardiac) of study treatment (CY/Flu or enoblituzumab) start defined as the 
following: 
 Hematologic: platelets ≥ 75,000 x 109/L; absolute neutrophil count 
(ANC) ≥ 1000 x 109/L, unsupported by G-CSF or granulocytes 
 Creatinine: Estimated glomerular filtration rate (eGFR) ≥ 60 
mL/min/1.73m2 per current institutional calculation formula 


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 Hepatic: AST and ALT ≤ 3 x upper limit of institutional normal 
 Pulmonary Function: Oxygen saturation ≥ 90% on room air; PFTs are 
performed only if known history or as medically indicated – if done, must 
have pulmonary function >50% corrected DLCO and FEV1.   
 
Cardiac Function: LVEF ≥ 40% by echocardiography, MUGA, or cardiac 
MRI; no clinically significant cardiovascular disease including any of the 
following: stroke or myocardial infarction within 6 months prior to first 
study treatment; unstable angina or congestive heart failure of New York 
Heart Association (NYHA) Grade 2 or higher (Appendix I). 
5.1.8 Agrees to the placement of an intraperitoneal catheter before the 1st dose of 
study directed drug (chemotherapy or enoblituzumab for Cohort 5 and 6) and 
remains in place through Day 36 or longer if retreatment is planned. Refer to 
Section 6.4 if catheter cannot be successfully placed. 
5.1.9 Agrees to undergo a tumor biopsy if feasible at the time the catheter is placed 
and removed – Accessible tumor for biopsy is not required for eligibility. 
5.1.10 If history of brain metastases must be stable for at least 3 months after 
treatment – A brain CT scan or MRI is only be required in patients with known 
brain metastases at the time of enrollment or in those with clinical signs or 
symptoms suggestive of brain metastases. 
5.1.11 Must agree to and sign the consent for the companion Long-Term Follow-Up 
study (CPRC# 2021LS077) to fulfill the FDA recommended 15 years of follow-
up for a genetically modified cell product.  
5.1.12 Voluntary written consent prior to the performance of any research related 
procedures. 
5.2 Exclusion Criteria 
5.2.1 Pregnant or breastfeeding or planning on becoming pregnant in the next 6 
months. If of childbearing potential (have a uterus and ovaries) and engaged 
in heterosexual intercourse, must have a negative pregnancy test (serum or 
urine) within 14 days before the 1st CY/Flu or, enoblituzumab, if applicable. 
Patient must agree to use highly effective method of birth control from the 
screening visit until at least 12 months after the final dose of CY, at least 4 
months after the final dose of FT538, or at least 3 months after the final dose 
of enoblituzumab, whichever is longer.  
5.2.2 Currently receiving or likely to require systemic immunosuppressive therapy 
(e.g., prednisone >5 mg daily) for any reason from Day -5 to 14 days after the 
last FT538 infusion) with the exception of corticosteroids as a pre-medication 
per institutional standard of care – topical and inhaled steroids are permitted. 


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5.2.3 Active autoimmune disease requiring systemic immunosuppressive therapy. 
5.2.4 History of severe asthma and currently on chronic systemic medications. 
5.2.5 Uncontrolled bacterial, fungal or viral infections with progression of clinical 
symptoms despite therapy. 
5.2.6 Receipt of any biological therapy, chemotherapy, or radiation therapy (except 
palliative RT), within 2 weeks prior to the first dose of FT538 (or enoblituzumab 
for Dose Cohorts 5 and 6) or five half-lives, whichever is shorter; or any 
investigational agent within 28 days prior to the first dose of FT538 (or 
enoblituzumab for Dose Cohorts 5 and 6). 
5.2.7 Live vaccine within 6 weeks prior to start of lympho-conditioning. 
5.2.8 Known allergy to the following FT538 components: albumin (human) or 
dimethyl sulfoxide (DMSO). 
5.2.9 Prior enoblituzumab. 
5.2.10 Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis, or 
neurodegenerative disease or receipt of medications for these conditions in 
the 2-year period leading up to study enrollment. (Refer to Section 5.1.8 
regarding history of brain metastases.) 
5.2.11 Known history of HIV positivity or active hepatitis C or B - chronic 
asymptomatic viral hepatitis is allowed. 
5.2.12 Presence of any medical or social issues that are likely to interfere with study 
conduct or may cause increased risk to patient. 
5.2.13 Any medical condition or clinical laboratory abnormality that, per investigator 
judgement, precludes safe participation in and completion of the study or that 
could affect compliance with protocol conduct or interpretation of results. 
5.3 Retreatment Criteria 
A 2nd course of FT538 at the patient’s original Dose Cohort assignment may be 
considered for participants meeting the following criteria: 
5.3.1 Achieved clinical benefit from the 1st treatment course (stable disease, PR 
or CR based on RECIST) when comparing baseline CT scan and the CT 
scan performed around Day 36. 
5.3.2 A functioning IP catheter. 
5.3.3 No unacceptable toxicity (experienced toxicity that met the definition of a 
DLT and/or toxicity that caused a dose to be skipped during the first course 
of FT538). 


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5.3.4 All acute treatment related adverse events have resolved to ≤ Grade 1 or 
baseline, whichever is higher. 
5.3.5 No decline in GOG performance status from baseline as recorded at the 
Day 36 visit assessment. 
5.3.6 Continues to meet laboratory requirements found in Section 5.1.7. 
5.3.7 If receiving enoblituzumab, able to align retreatment to the third 
enoblituzumab infusion (receive lymphodepleting chemotherapy within the 
week after enoblituzumab infusion). 
5.3.8 Voluntary written consent using the retreatment consent (CPRC# 
2021LS103R) prior to any retreatment activities. 
6 Patient Screening and Study Enrollment 
Written consent must be obtained before the performance of any research related 
tests or procedures, although the results of routine tests and procedures (i.e. CT scan 
of the chest, abdomen and pelvis) performed prior to consent may be used to 
determine eligibility if within the study permitted timeframe. 
6.1 Consent and Study Screening Registration 
Any patient who is consented is to be registered in OnCore by the Study 
Coordinator or designee.  
If a patient is consented but is not enrolled in the study treatment (i.e. is found to 
be ineligible based on inclusion/exclusion criteria or eligible, but changes mind 
about participation), the patient’s record is updated in OnCore as a screen failure 
and reason for exclusion recorded.  
6.2 Patient Enrollment and Cohort Assignment 
To be eligible for study treatment, the patient must sign the treatment consent and 
meet each inclusion criteria and none of the exclusion criteria on the eligibility 
checklist based on an eligibility assessment documented in the patient’s medical 
record.  
The patient is assigned to the currently enrolling cohort once eligibility is confirmed 
and a “treatment slot” is available. 
 
 


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6.3 Optional 2nd Treatment Course with FT538 (Retreatment) 
After confirmation of eligibility in Section 5.3 and signing of the retreatment 
consent, the patient is enrolled to the retreatment study (2021LS103R) in OnCore 
releasing a new study calendar. Retreatment has no effect on the primary and 
secondary analysis; however, adverse events are documented and reported per 
Section 11.  
6.4 Inability to Begin Study Treatment 
If a patient is registered to the study and is later found not able to begin study 
treatment (i.e. inability to successfully place the intraperitoneal catheter, change in 
medical status, etc.), the patient is taken off of the study and treated at the 
physician’s discretion. The study staff will update OnCore with the patient’s non-
treatment status. The reason for off study must be clearly indicated in OnCore. The 
patient is replaced to complete enrollment.  
If a patient does not receive FT538, they also should be withdrawn from the LTFU 
study (CPRC #2021LS077). 
7 Treatment Plan 
In order to provide optimal patient care and to account for individual medical conditions, 
investigator discretion may be used in the prescribing of any concomitant medications not 
otherwise described as cautionary or prohibited therapy (refer to Section 7.7) or treatment 
deemed necessary to provide adequate supportive care. Supportive care may include 
anti-microbial prophylaxis, analgesics, transfusions, growth factors, etc. Only irradiated 
blood products should be used to minimize the risk of transfusion-associated GvHD. 
There is some flexibility in the timing of the treatment as long as the ordering of the 
treatment is maintained and a minimum of 48 hours separates the last dose of fludarabine 
and the 1st FT538 infusion. If receiving enoblituzumab, at least 1 day must separate the 
dose of enoblituzumab and the start of the lymphodepletion chemotherapy. The 1st dose 
of FT538 may be delayed for up to 7 days after the last dose of fludarabine in the event 
FT538 cannot be given as planned. Day 1 is the day of the 1st FT538 infusion. There is 
no Day 0. 
7.1 Peritoneal Port/Intraperitoneal Catheter Placement (Day – 6 or earlier) 
Successful placement of the IP catheter/peritoneal port is required before 
proceeding with the lymphodepleting chemotherapy (or the 1st dose of 
enoblituzumab, if applicable). If an IP catheter cannot be placed, the patient will be 
taken off study per Section 6.4. 
 


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The peritoneal site where the catheter is to penetrate the peritoneum is identified 
under direct vision by Interventional Radiology. It is important to enter the 
peritoneal cavity under direct vision because a previous staging laparotomy for 
ovarian cancer is likely to have resulted in adhesion formation, particularly between 
the bowel and anterior abdominal wall. The catheter insertion site through the 
peritoneum must be separate from other incisions.  
 
The intraperitoneal catheter to be used in the proposed clinical study is PLEURX 
PERITONEAL CATHETER KIT AND PLEURX DRAINAGE KITS, which is 
manufactured by Becton Dickinson in Franklin Lakes, NJ. The catheter is Device 
Class 2 and is 510K-clearedK051711. 
 
There is a risk for spread of cancer cells that are located within the peritoneum to 
surrounding tissues such as the abdominal wall. This risk is associated with the 
penetration of the abdominal cavity during the IP catheter placement as it exposes 
new surfaces for the cancer cells to attach. Implantation of malignant cells within 
surgical incisions and along biopsy needle and drainage catheter tracts is a 
recognized mechanism for the dissemination of cancer. In one review published of 
255 patients with epithelial ovarian carcinoma, Dauplat et al. (Dauplat, et al. 1987) 
included nine cases (3.5%) with skin metastases, one of which occurred at the site 
of a catheter used for intraperitoneal chemotherapy. Kohler et al. (Kohler, et al. 
1991) described two patients who were treated with intraperitoneal administration 
and subsequently developed abdominal wall metastases. In one case the lesions 
were at the site of previous surgical incisions. In the other, metastasis occurred at 
the former site of the peritoneal access catheter which had been removed after 
therapy 2.5 years earlier. Implantation metastases is a potential hazard of all 
invasive procedures in the case of malignancy. Although thought to be a rare 
event, placement of a peritoneal access catheter in ovarian cancer may be a risk 
for seeding tumor cells. 
 
The baseline research related peritoneal cell collection (ascites or intraperitoneal 
washing) and a tumor biopsy, if feasible, will be done at placement. Refer to 
Section 10.2.1 and Section 10.2.2. 
 
The catheter will remain in place until approximately Day 36 for peritoneal cell 
collection and biopsy unless progression is confirmed earlier or there are issues 
related to the functioning or safety of the catheter (i.e. infection, plugged up, etc.). 
If the patient agrees to and qualifies for retreatment, the IP catheter remains in 
place until approximately retreatment Day 29 (rDay 29). 
 
 


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7.2 Enoblituzumab (Day -6 then Day 22 and every 3 weeks thereafter) - Cohort 5 
and 6 only 
Treatment may be administered in the outpatient setting or as an inpatient. 
Enoblituzumab 15 mg/kg is given as an intravenous infusion over 120 minutes (±15 
minutes) using a commercially available pump. A sterile, non-pyrogenic, low-
protein binding polyethersulfone (PES) 0.2 micron in-line filter administration set 
must be used for IV administration of enoblituzumab. 
The full, calculated dose will be administered based on the patient’s actual weight 
at baseline; a significant (≥10%) change in body weight from baseline should 
prompt recalculation of the dose. For patients with a body mass index (BMI) ≥30 
kg/m2, the enoblituzumab dose will be calculated using ideal body weight (IBW).  
There are no other enoblituzumab dose modifications; however, reduction in the 
infusion rate is permissible if the patient has experienced an infusion-related 
reaction 
The 1st dose of enoblituzumab is given Day -6 with some flexibility as provided in 
the Section 7 introduction.  
Subsequent doses of enoblituzumab are given every 3 weeks (±2 days) starting 
on Day 22 using the 1st dose of FT538 as Day 1. Refer to Section 7.2.1 regarding 
corticosteroid use relative to FT538 administration which may affect the Day 22. 
Enoblituzumab may continue until disease progression, unacceptable side effects, 
patient refusal or non-compliance, or felt to no longer be of benefit to the patient 
by the treating investigator. 
If a patient is eligible for retreatment per Section 6.3, the 3rd dose of enoblituzumab 
(around Day 43) ideally serves as the anchor for the CY/FLU and FT-538 
administration. 
7.2.1 Enoblituzumab Pre-Medications and Prophylaxis Guidelines  
Required prior to the first infusion of enoblituzumab: 
 Acetaminophen 650-1000 mg orally (PO) or ibuprofen 400 mg PO, or 
equivalent 
 Diphenhydramine 50 mg PO or IV or equivalent H1 antagonist 
 Ranitidine 300 mg PO or IV or equivalent H2 antagonist 
 Dexamethasone 10-20 mg IV 
No pre-infusion prophylactic steroids are required for subsequent infusions. Non-
steroidal pre-medications may be administered prior to the subsequent infusion, if 
warranted.  


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If the patient experiences a ≥ Grade 1 infusion related reaction with the first infusion 
refer to the recommended pre-medications found in the Infusion Related Reaction 
in Section 7.2.2. If a patient requires corticosteroid pre-medication for subsequent 
doses, the Day 22 dose must be delayed until Day 29 (or 14 days after the final 
dose of FT538). Beyond Day 29, steroid use is permitted as a pre-medication; 
however, if the patient qualifies for retreatment, the same 14 day rule for 
corticosteroid use applies. Changes to the enoblituzumab schedule are not a 
protocol deviation.  
Antiemetic therapy including but not limited to neurokinin 1 (NK1) receptor 
antagonists, 
serotonin 
(5HT3) 
receptor 
antagonists, 
benzodiazepines, 
antihistamines, cannabinoids, cholinergic antagonists and dopamine receptor 
antagonists may be administered according to good clinical practice and local 
guidelines.  
7.2.2 Monitoring During the Enoblituzumab Infusion Period 
To date, the most important safety risk that has been identified with enoblituzumab 
is infusion-related reactions (IRR), including cytokine release syndrome (CRS) due 
to the release of small proteins (cytokines) from the cells. IRRs are generally 
temporary effects due to a drug that may occur during or shortly after infusion of 
the drug. Signs and symptoms of an infusion-related reaction may include fever, 
chills, nausea, vomiting, headache, muscle stiffness, rash, itching, low blood 
pressure, and difficulty breathing. IRRs can be life threatening and, in rare cases, 
may cause death.  
Obtain vital signs (temperature, blood pressure, respiration and pulse) upon 
arrival, within 15 minutes prior to start of the enoblituzumab, every 15 minutes (± 
5 minutes for the first hour of the infusion, every 30 minutes (±5 minutes) thereafter 
until infusion end, upon discontinuing the infusion, and before the patient is 
discharged from the clinic. 
7.2.3 Management of Enoblituzumab Infusion Related Reactions 
Refer to Section 9 for a list of the most common side effects associated with 
enoblituzumab.  
Grade 3 or greater infusion related reactions are reportable as a DLT (the DLT 
period for Dose Cohorts 5 and 6 begins with the 1st dose of enoblituzumab through 
28 days after the 1st FT538 infusion), adverse events of special interest (AESI) 
and/or SAEs, as applicable per Section 11.2. In the event, Cohort 5 or 6 is reached 
while enrollment is still in Stage 1 Step 1, a Grade 3 infusion reaction is pre-defined 
adverse event that triggers movement to either Stage 1 Step 2 or Stage 2 as 
detailed in the study design. 


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The following are treatment guidelines (which may be modified as needed by the 
Investigator according to the best practices of medicine) for infusion reactions: 
Grade 1 Infusion Related Reaction: 
 Slow the infusion rate by 50%. 
 Monitor the patient for worsening of condition. 
 Continue rate at 50% reduction and increase dose rate to the original rate by 
doubling the infusion rate after 30 minutes, as tolerated to the initial rate. 
Consideration can be given to beginning subsequent infusions at 50% rate and 
increasing as tolerated. 
 The following prophylactic pre-infusion medications are recommended prior to 
future infusions of enoblituzumab for patients who experience Grade 1 infusion 
reactions (restrictions apply to the Day 43 infusion if FT538 retreatment is 
planned): 
o Diphenhydramine 25 to 50 mg (or equivalent) PO/IV. 
o Acetaminophen 650 mg PO and/or ibuprofen 400 mg PO, or equivalent, at 
least 30 minutes before additional enoblituzumab infusions. 
o Ranitidine 300 mg PO or 50 mg IV or equivalent H2 antagonist before 
additional enoblituzumab infusions. 
Grade 2 Infusion Related Reaction: 
 Stop the enoblituzumab infusion. 
o Administer diphenhydramine hydrochloride 25 to 50 mg IV. 
o Acetaminophen 650 mg PO or ibuprofen 400 mg PO, or equivalent, for fever. 
o Oxygen and bronchodilators for mild bronchospasm. 
 Resume the enoblituzumab infusion at 50% of the prior rate once the infusion 
reaction has resolved or decreased to Grade 1. The rate may then be escalated 
to the original rate after 30 minutes, as tolerated. Consideration can be given 
to beginning all subsequent infusions at 50% rate and increasing as tolerated. 
 Monitor for worsening condition. If symptoms recur, discontinue the 
enoblituzumab infusion; no further enoblituzumab will be administered at that 
visit. 
 Prophylactic pre-infusion medications should be given prior to subsequent 
infusions of enoblituzumab.  
o Patients who experience Grade 2 infusion reaction, for subsequent doses of 
enoblituzumab, pre-medicate with diphenhydramine hydrochloride 25 to 50 
mg IV/PO and acetaminophen 650 mg PO and/or ibuprofen 400 mg PO (or 
equivalent) at least 30 minutes before additional enoblituzumab 
administrations.  
o For patients with Grade 2 enoblituzumab infusion reactions, despite 
premedication with diphenhydramine and acetaminophen and/or ibuprofen 


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(or equivalent), corticosteroids (10 to 20 mg dexamethasone IV or 
equivalent) may be added to the premedication regimen for the next dosing 
of enoblituzumab. Reduce corticosteroid dosing by 50% for the subsequent 
dose and hold thereafter, if there are no reactions. 
  
Grade 3 Infusion Related Reaction: 
 
STOP THE ENOBLITUZUMAB INFUSION AND DISCONNECT THE 
INFUSION TUBING FROM THE PATIENT. 
 
TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL ENOBLITUZUMAB FROM 
THE PORT LUMEN. 
 
Administer diphenhydramine hydrochloride 25 to 50 mg IV, dexamethasone 
20 mg IV (or equivalent), and other medications/treatment as medically 
indicated. Higher doses of corticosteroids (e.g., methylprednisolone 2 to 4 
mg/kg IV or the equivalent) may also be considered for acute management. 
 
Consider administering, tocilizumab (an IL6 receptor antagonist) 4 mg/kg IV. 
 IV fluids, supplemental oxygen, H2 blockers such as ranitidine and 
bronchodilators should be considered, as appropriate. 
 If the Grade 3 infusion reaction occurs with any enoblituzumab dose, it will be 
discontinued for that day.  
o If symptoms have resolved to baseline within 12 hours, enoblituzumab may 
be infused at the next scheduled dose, with a 50% reduction of infusion rate. 
In addition, patients should be pre-medicated for this re-challenge and for 
any 
subsequent 
doses 
of 
enoblituzumab 
with 
the 
following: 
diphenhydramine hydrochloride 25 to 50 mg IV, acetaminophen 650 mg PO 
and/or ibuprofen 400 mg PO (or equivalent); corticosteroids should be 
considered as well (dexamethasone 10 to 20 mg IV or equivalent). Reduce 
corticosteroid dosing by 50% for the subsequent dose and hold thereafter, if 
there are no reactions. 
o Patients who have a Grade 3 infusion reaction that does not resolve within 
12 hours despite medical management should be discontinued from 
enoblituzumab. 
 Patients who experience a second Grade 3 infusion reaction to enoblituzumab 
at the time of re challenge of enoblituzumab will permanently discontinue 
enoblituzumab. 
Grade 4 Infusion Related Reaction: 
 STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PATIENT. 


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 TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING. ASPIRATE ENOBLITUZUMAB FROM THE PORT 
LUMEN 
 Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 20 mg IV 
(or higher doses of steroids, e.g., methylprednisolone 2 to 4 mg/kg IV or the 
equivalent, as considered appropriate). 
 Consider administering, tocilizumab (an IL6 receptor antagonist) 4 mg/kg IV. 
 Give epinephrine or bronchodilators as indicated. 
 Support ventilation and blood pressure as indicated. 
 Patients who have a Grade 4 infusion reaction will permanently discontinue 
enoblituzumab. 
7.3 Preparative Regimen (Day -5 and Day -4) 
A lymphodepleting regimen of fludarabine and cyclophosphamide is given in the 
outpatient setting on two consecutive days. A minimum of 48 hours must be 
maintained between the last dose of fludarabine and the 1st dose of FT538 on 
Day 1. 
Cohort 5 and Cohort 6 only: If there is unresolved toxicity associated with the 
enoblituzumab, the treatment plan may be delayed as needed; however, a 
minimum of 48 hours must be maintained between the last dose of fludarabine and 
the 1st dose of FT538 (Day 1).  
The administration of the preparative regimen will follow the institutional dosing 
guidelines. Dose and/or schedule adjustments consistent with the standard of care 
may be made on an individual patient basis as needed for safety.  
Fludarabine 25 mg/m2 is administered as a 1 hour intravenous (IV) infusion per 
institutional guidelines once a day on 2 consecutive days. 
Cyclophosphamide 300 mg/m2 is administered as a 2 hour intravenous infusion 
per institutional guidelines once a day on the same 2 days fludarabine is given.  
Cyclophosphamide dosing is calculated based on ABW (Actual Body Weight) 
unless ABW is >150% of the IBW (Ideal Body Weight). 
Adjusted body weight = IBW + 0.5(ABW-IBW). 
Cyclophosphamide associated hydration will be given according to recommended 
institutional standards. 
 
 


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7.4 FT538 (Day 1, Day 8, and Day 15) 
A minimum of 48 hours must separate the last dose of fludarabine and the 1st dose 
of FT538. The 1st dose of FT538 may be delayed for up to 7 days after the last 
dose of fludarabine if the study physician feels a delay is in the best interest of the 
patient. The 1st dose of FT538 equals Day 1. There is no Day 0. 
A ±1 day window is permitted for subsequent infusions to accommodate 
scheduling issues. 
7.4.1 Decision to Treat on Day of Planned FT538 
If a patient experiences a dose limiting toxicity with the previous dose of FT538, 
FT538 is permanently discontinued.  
Three weekly doses of FT538 are planned; however, if on the day of treatment, 
the study physician feels it is not in the best interest of the patient to receive 
treatment: 
 The FT538 may be delayed for up to 48 hours adjusting future time points 
to maintain timing if subsequent FT538 is to be given OR 
 The FT538 dose is skipped and the patient is scheduled for the next 
planned visit. Skipped dose(s) are not made up. 
For AE(s) considered not related or unrelated to FT538, schedule modification of 
FT538 is not required if in the opinion of the treating investigator, such AE(s) do 
not represent a safety risk to the patient. 
Additional modifications to the FT538 dosing schedule, including dosing delays, 
will be based on consultation between the treating investigator and the PI, and 
Fate Therapeutics, if applicable. 
7.4.2 FT538 Intraperitoneal Infusion Guidelines 
Pre-medications: Patients should be pre-medicated with acetaminophen 650 mg 
orally and diphenhydramine 25 mg orally before and 4 hours after the 
administration of FT538. Corticosteroids should not be used as pre-medication for 
FT538.  
Vital Signs include oral temperature, blood pressure, heart rate, respiratory, and 
pulse oximetry. On days of FT538 administration, collect as follows: within 15 
minutes prior to the infusion of FT538, after the final flush/prior to start of 
repositioning, and every 15 minutes (±5 minutes) for 1 hour from the end of the 
administration. The end of administration time is after the rinse step has been 
completed for the last administered bag of FT538. 
 
 


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FT538 Infusion guidelines: FT538 is provided in one or more cryopreserved bags 
depending on the patient’s assigned FT538 cell dose. 
FT538 must be administered using an IV administration set without an in line filter 
(filter is not required for IP administration). FT538 is administered as an IP infusion 
via gravity after any ascites or IP wash fluid has been drained.  
After priming and set up have been performed, administer as follows:  
1. Close all roller clamps on the infusion set.  
2. Fully spike saline source container and prime the infusion set following the 
applicable package instructions.  
3. Connect set to recipient.  
4. Fully spike an inverted FT538 bag with the unused Y-lead. Do not spike FT538 
bag while it is hanging.  
5. Slowly open the roller clamp below FT538 bag and adjust for desired flow rate.  
6. When FT538 bag is empty, close all clamps.  
7. It is recommended each bag and tubing be flushed with up to 50 cc of room 
temperature normal saline; however, the flush volume may be adjusted at the 
discretion of the treating investigator. Close all clamps and invert FT538 bag 2-
3 times to ensure thorough rinsing. 
8. Open the roller clamp that is nearest to the subject and then slowly open the 
roller clamp below FT538 bag and adjust for desired flow rate.  
9. When FT538 product container is empty, close the clamp below the FT538 bag.  
10. If additional FT538 bags are to be infused, once the new FT538 bag is thawed, 
remove the empty FT538 bag and spike the new FT538 bag. Repeat Steps 1-
9 for each additional bag.  
11. Record the end of administration time after the rinse step has been completed 
for the last FT538 bag. 
 
After the final flush, the patient is asked to change position at 15-minute intervals 
for two hours to ensure adequate intra-abdominal distribution. No attempt will be 
made to retrieve the infusate.  
7.4.3 Monitoring During and Post-Infusion 
Monitor the patient for signs of acute infusion related reaction during and after IP 
infusion. For IV infusion signs of a possible reaction are rigors and chills, rash, 
urticaria, hypotension, dyspnea, and angioedema. Abdominal pain and/or 
cramping was the most common adverse event with IP administration of other Fate 
NK products (FT516, NK100), and NK cell products in general (all given with IL-2). 


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If an acute infusion reaction of any grade occurs do not give any remaining bags 
of cells (if relevant). Refer to Table 1 for management guidelines based on infusion 
related reaction CTCAE v5 grading. 
7.4.4 Potential Risks Associated with FT538 
In this study FT538 is infused by intraperitoneal (IP) infusion. In our previous 
studies of IP infusion of NK cell products including Fate NK100 and FT516 (each 
given with IL-2) abdominal pain and cramping were observed in the majority of 
patients. Most were CTCAE 5 Grade 1 or Grade 2, with an occasional Grade 3 
event. The pain usually was managed with oral and/or intravenous analgesics. 
The following are potential risks of FT538 when given as an intravenous (IV) 
infusion. Refer to the current FT538 Investigator Brochure for a complete list of 
expected toxicities. 
7.4.4.1 Acute Allergic/Infusion Reaction  
Acute allergic/infusion reactions may occur with any treatment, including with 
the use of CY, FLU, and mAbs. Patient should be closely monitored for the 
occurrence of acute allergic/anaphylactoid infusion reactions such as rigors 
and chills, rash, urticaria, hypotension, dyspnea, and angioedema during and 
following completion of the infusion.  
Acute allergic/infusion reactions may also be a manifestation of FT538 
immunogenicity given that FT538 is an allogeneic cell product. Recommended 
guidelines for management of subjects who develop acute allergic/infusion 
reactions to FT538 are provided in Section 8.2.1 Table 1.  
7.4.4.2 Immunogenicity Risks  
It is possible that FT538 may induce an immune response, which may manifest 
only through laboratory assessments, or may manifest clinically, e.g., as 
infusion-related reactions with varying degrees of severity, including serious 
life-threatening anaphylactic reactions. In addition, FT538 immunogenicity may 
have an impact on FT538 PK, which in turn may have an impact on FT538 anti-
tumor activity. Evidence of FT538 immunogenicity and its clinical impact will be 
monitored during the study. AEs arising from FT538 immunogenicity will be 
managed per institutional practice.  
7.4.4.3 
DMSO-Related Risks  
FT538 is formulated in DMSO to enable cryopreservation. DMSO side effects 
and symptoms are generally associated with histamine release and include 
coughing, flushing, rash, chest tightness and wheezing, nausea and vomiting, 
and cardiovascular instability. Treat by slowing the rate of infusion, medicating 


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with antihistamines, and treating symptoms per institutional practice (AABB 
2016).  
7.4.4.4 
Infection  
FT538 is cell therapy of human origin. During processing, the cells are in 
contact with reagents of animal origin, and FT538 has a final formulation which 
contains albumin (human). As with any product of human and/or animal origin, 
transmission of infectious disease and/or disease agents by known or unknown 
agents may occur. FT538 has been extensively tested to minimize the potential 
risk of disease transmission. However, these measures do not completely 
eliminate the risk. For some infectious agents, there are no routine tests to 
predict or prevent disease transmission (AABB 2016).  
7.4.4.5 
Cytokine Release Syndrome  
CRS is a symptom complex associated with multiple therapeutic modalities, 
including mAbs and CAR T-cell therapies that arise from lymphocyte activation, 
which in turn results in the release of cytokines. Clinical manifestations of CRS 
include cardiac, gastrointestinal, hepatic, coagulation, renal, respiratory, skin, 
and constitutional (fever, rigors, headaches, malaise, fatigue, arthralgia, 
nausea, and vomiting) signs and symptoms. Treatment-emergent adverse 
events (TEAEs) that may be attributed at least in part to CRS include fever, 
febrile neutropenia, hypotension, acute vascular leak syndrome, renal failure, 
hypoxia, and pleural effusion. Because the signs and symptoms of CRS are 
not unique to CRS, other causes of fever, hypotension, and/or hypoxia must be 
excluded. Notably, bacteremia and other severe infections have been reported 
concurrent with and even mistaken for CRS (Lee et al. 2019). While CRS is a 
clearly defined syndrome with CAR T-cell therapy, it is generally not believed 
to be a toxicity associated with NK-cell therapies unless administered with 
systemic cytokines that may independently drive the proliferation and activation 
of CD8+ T cells, e.g., exogenous IL-15 (Cooley et al. 2019). To consistently 
characterize its severity, CRS should be graded according to ASTCT CRS 
consensus grading (Lee et al. 2019; Table 6). In addition to clinical 
manifestations, if CRS is suspected, CRP and ferritin levels should be 
assessed locally, and blood samples should be collected for central cytokine 
analysis per Section 10.2. Recommended guidelines for management of 
subjects who develop CRS are provided in Section 8.2.2. 
7.4.4.6 
Tumor Lysis Syndrome  
TLS is a possible fatal risk associated with anti-tumor therapy in both 
hematologic and solid tumors, especially with large tumor burden (Mirrakhimov 
et al. 2014). TLS symptoms include nausea, vomiting, diarrhea, muscle cramps 
or twitches, weakness, numbness or tingling, fatigue, decreased urination, 


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irregular heart rate, restlessness, irritability, delirium, hallucinations, and 
seizures. TLS is comprised of abnormal laboratory changes that include 
hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. TLS 
has been reported to occur within 7 days following chemotherapy across 
various solid tumor settings, with 10 published reports of TLS cases in patients 
with gynecological cancer (Mirrakhimov et al. 2014). One case of fatal 
metabolic syndrome compatible with TLS was reported following NK-cell 
therapy in a patient with ovarian cancer 5 days after receiving CY (Geller et al. 
2011). Prophylaxis for and management of TLS should be done in accordance 
with standard institutional practice. Following FT538 administration, subjects 
should be followed closely for signs and symptoms of TLS, with regular clinical 
(including telemetry where applicable) and laboratory monitoring. Laboratory 
abnormalities suggestive of TLS should prompt immediate action by the 
treating clinicians, and TLS should be treated aggressively per institutional 
practice.  
7.4.4.7 
Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Neurologic toxicity has been reported frequently with blinatumomab and CAR 
T-cell therapy (Blincyto® USPI; Kochenderfer et al. 2015; Maude et al. 2014). 
The etiology of toxicity in these settings is not known and may not be 
responsive to cytokine-directed therapy such as tocilizumab but has generally 
improved with treatment discontinuations and corticosteroids (Blincyto USPI; 
Goebeler et al. 2016; Kochenderfer et al. 2015) While CNS toxicity is a clearly 
defined syndrome associated with CAR T-cell-based therapies, it is rare and 
generally not believed to be a toxicity associated with NK-cell therapies. 
Neurotoxicity was reported in one trial of adoptively transferred NK cells given 
with subcutaneous IL-15, but the mechanism of the toxicity was not well defined 
(Cooley et al. 2019). Nervous system toxicities following CD19 CAR T-cell 
therapy is characterized by encephalopathy, confusion, delirium, aphasia, 
obtundation, and seizures (Kymriah USPI; Yescarta USPI). Cases of cerebral 
edema have also been reported (Brudno and Kochenderfer 2016). To 
consistently characterize its severity, neurotoxicity must be graded using 
ASTCT consensus for grading ICANS (Lee et al. 2019; Table 4). 
Recommended guidelines for management of subjects who develop 
neurotoxicity are provided Section 8.2.3. 
7.4.4.8 
Acute Graft-versus-Host Disease  
Because FT538 is an allogeneic immune effector cell product, there is a 
potential risk of GvHD even though allogeneic NK-cell therapies have not been 
associated with GvHD (Veluchamy et al. 2017). Acute GvHD assessments will 


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be performed with assignment of the overall severity based on the CIBMTR 
acute GvHD grading scale (Table 5). Management of GvHD should be done in 
accordance with local institutional practice. 
Refer to Section 8 for Management of Selected Adverse Events including dose 
delays and modifications. 
7.5 Monitoring for Dose Limiting Toxicities and Excessive Toxicity 
Toxicity and adverse events is classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 5.0 (CTCAE) unless otherwise noted in 
Section 11.  
All patients are monitored for dose limiting toxicity (DLT) and excessive toxicity 
during the 1st 28 days after the 1st FT538 infusion. For Dose Cohorts 5 and 6, the 
monitoring begins with enoblituzumab and continues for 28 days after 1st FT538. 
In addition, during the fast-track dose escalation only (Stage 1, Step 1), 
patients also are monitored for the pre-defined treatment emergent events of within 
28 days after the 1st FT538 infusion (for Cohort 5 and 6, DLT assessment starts 
with enoblituzumab and continues for 28 days after 1st FT538): 
• Grade 3 abdominal pain, not attributable to the cancer, within 28 days after the 
1st FT538 infusion lasting more than 48 hours despite treatment with standard 
analgesics  
or  
• 
Grade 3 infusion related reaction within 24 hours after the 1st FT538 infusion 
in any Dose Cohort or 1st enoblituzumab infusion in DC 5 or DC 6 and 
symptoms resolve to baseline within 12 hours.  
 
Dose Limiting Toxicity (DLT) is defined as any treatment emergent toxicity at 
least possibly related to the investigational product(s) meeting one of the following 
criteria based on CTCAE v5 within 28 days (within 14 days for ascites) after the 1st 
FT538 infusion: 
• Grade 3 organ disorders (pulmonary, hepatic, renal, or neurologic) and lasting 
more than 72 hours  
• Grade 3 abdominal pain not attributable to cancer lasting more than 4 
consecutive days and not controlled by standard analgesics 
• Grade 3 or greater ascites within 14 days after FT538 administration in patients 
who had no ascites or Grade 1 ascites at enrollment and is not attributable to 
disease progression 
• Any non-hematologic Grade 4 or 5 toxicity 


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• Grade 4 neutrophil count decreased that persists at Day 28 despite use of 
growth factor support 
All patients are monitored for DLT events during the 1st 28 days after the initial 
FT538 infusion. The DLT period does not end until: 
1) results from lab work drawn Day 29 (+3 days) does not meet a DLT and  
2) a patient assessment on Day 29 (+3 days), confirms no new DLT since the last 
assessment or ongoing DLT events. 
Monitoring for Excessive Toxicity (all patients) 
Monitoring guidelines are in place for excessive toxicity. Refer to Section 14.4 for 
complete details: 
• 
Excessive dose limiting toxicity (DLT) events - the trial will be stopped if the 
posterior probability that the lowest dose is unacceptably toxic (> 25% of 
patients) is greater than 80% as determined by the study statistician. 
• 
Grade 3 or greater Infusion Related Reaction through Day 28 in association 
with any FT538 infusion in any Dose Cohort or in association with 
enoblituzumab in Dose Cohort 5 and 6. 
• 
Early Death (Grade 5 Event) within 28 days after the last dose of FT538. 
7.6 Supportive Care 
Throughout the study, the investigator may prescribe any concomitant medications 
not otherwise described as cautionary therapy or prohibited therapy (refer to 
Section 7.7) or treatment deemed necessary to provide adequate supportive care.  
 
Supportive care may include antibiotics, analgesics, transfusions, growth factors, 
etc. Only irradiated blood products should be used to minimize the risk of 
transfusion-associated GvHD.  
7.7 Cautionary and Prohibited Therapy 
Systemic corticosteroids should be avoided during the treatment, unless absolutely 
required, because they may inhibit NK-cell function. Because of their deleterious 
effect on NK-cell-based therapy, corticosteroids as pre-medication for CY and FLU 
should be avoided unless considered necessary by the investigator and should not 
be administered within 3 days before or within 14 days after FT538 administration. 
Intravenous glucocorticoid as pre-medication for cyclophosphamide, fludarabine, 
and enoblituzumab may be administered per the USPI or institutional guidelines. 
Methylprednisolone should be used as the preferred glucocorticoid pre-medication 
given its shorter half-life. Long-acting corticosteroids, such as dexamethasone, 
should not be used.  
Glucocorticoids must not be used as pre-medication for FT538. 


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Any antineoplastic agent for therapeutic intent other than protocol-designated study 
treatment(s) is prohibited until after the 1st disease reassessment. 
7.8 Duration of FT538 Treatment and Possible Retreatment 
Treatment with FT538 consists of a single treatment course of 3 weekly doses on 
Day 1, Day 8, and Day 15 in the absence of a dose limiting toxicity or 
contraindication for treatment as detailed in Section 7.4.1. For participants 
assigned to Dose Cohort 5 or Dose Cohort 6, enoblituzumab may continue every 
3 weeks per Section 7.9.  
If a patient has clinical benefit (SD, PR or CR per RECIST and no decline from the 
baseline performance status) at the 1st disease re-assessment around Day 36, 
they may be eligible to repeat the treatment using their same Dose Cohort provided 
the criteria in Section 5.3 is met.  
Retreatment has no effect on the primary and secondary analysis; however, 
adverse events (safety data) are documented in 2021LS103R and reported per 
Section 11. Study endpoints progression free survival and overall survival remain 
at 6 months and 12 months from the 1st dose of FT538 (Day 1). 
7.9 Duration of Enoblituzumab (COHORT 5 or 6 ONLY) 
Enoblituzumab may continue until disease progression, unacceptable side effects, 
patient refusal or non-compliance, or felt by the treating investigator to no longer 
be of benefit to the patient.  
If ongoing at the end of the planned study participation at 12 months, 
enoblituzumab may continue beyond 12 months in the absence of disease 
progression and unacceptable toxicity. 
An End of Treatment visit should occur approximately 3 weeks after the last dose 
of enoblituzumab.  
7.10 Duration of Study Participation 
Patients will be followed for disease response per standard of care until disease 
progression/relapse or the start of a new treatment, and then survival only for 12 
months from the 1st FT538 infusion unless: 
 consent for follow-up is withdrawn  
 patient did not receive FT538 – if a patient is not evaluable, follow only until the 
resolution or stabilization of treatment related toxicity 
 patient is discharged to hospice (terminal) care - follow for survival only   
 


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Research related safety samples for Fate are collected per Section 10.2 at a 
standard of care visit closest to the targeted timepoint for those continuing their 
care at the University of Minnesota.  
 
If a patient is not returning to the University of Minnesota for care, disease 
response (if progression was not previously established) and survival information 
may be obtained from the local medical doctor or other sources, such as public 
records.  
 
If applicable, enoblituzumab may continue every 3 weeks beyond 12 months in the 
absence of disease progression and unacceptable toxicity. 
 
Any patient receiving at least one dose of FT538 is followed for up to 15 years for 
late effects and survival. During the 1st year LTFU data is collected and recorded 
under the LTFU study. After the final treatment study endpoint at 12 months, the 
patient continues on the long-term follow-up protocol for safety, anti-tumor activity, 
and survival for up to 15 years from the 1st FT538 infusion. 
8 Management of Adverse Events Related to FT538 
Refer to Appendix III for expected toxicities of the lymphodepleting regimen and Section 9 
for management of toxicities related to enoblituzumab. 
8.1 Management Guidelines for Specific FT538 Adverse Events 
In this study FT538 is infused intraperitoneally. In our previous studies of 
intraperitoneal (IP) Fate NK100 and FT516 (each given with IL-2) abdominal pain 
and cramping was seen in association with the administration of the investigational 
product. The pain was usually managed with oral and/or intravenous analgesics.   
Recommended guidelines for the management of specific AEs associated with 
intravenous (IV) administration are outlined below.  
For cases in which management guidelines are not covered in the protocol or 
current local prescribing information, participants should be managed as deemed 
appropriate by the investigator according to best medical judgement. 
8.1.1 Acute Allergic/Infusion Reactions 
Acute allergic/infusion reactions may occur with any treatment, including with the 
use of CY, FLU, and enoblituzumab.  
Patients are monitored for acute infusion related reactions associated with 
intravenous infusions including rigors and chills, rash, urticaria, hypotension, 
dyspnea, and angioedema during and after IP infusion  


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The recommended management of acute infusion or allergic reactions that occur 
during FT538 administration is described in Table 1 based on intravenous infusion.  
Appropriate medical care beyond what is described in the protocol should be 
instituted as per the respective current local prescribing information or standard 
institutional practices. Because they may inhibit NK-cell function, systemic 
corticosteroids should be avoided unless absolutely required for the management 
of acute allergic/infusion reactions, as determined by the investigator. 
Table 1: Recommended Guidelines for the Management of Acute Allergic/Infusion Reaction 
with FT538 Administration (Based on IV Infusion) 
Grade based 
on CTCAE v5 
Management 
Any Grade 
• Interrupt FT538 administration.  
• Manage symptoms, e.g., with antihistamines, antipyretics, and analgesics, 
according to standard institutional practice standards 
Grade ≤3 
• Resume FT538 administration only upon complete resolution of the infusion-
related reaction and at the discretion of the investigator. Given that FT538 
administration may involve single or multiple bags depending on the total planned 
dose and accounting for the stability of FT538 post-thaw, FT538 administration 
may continue following resolution of Grade ≤3 infusion-related reactions as 
follows: 
If single-bag FT538 dosing:  
− No additional FT538 may be administered.  
− The volume of FT538 administered prior to the infusion-related reaction must 
be documented; retain any remaining product and contact the Sponsor for 
further instruction.  
− Additional bags may not be administered to make up for FT538that was not 
administered from the bag during which the infusion-related reaction occurred.  
If multiple-bag FT538 dosing: 
− The volume of FT538 administered from the bag during which the infusion-
related reaction occurred must be documented; retain any remaining product 
from the bag and contact the PI or designee for further instructions.  
− If dosing with additional FT538 bags was planned, they may be thawed and 
administered.  
− Additional bags beyond what was originally planned may not be 
administered to make up for FT538 that was not administered from the bag 
during which the infusion-related reaction occurred.  
Grade 4 
• Stop FT538 administration. Do not restart.  
− The volume of FT538 administered prior to the infusion-related reaction must 
be documented; retain any remaining product and contact the PI or designee 
for further instructions. 
 
 


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8.1.2 Cytokine Release Syndrome or CRS-Like Syndrome 
If CRS is suspected or diagnosed, CRP, ferritin, IL-6 levels should be assessed. 
If indicated by the presence of medically significant symptoms and/or high IL-6 
levels or any symptoms requiring intervention, corticosteroids are the first line of 
treatment. 
To consistently characterize its severity, CRS should be graded according to 
ASTCT CRS consensus grading (Lee et al. 2019; Table 2). In addition to clinical 
manifestations, if CRS is suspected, CRP, ferritin, IL-6 levels should be assessed.  
Recommended guidelines for management of subjects who develop CRS are 
provided in Table 3. 
If CRS occurs (e.g. a differential diagnosis is recorded in the institutional medical 
record), CRP and ferritin levels should be done three times weekly until the 
resolution of CRS per Section 10.1. In addition, a serum sample should be 
collected for an IL-6 level at the time of any change (increase or decrease) in the 
CRS grade. Because patients may be outpatients any missed collection time 
points will not be a protocol deviations. 
 
Table 2. ASTCT Consensus Grading for Cytokine Release Syndromea  
CRS Parameter 
Grade 1 
Grade 2 
Grade 3  
Grade 4 
Feverb 
Temperature 
≥38˚C 
Temperature 
≥38˚C 
Temperature 
≥38˚C 
Temperature 
≥38˚C 
With either: 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring 
vasopressors 
with/without 
vasopressin 
Requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
And/orc 
Hypoxia 
None 
Requiring low-
flow nasal 
cannulad or 
blow-by 
Requiring high-
flow nasal 
cannula, 
facemask, non-
rebreather mask, 
or venturi mask 
Requiring 
positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
Source: Lee et al. 2019 
a Organ toxicities associated with CRS may be graded according to NCI CTCAE, v5.0, but they do not 
influence CRS grading.  
b Fever is defined as temperature ≥38°C not attributable to any other cause. Constitutional symptoms of CRS, 
such as myalgia, arthralgia, and malaise, are by themselves nonspecific; however, when coincident with fever 
in the expected timeframe, the etiology of CRS is more likely. In subjects who have CRS then receive 


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antipyretics or anti-cytokine therapy such as tocilizumab or corticosteroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.  
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other 
cause. For example, a subject with temperature of 39.5°C, hypotension requiring one vasopressor and 
hypoxia requiring low flow nasal cannula is classified as having Grade 3 CRS.  
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 liters/minute. Low flow also includes blow-by 
oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 
liters/minute.  
ASTCT = American Society for Transplantation and Cellular Therapy  
BiPAP = Bilevel positive airway pressure  
CPAP = Continuous positive airway pressure  
CRS = Cytokine release syndrome  
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5. 
 
Management of CRS should follow the recommended management algorithm 
provided in Table 3 (Neelapu 2018) and/or institutional practice. 
Table 3: Recommendations for the Management of Cytokine Release Syndrome 
Grade 
Sign/Symptom  Management 
Grade 1 
Fever or organ 
toxicity 
 Acetaminophen and hypothermia blanket for the treatment of fever 
 Ibuprofen can be used as second treatment option for fever, if not 
contraindicated 
 Assess for infection using blood and urine cultures, and chest 
radiography 
 Empiric broad‑spectrum antibiotics and filgrastim if neutropenic 
 Maintenance IV fluids for hydration 
 Symptomatic management of constitutional symptoms and organ 
toxicities 
 Consider tocilizumab 8 mg/kg a IV or siltuximab 11 mg/kg IV for 
persistent (lasting ≥3 days) and refractory fever 
Grade 2 
Hypotension 
 IV fluid bolus of 500–1,000 mL of normal saline 
 Can give a second IV fluid bolus if systolic blood pressure remains 
<90 mmHg 
 Tocilizumab 8 mg/kg a IV or siltuximab 11 mg/kg IV for the treatment 
of hypotension that is refractory to fluid boluses; up to 3 additional 
doses of tocilizumab may be administered, and the interval between 
consecutive doses should be at least 8 hours. 
 If hypotension persists after two fluid boluses and anti‑IL‑6 therapy, 
start vasopressors, consider transfer to ICU, obtain echocardiogram, 
and initiate other methods of hemodynamic monitoring 
 In subjects at high-risk b or if hypotension persists after 1–2 doses of 
anti‑IL‑6 therapy, dexamethasone can be used at 10 mg IV every 6 
hours 
 Manage fever and constitutional symptoms as in Grade 1 
Hypoxia 
 Supplemental oxygen 
 Tocilizumab or siltuximab ± corticosteroids and supportive care, as 
recommended for the management of hypotension 


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Table 3: Recommendations for the Management of Cytokine Release Syndrome 
Grade 
Sign/Symptom  Management 
Organ toxicity 
 Symptomatic management of organ toxicities, as per standard 
guidelines 
 Tocilizumab or siltuximab ± corticosteroids and supportive care, as 
indicated for hypotension 
Grade 3 
Hypotension 
 IV fluid boluses as needed, as recommended for the treatment of 
Grade 2 CRS 
 Tocilizumab and siltuximab as recommended for Grade 2 CRS, if not 
administered previously 
 Vasopressors as needed 
 Transfer to ICU, obtain echocardiogram, and perform hemodynamic 
monitoring as in the management of Grade 2 CRS 
 Dexamethasone 10 mg IV every 6 hours; if refractory, increase to 20 
mg IV every 6 hours 
 Manage fever and constitutional symptoms as indicated for Grade 1 
CRS 
Hypoxia 
 Supplemental oxygen including high‑flow oxygen delivery and 
non‑invasive positive pressure ventilation 
 Tocilizumab or siltuximab plus corticosteroids and supportive care, as 
described above 
Organ toxicity 
 Symptomatic management of organ toxicities as per standard 
guidelines 
 Tocilizumab or siltuximab plus corticosteroids and supportive care, as 
described above 
Grade 4 
Hypotension 
 IV fluids, anti‑IL‑6 therapy, vasopressors, and hemodynamic 
monitoring as defined for the management of Grade 3 CRS 
 Methylprednisolone 1 g/day IV 
 Manage fever and constitutional symptoms as in Grade 1 CRS 
Hypoxia 
 Mechanical ventilation 
 Tocilizumab or siltuximab plus corticosteroids and supportive care, as 
described above 
Organ toxicity 
 Symptomatic management of organ toxicities as per standard 
guidelines 
 Tocilizumab or siltuximab plus corticosteroids and supportive care, as 
described above 
Source: Neelapu et al. 2018; Actemra® USPI. 
CRS = cytokine release syndrome; ICU = intensive care unit; IV = intravenous, USPI = United States 
Prescribing Information 
NOTE: All medication doses indicated are for adults.  
a Maximum amount of tocilizumab per dose is 800 mg.  
b High-risk subjects include those with bulky disease and those with comorbidities. 
 
8.1.3 Neurotoxicity 
To consistently characterize its severity, neurotoxicity must be graded using the 
ASTCT guidelines for grading ICANS provided in Section 11 based on the Immune 


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Effector Cell-Associated Encephalopathy (ICE) score and Table 4. Per Section 11 
an assessment is done prior to each FT538, 2 to 4 hours later, and prior to 
discharge if the post-infusion stay extends beyond 4 hours.  
Determinants of the ICE score are: 
 Orientation: Orientation to year, month, city, hospital: 1 point each for 
maximum of 4 points 
 Naming: Name 3 objects (e.g., point to clock, pen, button): 1 point each for 
maximum of 3 points 
 Following commands: (e.g., show me 2 fingers or close your eyes and stick 
out your tongue): 1 point 
 Writing: Ability to write a standard sentence (e.g., our national bird is the bald 
eagle): 1 point 
 Attention: Count backwards from 100 by ten: 1 point 
Management of clinical neurotoxicity, i.e., encephalopathy syndrome, status 
epilepticus, 
and 
raised 
intracranial 
pressure, 
should 
follow 
current 
recommendations for CAR T-cell therapies (Neelapu 2018; Appendix IV: Table A-
1, Table A-2, and Table A-3) and/or institutional practice. 
Table 4: ASTCT Immune Effector Cell-Associated Neurotoxicity Syndrome Grading a 
Neurotoxicity 
Domain  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
ICE Score b  
7–9   
3–6  
0–2  
0 (subject is unarousable 
and unable to perform ICE.) 
Depressed level 
of 
consciousness c  
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to 
tactile stimulus 
Subjects is unarousable or 
requires vigorous or 
repetitive tactile stimuli to 
arouse. Stupor or coma. 
Seizure 
N/A 
N/A 
Any clinical seizure 
Focal/generalized 
that resolves rapidly; 
or Non-convulsive 
seizures on EEG that 
resolve with 
intervention 
Life-threatening prolonged 
seizure (>5 minutes); or 
Repetitive clinical or 
electrical seizures without 
return to baseline in 
between. 
Motor Findings d 
N/A 
N/A 
N/A 
Deep focal motor weakness 
such as hemiparesis or 
paraparesis 
Raised ICP/ 
Cerebral Edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging e 
Diffuse cerebral edema on 
neuroimaging; Decerebrate 
or Decorticate posturing; or 
Cranial nerve VI palsy; or 
Papilledema; or Cushing's 
triad 
ASTCT, American Society for Transplantation and Cellular Therapy; CTCAE, Common Terminology Criteria for 
Adverse Events; ICANS, immune effector cell-associated neurotoxicity syndrome; ICE, immune effector cell-
associated encephalopathy; ICP, intracranial pressure; EEG, electroencephalogram; N/A, not applicable. 


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a 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause. For example, a subject with an ICE score of 3 
who has a generalized seizure is classified as having Grade 3 ICANS. 
b 
A subject with an ICE score of 0 may be classified as having Grade 3 ICANS if the subject is awake with global 
aphasia. But a subject with an ICE score of 0 may be classified as having Grade 4 ICANS if the subject is 
unarousable. 
c 
Depressed level of consciousness should be attributable to no other cause (e.g. no sedating medication). 
d 
Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0 
but they do not influence ICANS grading. 
e 
Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is 
excluded from ICANS grading. It may be graded according to CTCAE v5.0. 
Reference: Lee 2019. 
Management of clinical neurotoxicity, i.e., encephalopathy syndrome, status 
epilepticus, 
and 
raised 
intracranial 
pressure, 
should 
follow 
current 
recommendations for CAR T-cell therapies (Neelapu 2018; Appendix IV: Table A-
1, Table A-2, and Table A-3) and/or institutional practice. 
8.1.4 Graft versus Host Disease 
Acute GvHD will be assessed according to criteria established by the CIBMTR 
Scale (Table 5). Management of GvHD should be done in accordance with local 
institutional practice. 
Table 5: Acute GvHD Scoring System for Individual Organs: CIBMTR Scale 
 
Skin 
Liver 
Gut 
stage 
 
 
 
1 
Rash on < 25% of skina 
Bilirubin 2-3 mg/dLb 
Diarrhea >500 mL/dayc or persistent 
nausead 
2 
Rash on 25%-50% of 
skin 
Bilirubin 3-6 mg/dL 
Diarrhea >1000 mL/day 
3 
Rash on >50% of skin 
Bilirubin 6-15 mg/dL 
Diarrhea >1500 mL/day 
4 
Generalized 
erythroderma with 
bullous formation 
Bilirubin >15 mg/dL 
Severe abdominal pain with or without 
ileus 
Grade 
I 
Stage 1-2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1  
III 
--- 
Stage 2-3 or 
Stages 2-4 
IV 
Stage 4 
Stage 4 
--- 
Source: CIBMTR 2020.  
a Use “Rule of Nines” or burn chart to determine extent of rash.  
b Range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin 
has been documented.  
c Volume of diarrhea applies to adults. For pediatric subjects, the volume of diarrhea should be 
based on body surface area. Downgrade one stage if an additional cause of diarrhea has been 
documented.  
d Persistent nausea with histologic evidence of GvHD in the stomach or duodenum.  
e Criteria for grading given as minimum degree of organ involvement required to confer that grade.  
f Grade IV may also include lesser organ involvement with an extreme decrease in Performance 
Status.  


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CIBMTR = Center for International Blood and Marrow Transplant Research GvHD = Graft-versus-
host disease 
 
9 Management of Selected Expected Toxicities Associated with 
Enoblituzumab (Dose Cohort 5 and 6) 
Refer to Appendix III for expected toxicities of the lymphodepleting regimen. 
9.1 Known Infusion Related Reaction (IRR) to Enoblituzumab  
Refer to Section 7.2.3 for the management of enoblituzumab related infusion 
reaction. 
To date, the most important safety risk that has been identified with enoblituzumab 
is infusion-related reactions (IRR), including reactions known as cytokine release 
syndrome (CRS) due to the release of small proteins (cytokines) from the cells. 
IRRs are generally temporary effects due to a drug that may occur during or shortly 
after infusion of the drug.  
Signs and symptoms of an infusion-related reaction may include fever, chills, 
nausea, vomiting, headache, muscle stiffness, rash, itching, low blood pressure, 
and difficulty breathing. Infusion related reaction or cytokine release syndrome was 
reported in 48.5% of 373 patients in MacroGenics-sponsored clinical trials of 
enoblituzumab, with 42.1% of patients experiencing IRR/CRS that were mild to 
moderate in severity. Events of IRR/CRS ≥ Grade 3 in severity were seen in 6.4% 
(n=24) of patients. Two of these patients with a ≥ Grade 3 IRR/CRS event 
experienced an event of life-threatening IRR/CRS (1 received enoblituzumab in 
combination with ipilimumab and 1 received enoblituzumab in combination with 
pembrolizumab). Refer to the Reference Safety Information of the current 
Enoblituzumab Investigator’s Brochure. 
9.2 Most Common Side Effects of Single Agent Enoblituzumab 
General risks associated with drugs similar to enoblituzumab: 
 Infusion reactions – Refer to Section 7.2   
 Immune-related side effect:  
o Pneumonitis (inflammation in the lungs) 
o Colitis (inflammation of the colon) 
o Hepatitis (inflammation of the liver) 
o Hypothyroidism  
o Adrenal insufficiency  


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o Kidney problems. 
o Encephalitis (inflammation of the brain) 
o Skin problems, including Stevens-Johnson syndrome (SJS) and toxic 
epidermal necrolysis (TEN) 
o Myocarditis (inflammation of the heart muscle) 
o Other issues including changes in eyesight, severe muscle or joint pain or 
weakness, and/or anemia. 
The following were the most common side effects that were considered related to 
single-agent enoblituzumab administration and were seen in at least 1 of 10 adult 
participants. As of 15 June 2021 Investigator’s Brochure, these side effects have 
been generally mild or moderate. 
Very Common (≥10%): 
• Infusion related reactions (IRRs) including CRS – Refer to Section 9.1 
• Fatigue 
• Nausea 
• Chills 
• Vomiting 
Common  
• Fever 
• Flu like symptoms 
• Decreased appetite 
• Headache 
• Pruritus 
10 Schedule of Patient Activities 
Virtual visits may replace in person clinic visits as relevant. Lab work and disease 
reassessments must be performed at the enrolling site, unless other arrangements 
are permitted as discussed with the study PI. In the event re-consent is required, it 
may be performed electronically (e-consent). 
There is some flexibility in the timing of the treatment as long as the ordering of 
the treatment is maintained and a minimum of 48 hours separates the last dose of 
fludarabine and the 1st FT538 infusion. If receiving enoblituzumab, at least 1 day must 
separate the dose of enoblituzumab and the start of the lymphodepletion 
chemotherapy. The 1st dose of FT538 may be delayed for up to 7 days after the last 
dose of fludarabine in the event FT538 cannot be given as planned. Day 1 is the day 
of the 1st FT538 infusion. There is no Day 0. 


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For Dose Cohorts 5 and 6 only: The 1st dose of enoblituzumab is given on Day -6 
before the start of the cyclophosphamide/fludarabine. Subsequent doses are given 
starting on Day 22 and every 3 weeks (±2 days) until no longer of benefit. Refer to 
Section 7.2.1 if the patient has an infusion related reaction with Dose 1 and it is 
recommended Dose 2 be given with steroid containing pre-medication. Adjustment to 
the enoblituzumab dosing to permit steroid use is not a protocol deviation. 
A window of ±1 day for scheduling issues is permitted for Day 1, Day 8, Day 15, and 
Day 22.  
As detailed in Section 7.4.1, if on the day of the planned treatment, the study 
investigator feels it is not in the best interest to treat the patient, the FT538 may be: 
 Delayed for up to 48 hours adjusting future time points to maintain timing OR 
 Skipped and the patient scheduled for the next planned visit. Skipped dose(s) are 
not made up. 
All patients are monitored for dose limiting toxicity (DLT) during the 1st 28 days 
after the initial FT538 infusion. The DLT period does not end until: 
1) None of the bloodwork results from the labs drawn Day 29 (+3 days) meet the 
definition of a DLT event and  
2) A patient assessment on Day 29 (+3 days), confirms no new DLT since the last 
assessment or ongoing DLT events. 
Assessments to be performed after Day 29 through the End of Treatment visit may be 
done ±3 days of the targeted date. In addition, targeted days may be altered as 
clinically appropriate. 
The same guidelines apply during retreatment with retreatment Day 29 (rDay29) being 
the final visit tied to retreatment. 
During follow-up, until disease progression or the start of a new treatment, the 
standard of care disease reassessment closest to the targeted follow-up date should 
be used for the Month 3, 6, 9, and 12 follow-up time points. Once disease progression 
is confirmed, follow-up is for survival only. Note: these same time points apply to 
patients who are continuing enoblituzumab, as disease status and survival are 
secondary endpoints.   
 
Standard of care (SOC) assessments and procedures are considered part of good 
clinical care and are charged to the patient and their health plan/health insurance. 


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10.1 Required Standard of Care Activities Refer to the introduction in Section 10 regarding timing of treatment. 
Shaded columns apply to Dose Cohorts 5 and 6 only. 
 
Screening1 
Within 28 days 
prior the 1st 
dose of 
CY/FLU or Eno 
(if applicable) 
Prior to the 
1st dose of  
CY/FLU or 
Eno (if 
applicable) 
Enoblituzumab 
(Eno) (Day -6) 
Cohort 5 and 
cohort 6 only 
CY/FLU  
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
22 
Day 29 (end 
of DLT 
period) 
Day 36 
End of Treatment 
(EOT) visit for 
FT538, unless 
retreated9 
for Cohort 5 and 6 only while 
receiving Enoblituzumab  
 
Follow-up all 
patients 3, 6, 9 
and 12 months 
from Day 15 
#1  
(Day -5) 
#2  
(Day -4) 
FT538 
#1 
 
FT538 
#1 
FT538 
#3 
Eno 
#2 
Day 43 and 
every 3 weeks  
End of 
Treatment 
visit10   
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess for Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Review of concurrent medications 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
X 
X 
As needed 
X 
 
Provider Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Determine if retreatment with FT538 
is an option, if yes refer to Section 
10.3 
 
 
 
 
 
 
 
 
 
 
 
X9 
 
 
 
Weight 
X 
 
X 
X 
 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals and Pulse Oximetry 
X 
 
X6 
 
 
X6 
 
X6 
X6 
X 
X 
 
X 
 
 
GOG Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ICANS (neurotoxicity) monitoring7 
 
 
X 
 
 
X7 
X 
X7 
X7 
X 
X 
X 
 
 
 
Toxicity Assessment: observed, 
patient reported or eMR abstraction 
(refer to Section 11.2 for AE 
documentation requirements) 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CBC, diff, plt 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Basic metabolic panel (BMP)3 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Comprehensive metabolic panel 
(CMP) or equivalent4 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
CRP and Ferritin (SOC)12 
 
 
Perform CRP and Ferritin 3 times weekly if CRS is suspected or diagnosed per Section 8.2.2. 
 
 
 
CA-125 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X5 
Urine or serum pregnancy test11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease staging by RECIST 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X5 
CT or PET-CT of chest, abdomen 
and pelvis 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X5 
Brain CT or MRI 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFTs 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEVF (ECHO, MUGA, or cardiac 
MRI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP catheter placement / removal if 
no retreatment 
 
X13 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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1 For screening, prior disease assessments may be used if they were performed within 42 days of the 1st FT538 infusion in the absence of intervening anti-cancer therapy. Consent is exempt 
from 28 day limit - may be performed at any time prior to starting study related activity, labs for eligibility and pregnancy testing must be repeated prior to the 1st dose of CY/Flu or enoblituzumab 
if > 14 days since done for eligibility. 
2 perform only if known history or as medically indicated 
3 basic metabolic panel consists of BUN, creatinine, calcium, glucose, lytes (CO2, Cl, Na, K)  
4 comprehensive metabolic panel consists of albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, 
creatinine, glucose, electrolytes (CO2, Cl, Na,, K), total bilirubin, and total protein 
5 Disease restaging per standard of care every 3 months until disease progression or start of a new treatment then follow for survival only for 12 months from the 1st FT538. Imaging/CA-125 
closest to the targeted follow-up date should be used for Month 3, 6, 9, and 12 follow-up. Note: these same time points apply to patients who are continuing enoblituzumab as disease status 
and survival are secondary endpoints.  
6 Additional vital sign timepoints on days of investigational product administration:  
Vital signs for FT538 - include oral temperature, blood pressure, heart rate, respiration rate, and pulse oximetry. On days of FT538 administration, collect as follows: within 15 minutes prior to 
infusion of FT538, after the final flush/prior to repositioning and every 15 minutes (±5) minutes for 1 hour following the end of infusion of the last administered bag of FT538.  
Vital signs for enoblituzumab – include oral temperature, blood pressure, heart rate, respiration rate. On days of enoblituzumab administration, collection as follows: upon arrival, within 15 
minutes prior to start of the enoblituzumab, every 15 minutes (± 5 minutes for the first hour of the infusion, every 30 minutes (±5 minutes) thereafter until infusion end, upon discontinuing the 
infusion, and before the patient is discharged from the clinic. 
7 Neurotoxicity will be monitored using the ASTCT guidelines for grading ICANS based on the criteria in Section 8.2.3. ICANS monitoring will occur just prior to start of lympho-conditioning, at 
specified time points, and as needed in to document complete resolution to baseline status. On FT538 dosing days, assessment for ICANS should be done prior to infusion, 2 to 4 hours 
after FT538 administration and at time of discharge the post-infusion extends beyond 4 hours. Unscheduled assessments should be performed if new or worsening ICANS is 
suspected. In cases of documented changes in the ICANS grading, follow-up assessments should be performed until resolution to baseline or patient discontinuation from the study, whichever 
occurs earlier. Refer to Section 8.2.3 for details.  
8 To monitor for vascular leak syndrome per Section 11.2. 
9 Retreatment may be an option for patients with stable disease or better based on the Day 36 reassessment. Refer to Section 5.3, Section 6.3, and Section 7.8 for additional information.  
10 
Cohort 5 and cohort 6 - End of Treatment visit approximately 3 weeks (± 8 days) after the last dose of enoblituzumab  
11 
Person of childbearing potential and still has the anatomy (uterus and ovaries) to get pregnant must have a negative pregnancy test (urine or serum) within 14 days of 1st dose of CY/FLU or 
Eno  (if applicable). 
12 
If CRS occurs (e.g. a differential diagnosis is recorded in the institutional medical record), CRP and ferritin levels should be done three times weekly until the resolution of CRS. In addition, a 
serum sample should be collected for an IL-6 level at the time of any change (increase or decrease) in the CRS grade. Because patients may be outpatients any missed collection time points 
will not be a protocol deviations.  
13 
If the IP catheter cannot be placed by interventional radiology, the patient will be taken off study per Section 6.4. 
 
 
 


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10.2 Research Related Evaluations 
Shaded columns apply to Dose Cohorts 5 and 6 only. 
Refer to Section 10.3 for research related activities during retreatment. 
 
Baseline: Prior to 
the 1st dose of 
CY/FLU or Eno (if 
applicable)) 
Prior to 
enoblituzumab 
(Day -6) Cohort 5 
and Cohort 6 only 
Prior to 
CY/Flu 
chemo 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 43 
Cohort 5 
and 6 
only 
Research Sample Drawing Coincides with a SOC 
visit closest to the targeted time point 
3 months 
from Day 1 
6 months 
from Day 1 
9 months 
from Day 1 
12 months 
from Day 1 
Enoblituzumab (Cohort 5 and 6 only) 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
FT538 infusion 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Six 10 ml green top tubes – collect prior to the day’s 
treatment (if applicable)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
(30 ml) 
X  
(30 ml)  
X  
(30 ml) 
X  
(30 ml) 
One 10 ml of red top tube – collect prior to the day’s 
treatment (if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP and ferritin to FV lab 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PRA anti-HLA antibodies to FV lab 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
IP fluid (ascites preferred over washings) – collect in a 
urine or similar container prior to the day’s treatment (if 
applicable) Refer to Section 10.2.1 
At time of IP 
catheter 
placement 
 
 
X 
 
X 
X 
X 
X 
X1 
 
 
 
 
 
Tumor biopsy by IR (if feasible)  6 cores (5-10 mm) 
preferred but less is acceptable – to BioNet 
At time of IP 
catheter 
placement 
 
 
 
 
 
 
 
 
X1 
 
 
 
 
 
Complete Data collection for LTFU study  
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Safety Samples for Fate  
1 x 3 ml red top serum tube  
1 x 10 ml green top tube 
– store frozen and batch ship to Fate 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
(not 
collected 
at 9 
months) 
X 
 
1 - at time of IP catheter removal (Day 36 if no retreatment or at time of IP catheter removal if retreatment) 
2 - At TTL: PBMCs are isolated from the heparin/green tube at pre-designated time points for PCR testing by Fate  


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Note: if a patient is not abiding by the required clinical care calendar (Section 10.1), the 
collection schedule of research related samples may be altered or discontinued on an 
individual patient basis, as appropriate. During follow-up no visit will be solely for research 
and instead be linked with a standard of care visit closest to the targeted research related 
timepoint.  
All research samples go to the Masonic Cancer Center’s Translational Therapy Lab (TTL) 
unless otherwise indicated. Baseline and Day 29 ferritin/CRP and PRA anti-HLA 
antibodies testing are charged to research but run in the treatment center’s clinical lab. If 
additional ferritin and/or CRP levels are collected as part of good medical care (i.e. 
development of signs of CRS) they are to be charged as standard of care. 
For all patients receiving FT538, samples as designated in the above table are shipped 
from TTL to Fate.  
For Cohorts 5 and 6 only, serum and ascites samples (not IP wash samples) are provided 
to MacroGenics by TTL to determine enoblituzumab levels.  
It is recognized that with novel therapies as used in this study, the timing of protocol 
directed research samples may miss important patient specific events. For this reason, 
blood and/or IP fluid may be collected at up to 3 additional time points that are not 
specified above.  
Samples to evaluate lymphocyte number and phenotype will be collected as detailed 
above for the Masonic Cancer Center Translational Therapy Lab (TTL) along with serum 
(red top tubes) for measure of cytokines that can reflect immune activation.  
Flow cytometry analysis of a fraction of the PBMC will detect surface markers that define 
lymphocyte subsets (NK, NKT, B, and T cells, both CD4 and CD8), as well as intracellular 
markers that define regulatory T cells (Foxp3) and proliferating cells (Ki67). All remaining 
PBMC will be cryopreserved in 10% DMSO and stored in liquid nitrogen for future testing, 
if subject agreed to future storage at the time of initial consent. 
Samples may be sent to laboratories outside of the University of Minnesota in cases 
where testing is not available internally as embedded in the patient consent form. 
10.2.1 Intraperitoneal (IP) Fluid Collection 
Ascites is preferred and a collection of such should be attempted first. It is 
recommended to obtain a minimum of 200cc and up to 500cc if ascites is present. 
Lower or higher volumes are acceptable. Any ascites collected, regardless of the 
volume, will be submitted to TTL as a separate sample from peritoneal washings 
if both obtained. The higher the volume of ascites submitted, the better the yield of 
Tumor Ascites Lymphocytes (TALs).  
 


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If ascites is drained for clinical care at other times during this timeframe, a sample 
(up to 500 cc) may be submitted to TTL as an additional time point.  
If no ascites is present or less than 50cc is collected, peritoneal washings will be 
performed. A volume of 250cc of room temperature NS will be infused into the 
abdomen. After infusion the patient will be asked to change position (right lateral, 
left lateral, Trendelenburg (feet higher than head by 30 degrees), reverse 
Trendelenburg) at 5-minute intervals to ensure adequate intra-abdominal 
distribution. Fifty (50) cc of infusate will then be retrieved through the indwelling 
catheter. 
If a minimum of 50cc of infusate is not retrieved, another 250 cc of NS will be 
infused and the above process repeated. If after this 50cc of infusate have not 
been retrieved, the process will be terminated, however, any amount of infusate 
that is retrieved should be sent to TTL for testing. 
10.2.2 Tumor Biopsies  
Tumor biopsies will be performed if feasible. The inability or failure to do a biopsy 
will not be considered a protocol deviation. It is preferred that 6 cores (5-10 mm) 
be collected. It is understandable that it may not always be possible to obtain 6 
cores and in such cases testing will be prioritized based on the number of cores 
received. The inability to collect any tumor samples or an insufficient amount will 
not be considered a protocol deviation. 
Samples go to BioNet and handled per the contract with BioNet.  
10.3 Retreatment Required Clinical Care and Research Related Evaluations 
Retreatment is offered to a sub-set of patients whose 1st disease re-assessment 
shows stable disease or better on a compassionate basis. Retreatment does not 
contribute to primary or secondary endpoints. Flexibility for the start of the 
retreatment course is permitted  
 
Retreatment requires signing of the retreatment consent and confirmation of 
ongoing eligibility per Section 5.3. Retreatment is a separate protocol entry in 
OnCore (CPRC# 2021LS103R) which releases a new set of case report forms 
specific to retreatment. Flexibility with the start of the retreatment course is 
permitted.  
 
After rDay 29, patient follow-up continues per Section 10.1 and Section 10.2 
beginning with the 3 month post Day 1 follow-up. 
 
 


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Shaded columns apply to Dose Cohorts 5 and 6 only. 
 
Additional 
retreatment 
activities 
(overlap with 
Day 36 visit) 
Enoblituzumab 
(rDay -6/Day 43 
visit) 
Cohort 5 and 
cohort 6 only 
CY/FLU  
rDay 
1 
rDay 
3 
rDay 
8 
rDay 
15 
rDay 
22 
rDay 
29  
#1  
rDay -5 
#2  
rDay -4 
Consent with retreatment consent and 
enroll in study 2021LS103R 
X 
 
 
 
 
 
 
 
 
 
Confirmation of ongoing eligibility per 
Section 5.3 
X 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
Provider Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
X 
X 
 
X3 
X3 
X3 
X3 
X3 
X3 
Vitals and Pulse Oximetry 
 
X1 
X 
 
X1 
 
X1 
X1 
X 
X 
GOG Performance Status 
 
 
 
 
 
 
 
 
 
X 
ICANS (neurotoxicity) monitoring)2 
 
X2 
 
 
X2 
X 
X2 
X2 
X 
X 
Toxicity Assessment: observed, 
patient reported or eMR abstraction 
(refer to Section 11.2 for AE 
documentation requirements) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
CBC, diff, plt 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Basic metabolic panel (BMP) 
 
 
 
 
X 
X 
 
 
 
 
Comprehensive metabolic panel 
(CMP) or equivalent 
 
X 
X 
 
 
 
X 
X 
X 
X 
Urine or serum pregnancy test  
 
 
 
 
 
 
 
 
 
 
eGFR 
 
 
 
 
 
 
 
 
 
 
Research Related Activities 
Enoblituzumab IV (Cohort 5 and 
Cohort 6 only) 
 
X 
 
 
 
 
 
 
X 
 
FT538 IP 
 
 
 
 
X1 
 
X1 
X1 
 
 
Six 10 ml green top tubes – collect 
prior to the day’s treatment (if 
applicable) 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
One 10 ml of red top tube – collect 
prior to the day’s treatment (if 
applicable) 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
PRA anti-HLA antibodies to FV labs 
 
 
 
 
 
 
 
 
X 
 
ferritin, CRP to FV lab  
 
 
 
 
 
 
 
 
 
X5 
IP fluid (ascites preferred over 
washings) – collect in a urine or 
similar container prior to the day’s 
treatment (if applicable) Refer to 
Section 10.2.1 
 
 
 
 
X 
X 
X 
X 
X 
X 
Tumor biopsy by IR (if feasible) at 
time the IP catheter is removed - 6 
cores (5-10 mm) preferred but less is 
acceptable – to BioNet 
 
 
 
 
 
 
 
 
 
X6 
1 Additional vital sign timepoints on days of investigational product administration:  
Vital signs for FT538 - include oral temperature, blood pressure, heart rate, respiration rate, and pulse oximetry. On days of FT538 
administration, collect as follows: within 15 minutes prior to infusion of FT538, after the final flush/prior to repositioning and every 15 
minutes (±5) minutes for 1 hour following the end of infusion of the last administered bag of FT538.  
Vital signs for enoblituzumab – include oral temperature, blood pressure, heart rate, respiration rate. On days of enoblituzumab 
administration, collection as follows: upon arrival, within 15 minutes prior to start of the enoblituzumab, every 15 minutes (± 5 minutes 
for the first hour of the infusion, every 30 minutes (±5 minutes) thereafter until infusion end, upon discontinuing the infusion, and before 
the patient is discharged from the clinic. 
2 Neurotoxicity will be monitored using the ASTCT guidelines for grading ICANS based on the criteria in Section 8.2.3. ICANS monitoring 
at specified time points, and as needed in to document complete resolution to baseline status. On FT538 dosing days, assessment 
for ICANS should be done prior to infusion, 2 to 4 hours after FT538 administration and at time of discharge the post-infusion 
extends beyond 4 hours. Unscheduled assessments should be performed if new or worsening ICANS is suspected. In cases of 


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documented changes in the ICANS grading, follow-up assessments should be performed until resolution to baseline or patient 
discontinuation from the study, whichever occurs earlier. Refer to Section 8.2.3 for details.  
3 To monitor for vascular leak syndrome per Section 11.2. 
4 Person of childbearing potential and still has the anatomy (uterus and ovaries) to get pregnant must have a negative pregnancy test 
(urine or serum) within 14 days of treatment start on the retreatment protocol.  
5 rDay 29 ferritin and CRP is paid for by the study – if CRS occurs, additional ferritin and CRP levels are done as part of clinical care per 
Section 10.1 as detailed in Section 8.2.2. 
6 Remove IP catheter after the Day 29 sample or sooner if warranted. 
11 Event Monitoring, Documentation, and Reporting 
FT538 is considered an investigational product for all patients.  
Enoblituzumab is an investigational product for patients treated in Dose Cohort 5 or 
Cohort 6.  
CY/FLU are study drugs. 
Adverse Reactions will be reported to the FDA per 21 CFR 312.32. 
Toxicity and adverse events is classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 5.0 (CTCAE) and reported on the schedule 
below. A copy of the CTCAE can be downloaded from the CTEP home page.  
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v
5_Quick_Reference_5x7.pdf) 
An exception to the use of CTCAE will be for the assessment of cytokine release 
syndrome (CRS). Individual adverse events which are associated with CRS will be 
graded per CTCAE; however the ultimate assessment will be made using a revised 
grading system for CRS as presented by Lee et al (2019). Refer to Section 8.2.2 
Table 2. 
The following definitions of adverse events (AEs) and serious adverse events (SAEs) 
will determine whether the event requires expedited reporting via the SAE Report 
Form in addition to routine documentation in the OnCore AE case report form (CRF).  
11.1 Event Terminology 
Adverse Event:  Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Adverse Reaction: Any adverse event caused by a drug. Adverse reactions are 
a subset of all suspected adverse reactions where there is reason to conclude that 
the drug caused the event. 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 


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relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
Serious Adverse Event or Serious Suspected Adverse Reaction:  An adverse 
event or suspected adverse reaction is considered “serious” if, in the view of either 
the Investigator or Sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization  
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect 
 An important medical event 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 
(SUSAR): An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed at the 
specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended.  
Note: IBs are available for both investigational products (FT538 and 
enoblituzumab). The current USPI is the source of expected adverse events for 
the study drugs (cyclophosphamide and fludarabine). 
Expedited (Rapid) Reporting: Certain events may require rapid notification to 
entities providing patient safety oversight (e.g. IRB). Refer to Section 11.5. 
11.2 Event Monitoring and Documentation Requirements 
Monitoring for adverse events begins with the insertion of the IP catheter. Between 
the time of consent signing and the 1st dose of CY/FLU or Eno (if applicable), only 
events directly related to the study and result in the inability to begin study 
treatment will be documented.  
Monitoring continues through the Dose Cohort specific End of Treatment visit.  
Note: if a patient is not abiding by the planned treatment schedule, the 
documentation of adverse events may be altered or discontinued on an individual 
patient basis, as appropriate. During follow-up, no visit will be solely for research 
and instead be linked with a standard of care visit closest to the targeted research 
related timepoint. 


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The toxicity associated with the cyclophosphamide and fludarabine (CY/FLU) 
preparative regimen is well known and will not be documented unless the event 
meets the definition of a serious adverse event. Potential risks of CY/FLU are 
detailed in Appendix III.  
Therefore, adverse event documentation for the purposes of this study will focus 
on the following events: 
 Adverse events of special interest (AESI) requiring targeted monitoring 
including infusion related reactions (IRR), neurotoxicity, vascular leak 
syndrome, and cytokine release syndrome. Refer to Section 11.1 for 
timing/details. 
 Any event within 28 days of the 1st FT538 infusion meeting the definition of 
dose limiting toxicity or for Step 1 only, a pre-defined adverse event per 
Section 11.3.  
 Any event meeting the definition of a serious adverse event, regardless of 
attribution through the Dose Cohort specific End of Treatment visit and then 
upon knowledge if felt related to the study treatment. 
 All Grade 3 and 4 adverse events regardless of attribution. 
 Grade 2 adverse events felt possibly, probably or related to either 
enoblituzumab or FT538. 
Exceptions to AE Documentation: 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) 
without clinical significance are not recorded as AEs or SAEs with the exception of 
abnormalities that meet the definition of DLT per Section 11.3.  
 
Other abnormal assessments (e.g., vital signs, ECG, X-rays) that are not 
associated with signs or are considered of no clinical significance do not need to 
be recorded unless they are a targeted toxicity.  
 
Clinically significant is defined as requiring medical or surgical intervention or 
leading to a study treatment delay or discontinuation. Any laboratory or other 
assessments meeting the definition of clinically significant must be recorded as an 
AE, as well as an SAE, if applicable.  
11.3 Dose Limiting Toxicity Event/Stopping Rule Documentation and Reporting 
The following events require special documentation and reporting in addition to 
recording as an adverse event. 


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11.3.1 During Fast-Track Enrollment Only 
During Stage 1, Step 1 of fast-track enrollment only, the 1st patient experiencing a 
pre-defined treatment emergent adverse event within 28 days of the 1st FT538 
dose triggers a change to 3 patients per cohort (Stage 1, Step 2).  
Pre-defined treatment emergent adverse events only are used for assessment in 
the single patient dose cohorts.  
 Grade 3 abdominal pain, not attributable to the cancer, within 28 days after the 
1st FT538 infusion lasting more than 48 hours despite treatment with standard 
analgesics  
or 
 Grade 3 infusion related reaction within 24 hours after the 1st FT538 infusion in 
any dose cohort or 1st enoblituzumab infusion in DC 5 or DC 6 and symptoms 
resolve to baseline within 12 hours.   
 
If a patent experiences a Dose Limiting Toxicity (defined in next Section), 
enrollment moves directly to Stage 2 (CRM). 
11.3.2 Dose Limiting Toxicity (All Patients) 
All patients are monitored for dose limiting toxicity (DLT). DLT is defined as any 
treatment emergent toxicity at least possibly related to the study treatment meeting 
one of the following criteria based on CTCAE v5 within 28 days (14 days for 
ascites) of the 1st FT538 infusion (for Cohort 5 and 6, DLT assessment starts with 
enoblituzumab and continues for 28 days after 1st FT538): 
 Grade 3 organ disorders (pulmonary, hepatic, renal, or neurologic) and lasting 
more than 72 hours  
 Any non-hematologic Grade 4 or 5 toxicity 
 Grade 4 neutrophil count decreased that persists at Day 28 despite use of 
growth factor support 
 Grade 3 or greater abdominal pain lasting more than 4 consecutive days and 
not controlled by standard analgesics 
 Grade 3 or greater ascites within 14 days after FT538 administration in patients 
who had no ascites or Grade 1 ascites at enrollment and is not attributable to 
disease progression 
In addition to documenting the event in the study’s CRF’s, DLTs are to be 
documented on the Event Form found in OnCore per Masonic Cancer Center 
procedures within 24 hours of knowledge.  


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11.3.3 Excessive Toxicity (All Patients) 
Stopping rules also are in place independent of dose escalation as detailed in Section 
14.4. 
o Stopping Rule for Excessive DLT as determined by the study statistician or 
designee 
 
The following events must be reported within 24 hours of knowledge: 
o Grade 3 or greater Infusion Related Reaction through Day 28 in association 
with any FT538 infusion in any Dose Cohort or in association with 
enoblituzumab in Dose Cohort 5 and 6. 
o Early Death (Grade 5 Event) within 28 days after the last dose of FT538 (21 
days after Dose 2 of enoblituzumab in Cohorts 5 and 6) and not attributable to 
disease progression. Any one death, suspends study enrollment per Section 
14.4. 
11.4 SAE Documentation  
Any event meeting the definition of a serious adverse event (SAE) requires 
documentation using the MCC SAE Report Form in OnCore.  
Deaths, including due to disease within 1 year after the 1st FT538 cell infusion will 
be recorded as an SAE. Deaths due to disease should be recorded as a Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and polyps) – 
Other (Progressive Disease).  
In addition, the death date and cause must be reported in the patient follow-up tab 
in OnCore using the comment field in the survival status section to record the 
cause.  
 


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11.5 Expedited Reporting Requirements 
The following events require expedited reporting: 
 
12 Investigational 
Product 
Description, 
Supply 
and 
Potential 
Toxicities  
Refer to Appendix III for expected toxicities associated with the cyclophosphamide and 
fludarabine lymphodepletion. 
12.1 Enoblituzumab 
Enoblituzumab will be administered at a dose of 15 mg/kg, initially calculated 
based on the patient’s actual weight prior to the 1st dose (baseline) measurement. 
Significant (≥ 10%) change in body weight from baseline should prompt 
recalculation of the dose. Patients with body mass index (BMI) greater than or 
equal to 30 kg/m2, the enoblituzumab dose will be calculated using ideal body 
weight (IBW). 
Report to: 
Criteria for reporting: 
Timeframe: 
Form to Use: 
Submission email address 
Advarra 
unanticipated problems involving risks to subjects 
or others; unanticipated adverse device effects; 
protocol violations that may affect the subjects’ 
rights, safety, or well-being and/or the 
completeness, accuracy and reliability of the study 
data; subject death; suspension of enrollment; or 
termination of the study 
promptly and 
no later than 2 
weeks (10 
business days) 
from the time 
the 
investigator 
learns of the 
event 
Refer to the 
Advarra IRB 
Handbook 
Advarra via study specific CIRBI 
Link 
UMN IRB 
Refer to Submitting Updates in ETHOS – External IRB Study/Site 
FDA 
Unexpected and fatal or unexpected and life 
threatening suspected adverse reaction 
no later than 7 
Calendar Days 
University of 
Minnesota SAE 
Report 
Submit to FDA as an 
amendment to IND  
with a copy to: 
Fate Therapeutics at 
safety@fatetherapeutics.com 
if Cohort 5 or 6 to MacroGenics 
saereports@MacroGenics.com   
1) Serious and unexpected suspected adverse 
reaction or 
2)  increased occurrence of serious suspected 
adverse reactions over that listed in the protocol or 
investigator 
brochure or 
3) findings from other sources (other studies, 
animal or in vitro testing) 
no later than 
15 Calendar-
Days 
All other events per CFR 312.33  
at time of 
annual report 
IND annual report 
As an amendment to the IND 
Fate 
Therapeutics 
Any event meeting the definition of a SAE  
no later than 5 
Calendar Days 
University of 
Minnesota SAE 
Report    
Fate Therapeutics at 
safety@fatetherapeutics.com 
Any event meeting the definition of a SUSAR 
no later than 3 
Calendar Days 
MacroGenics, 
Inc 
For patients assigned to enoblituzumab (Cohort 5 
or Cohort 6): all SAEs, regardless of causality or 
expectedness  
within 7 
calendar days 
of awareness 
University of 
Minnesota SAE 
Report 
saereports@MacroGenics.com 


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Refer to the Pharmacy Manual for further instructions on allowable parameters for 
dose rounding of enoblituzumab. 
12.1.1 Availability 
For the purposes of this study, enoblituzumab will be provided by MacroGenics. 
12.1.2 Dosage Forms and Strength  
Enoblituzumab DP is a sterile, preservative-free clear to slightly opalescent, 
colorless to pale yellow or pale brown solution supplied at a protein concentration 
of 25 mg/mL in a single dose 20 mL vial containing 17 mL DP (425 mg/vial). Some 
visible, proteinaceous enoblituzumab particles may be present. The product is 
formulated in 0.95 mg/mL sodium acetate trihydrate, 0.18 mg/mL glacial acetic 
acid, 90 mg/mL sucrose, and 0.1 mg/mL polysorbate 80, pH 5.1, in Sterile Water 
for Injection, USP. 
12.1.3 Storage 
Enoblituzumab will be stored in the University of Minnesota Investigational Drug 
Services (IDS) Pharmacy. Enoblituzumab should be stored under refrigeration at 
2°C–8°C (36°F–46°F). Enoblituzumab must not be frozen. Monitor temperature 
and document and report any excursions. Protect from light during storage. DO 
NOT SHAKE. 
12.1.4 Preparation 
The desired amount of enoblituzumab should be withdrawn from the vial(s) and 
diluted to the appropriate final concentration with 0.9% Sodium Chloride Injection 
USP (normal saline), according to the instructions provided in the Pharmacy 
Manual. A sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) 0.2 
micron in-line filter administration set must be used for IV administration of 
enoblituzumab. The infusion bag containing enoblituzumab should be gently 
inverted to mix the solution. The dose solution should be administered via IV 
infusion over 120 (± 15) minutes with a commercially available infusion pump. 
Before administration, the parenteral drug product should be inspected visually. If 
foreign particulate matter or discoloration is noted, drug should not be 
administered. 
12.1.5 Warnings and Precautions 
Enoblituzumab is an Fc-optimized humanized mAb administered via IV infusion. 
Infusion of mAbs can result in hypersensitivity reactions and/or CRS, therefore, 
precautions should be observed during enoblituzumab administration.  
Reactions that occur during or shortly following the infusion of monoclonal 
antibodies can be caused by various mechanisms, including acute anaphylactic 


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(IgE-mediated) or anaphylactoid reactions against the monoclonal antibody, and 
serum sickness (type III hypersensitivity). Another, type of infusion reaction that 
can sometimes be severe, is attributable to CRS. CRS is a disorder or collection 
of disorders characterized by fever, rigors, chills, arthralgia, cough, dizziness, 
fatigue, 
nausea, 
headache, 
diaphoresis, 
tachycardia, 
hypotension 
or 
hypertension, pruritus, rash including urticaria, shortness of breath, and 
bronchospasm caused by the release of cytokines from cells. 
Infusion related reaction or cytokine release syndrome was reported in 48.5% of 
373 patients in MacroGenics-sponsored clinical trials of enoblituzumab, with 
42.1% of patients experiencing IRR/CRS that were mild to moderate in severity. 
Events of IRR/CRS ≥ Grade 3 in severity were seen in 6.4% (n=24) of patients. 
Two of these patients with a ≥ Grade 3 IRR/CRS event experienced an event of 
life-threatening IRR/CRS (1 received enoblituzumab in combination with 
ipilimumab and 1 received enoblituzumab in combination with pembrolizumab). 
Patients treated with enoblituzumab should be pre-medicated as described in 
Section 7.2.1, monitored closely during the infusion and be advised of the potential 
to develop allergy-like symptoms.  
Refer to the current Investigator’s Brochure for additional information. 
12.1.6 Potential Toxicities 
As of April 2021, 349 adult patients had received enoblituzumab at doses up to 
15.0 mg/kg, which is the dose used in this study.  
So far, the most important safety risk that has been identified with enoblituzumab 
is infusion-related reaction (IRR), including reactions known as cytokine release 
syndrome (CRS). IRRs are effects due to a drug that may occur during or shortly 
after an infusion. Signs and symptoms of an infusion-related reaction may include 
fever, chills, nausea, vomiting, headache, muscle stiffness, rash, itching, low 
blood pressure, and difficulty breathing. IRRs can be life threatening and, in rare 
cases, may cause death. For all adult studies, IRRs (including CRS) have 
occurred in a 48% patients receiving treatment with enoblituzumab. Most of the 
infusion-related reactions observed in patients receiving enoblituzumab have 
been mild to moderate in severity with 6 % of patients having more severe 
infusion-related reactions (including two who experienced life-threatening IRR 
events). These patients, some of whom were hospitalized for these reactions, 
recovered after receiving treatment with steroids, antihistamines and intravenous 
fluids. 


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The following were the most common side effects that were considered related to 
enoblituzumab administration and were seen in at least 1 of 10 adult participants. 
These side effects have been generally mild or moderate. 
 
infusion related reactions (described above) 
 
fatigue  
 
nausea  
 
chills  
 
vomiting  
Eleven (11) patients have experienced serious side effects that were considered 
related to enoblituzumab. Serious side effects that occurred in 3 or more patients 
included: IRRs.  
 
Refer to the current Investigator’s Brochure for additional information. 
12.2 FT538 
FT538 drug product comprises expanded allogeneic natural killer cells, derived 
from a clonal, CD38 knockout, human-induced pluripotent stem cell line, that 
expresses high-affinity, non-cleavable CD16 receptor (hnCD16) and interleukin 
(IL)-15/IL-15 receptor fusion protein (IL-15RF).  
FT538 cells are suspended in infusion medium consisting of Plasma-Lyte A (pH 
7.4) with albumin (human) and dimethyl sulfoxide. The drug product is not 
manufactured with antibiotics. The formulated drug product is aseptically filled into 
pre-sterilized, single-use cryopreservation bags with approximately:  
• 2.8 × 106 viable cells (VC)/mL (total of 5 × 107 VC in an 18 mL/bag);  
• 5.6 × 106 VC/mL (total of 1 × 108 VC in an 18 mL/bag); or  
• 2.8 × 107 VC/mL (total of 5 × 108 VC in an 18 mL/bag).  
Dosing is based on hnCD16 expression, where 90% ± 10% of administered FT538 
cells express hnCD16. 
12.2.1 Availability and Storage 
FT538 is supplied by Fate Therapeutics for the purpose of this study in a pre-
sterilized, single-use CryoStore™ 50 EVA, 10-30 mL freezing bag.  
The cell product is delivered to and stored in the University of Minnesota Molecular 
Cellular Therapeutics (MCT) lab until needed for administration. At MCT the 
following occurs: 
 Upon receipt of the VPLN shipper, open the outer lid and remove the 
packing slip.  


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 Check the contents of the shipper against the packing slip. The shipping 
documentation should remain on file with other IMP documentation at the 
clinical study site.  
 Carefully open cassettes and confirm the product label against the packing 
slip. Visually inspect each FT538 bag to ensure it is not compromised in any 
manner and that there are no visible defects or leaks. Use care to conduct 
this inspection under temperature control to avoid temperature excursions.  
 Confirm that the contents arrived frozen.  
 Once the temperature monitoring data has been received, file it with the 
FATE Investigational Medicinal Product Accountability Log. 
FT538 must be stored in the vapor phase of liquid nitrogen (VPLN) at ≤-150°C, in 
a temperature-monitored and alarmed VPLN freezer in a controlled-access room 
with limited personnel access. Temperature excursions up to -135°C for 10 
minutes due to normal equipment use (e.g., opening and closing of the storage 
unit) are allowed. If the temperature warms to >-150°C up to -135°C for >10 
minutes or >-135°C for any amount of time, Fate Therapeutics (FATE) must be 
notified. 
12.2.2 Product Labeling 
FT538 labeling will include product name, volume, manufacturer, date of 
manufacture, Product Lot #, Bag ID #, and number of viable cells. The label will 
also contain the following statement: “Caution: New Drug – Limited by United 
States Law to Investigational Use.” 
12.2.3 Route of Administration 
The thaw procedure using a water bath or alternate equipment is set-up by MCT 
per established procedures and transferred to the place of administration.  
FT538 must be administered using an IV administration set without an in line filter 
(filter is not required for IP administration). FT538 is administered as an IP infusion 
via gravity after any ascites or IP wash fluid has been drained per Section 7.4 into 
the previously placed IP catheter/peritoneal port as described in Section 7.1 using 
a pleurx peritoneal catheter kit and pleurx drainage kits manufactured by Becton 
Dickinson, Franklin Lakes, NJ. The catheter is Device Class 2 and is 510K-
clearedK051711. 
 
Administration of FT538 should be initiated as soon as practical after thawing, 
preferably within 20 minutes. Do not initiate infusion of drug product that has been 
thawed for more than 60 minutes. Infusion of all thawed product (including 
subsequent saline rinse of empty bag) must be completed within 90 minutes from 


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when the bag was first thawed. Refer to Section 7.4.2 for details of post infusion 
flush and distribution of the infusate within the abdominal cavity. 
12.2.4 FT538 Product Resupply 
Frequent meetings are held between the study team and Fate Therapeutics to 
review each study in with Fate products at the University of Minnesota. Included 
as a part of these meetings is a summary of product used, remaining FT538 bags, 
and upcoming product need. 
12.2.5 Potential Risks Associated with FT538 
In this study FT538 is infused by intraperitoneal (IP) infusion. In our previous 
studies of IP infusion of NK cell products including Fate NK100 and FT516 (each 
given with IL-2) abdominal pain and cramping once observed in the majority of 
patients. Most were CTCAE 5 Grade 1 or Grade 2, with an occasional Grade 3 
event. The pain usually was managed with oral and/or intravenous analgesics.   
Refer to Section 8 for potential toxicities associated with intravenous (IV) 
administration. 
13 Study Data Collection and Monitoring 
13.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota 
CTSI’s instance of OnCore® (Online Enterprise Research Management 
Environment). The Oncore database resides on dedicated secure and PHI 
compliant servers. The production server is located in the UMN datacenter 
(WBOB).  
Additional immune monitoring data about correlative laboratory samples 
generated by the Masonic Cancer Center Translational Therapy Laboratory (TTL) 
from the protocol-directed correlative research samples is stored in their 
Laboratory Information Management System (LIMS).The LIMS database 
application is also stored on a production server located in the UMN datacenter 
(WBOB) and is managed by the Academic Health Center 
Key study personnel are trained on the use of OnCore and will comply with protocol 
specific instructions embedded within the OnCore. 
13.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report 
forms (e-CRF) developed within the University of Minnesota OnCore based on its 
library of standardized forms. The e-CRFs will be approved by the study PI and 
the UMN biostatistician prior to release for use. The Study Coordinator or designee 


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will be responsible for registering the patient into OnCore at time of study entry, 
completing e-CRF based on the patient specific calendar, and updating the patient 
record until patient death or end of required study participation.  
13.3 Data and Safety Monitoring Plan 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), which can be accessed at https://z.umn.edu/dsmp. 
For the purposes of data and safety monitoring, this study is classified as high risk 
(early in human, under locally sponsored IND). Therefore the following 
requirements will be fulfilled: 
 At least quarterly review of the study’s progress by the Masonic Cancer Center 
Data and Safety Monitoring Council (DSMC). 
 At least twice yearly monitoring of the project by the Masonic Cancer Center 
monitoring services. 
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the IND Sponsor (Dr. Geller) will 
submit a progress report annually. The report will be submitted within 60 days of 
the anniversary date that the IND went into effect.  
13.4 Regular Team Meetings to Review Safety  
Regular meetings will be held to facilitate communication regarding the study’s 
progress in terms of individual patient safety including events meeting the definition 
of dose limiting toxicity, excessive toxicity (early study stopping rule), serious 
adverse events (SAEs) and overall impact on future enrollment.  
At a minimum each patient is reviewed at the end 1st 28 days to document the DLT 
status and to confirm the timing and dose level for the next patient enrolled.  
The outcome of these discussion will be documented in the meeting minutes and 
the statistician or designee will send out a confirmatory email summarizing the 
discussion which will become part of the regulatory record.  
Other issues for discussion may include pending patients, patient updates, 
summary of safety reports, and case report form completion.  
The study assigned CRC or designee is responsible for arranging these meetings 
and preparing the agenda. Meetings will occur every 2 weeks; however, these may 
be scheduled more or less frequently at the discretion of the PI and/or the CRC. 
The safety discussion may be part of the regular PI meeting but must be 
documented as above (in study minutes and post-meeting email from the 
statistician or designee).  


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Expected participation includes the Principal Investigator, the Study Statistician or 
designee and relevant CTO staff (CRC-RN, CRC, Regulatory Specialist, and 
Program Manager) or appropriate designee.  
In the situation of a patient completing the DLT period between scheduled 
meetings, communication via email may be used in lieu of a meeting provided the 
patient was discussed at the prior meeting and will be included on the next 
meeting’s agenda. 
13.5 Record Retention 
The investigator will retain study records including source data, copies of case 
report form, consent forms, HIPAA authorizations, and all study correspondence 
in a secured facility until notified by the Masonic Cancer Center Clinical Trials 
Office that the study records may be destroyed. 
14 Statistical Considerations 
14.1 Study Design, Objectives and Endpoints 
 
This Phase I study will test up to 7 dose strategies of FT538 to determine the 
maximum tolerated dose (MTD) of FT538 with a maximum enrollment of 33 
patients.  
There are 7 potential dose cohorts defined for this study. The trial will be conducted 
with no intra-patient escalation. The starting dose will be 1x108 cells FT538 
cells/dose with no enoblituzumab. The subsequent planned cohorts will be 3x108 
FT538 cells/dose with no enoblituzumab, 1x109 FT538 cells/dose with no 
enoblituzumab, and then 1.5x109 FT538 cells/dose with no enoblituzumab, unless 
a dose-limiting toxicity (DLT) occurs at Cohort 1, when continual reassessment 
method (CRM) stage is initiated. Dose escalation will continue in combination with 
enoblituzumab starting at one dose below the highest dose reached from the 1st 
five cohorts given that we reach at least Cohort 2 without enoblituzumab. This will 
potentially continue up through 1.5x109 FT538 cells/dose + enoblituzumab. Given 
that little to no toxicity is expected, the MTD will be determined using an adaptation 
of the continual reassessment method (CRM) (O’Quigley, 1996). A cohort of two 
patients will start at Cohort 1 with subsequent planned cohorts as described in 
Table 6: 
 
 
 


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Table 6. Infuse FT53 cell product at the assigned dose on Day 1, Day 8 and Day 15  
Cohort 
FT538 Dose IP (cells per dose) 
-1# 
Monotherapy: IP FT538 at 5 x 10^7 cells/dose on Day 1, 8, and 15 
1 (start) 
Monotherapy: IP FT538 at 1 x 10^8 cells/dose on Day 1, 8, and 15 
2 
Monotherapy: IP FT538 at 3 x 10^8 cells/dose on Day 1, 8, and 15 
3 
Monotherapy: IP FT538 at 1 x 10^9 cells/dose on Day 1, 8, and 15 
4 
Monotherapy: IP FT538 at 1.5 x 10^9 cells/dose on Day 1, 8, and 15 
5 
IP FT538 at the safe dose (MTD-1) from the 1st 4 dose cohorts on 
Day 1, Day 8, and Day 15 plus IV enoblituzumab on Day -6, Day 22, 
then every 3 weeks until PD  
6 
IP FT538 at the highest dose (MTD) from the 1st 4 dose cohorts on 
Day 1, Day 8, and Day 15 plus IV enoblituzumab on Day -6, Day 22, 
then every 3 weeks until PD 
# Dose -1 may only be tested in Stage 2 
 
The Phase I trial will be conducted in two consecutive stages: Stage 1 Step 1 will 
enroll two patients with at least 14 days apart at consecutively increasing doses 
until either of the following pre-defined treatment emergent adverse events occurs 
within 28 days of the 1st dose of FT538:  
 Grade 3 abdominal pain not attributable to cancer lasting more than 48 hours 
and not controlled by standard analgesics  
 Grade 3 infusion reaction  
 
At this point Stage 1, Step 2 is initiated and the cohort size will increase from 2 to 
3 patients. At least 14 days must separate the 1st and 2nd patients in a 3 patient 
cohort and a minimum of 28 days separate each 3 patient cohort. Note: if a DLT 
occurs during Fast-track (Step 1), enrollment moves directly to Stage 2 and Step 
2 is not used.  
 
At the 1st dose-limiting toxicity (DLT, defined in Section 7.5) occurs, Stage 2 of the 
Phase I trial will be initiated. Skeleton estimates of the probability of DLT at each 
dose will be cited based on discussion between the statistician and the primary 
investigator that allow for attractive operating characteristics. At least 14 days must 
separate the 1st and 2nd patients in a 3 patient cohort and a minimum of 28 days 
separate each 3 patient cohort. A one-parameter model has been chosen to link 
the risk of a DLT to the dose, where the probability of toxicity at dose i is modeled 
as piexp(α) where pi is a constant and α is the parameter to be estimated. The goal 


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will be to identify one of the 7 dose level strategies corresponding to the desired 
maximum toxicity rate of ≤25%.  
If the CRM is initiated, the CRM will continually update the toxicity at the end of 28 
days after the 3rd patient in each cohort. Each new cohort of three patients will be 
sequentially assigned to the most appropriate dose based on the updated toxicity 
probabilities. The MTD will be identified by the minimum of the following criteria: 
(1) the total sample size of 33 is exhausted, (2) or 10 consecutive patients are 
enrolled at the same dose. The function ‘crm’ from the R package ‘dfcrm’ will 
calculate posterior means of toxicity probabilities. Dose escalation of more than 
one level is not permitted with this design. 
14.2 Sample Size 
A maximum of 33 patients will be enrolled. Based on the simulations from Table 7, this 
should be sufficient and safe to define the MTD.  
1. SAE’s without a DLT trigger step 2 in stage 1, DLT’s regardless of SAE’s trigger stage 2 
2. Expected/Excessive values are the hypothesized true values under the simulation  
3. Probability of dose chosen as the MTD using the Adaptive-CRM design  
4. The hypothesized number of patients enrolled at each dose during the trial under the assumed hypothesized “true” 
probabilities  
* Starting dose 
+ Dose -1 may only be tested in stage 2.  
Enrollment will most likely include 22 patients, or it could be as high as 33 patients if DLTs 
are encountered early. Accrual should range from 10-12 patients per year so study 
accrual is expected to be complete within 24-36 months. 
Any patient who does not receive at least 1 dose of FT538 will be replaced to complete 
enrollment at a specified dose (e.g. 10 evaluable patients at the MTD).  
14.3 Statistical Analysis  
The primary objective of this trial is to identify the maximum tolerated dose (MTD) 
which will be determined per the study design and consultation with the study 
statistician using R prior to each cohort enrollment. Due to small patient numbers 
Table 7. Operating characteristics for Adaptive-CRM 
 
Cells/ dose 
Expected DLT, Expected SAE1,2 
Excessive DLT, Expected SAE1,2 
True 
Probability 
Prob. of 
dose3 
N4 
True 
Probability 
Probability of 
dose 
N 
5 x 10^7 alone+ 
1%, 1% 
0% 
0 
20%,10% 
63% 
18 
1 x 10^8 alone* 
1%, 2% 
0% 
2 
25%,18% 
0% 
6 
3 x 10^8 alone 
3%, 5% 
0% 
2 
35%, 29% 
34% 
6 
1 x 10^9 alone 
6%, 8% 
0% 
2 
45%, 50% 
3% 
3 
1.5 x 10^9 alone 
7%, 10% 
0% 
3 
50%, 60% 
0% 
0 
Safe dose from 1st 3 levels 
(MTD-1) +enoblituzumab 
8%, 12% 
0% 
3 
60%, 66% 
0% 
0 
Highest dose from 1st 3 levels 
(MTD) + enoblituzumab 
10%, 15% 
100% 
10 
70%, 77% 
0% 
0 


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at the MTD, estimation of toxicity rates, clinical activity of progression free survival 
(PFS) at 12 months will be estimated in a descriptive format using simple 
frequencies, proportions, means, standard deviations/standard errors, medians 
and ranges and respective plots. Potential censored data such as PFS and 
relapse/progression and NRM may be estimated by Kaplan-Meier curves at 12 
months. Relapse/progression and NRM may be estimated by cumulative 
incidence, treating NRM and relapse as competing risks, respectively. 
14.4 Monitoring Guidelines (Early Study Stopping Rules) 
Stopping rules also are in place independent of dose escalation. (Ivanova 2005).  
 
Stopping Rule for Excessive DLT 
A stopping rule is in place during the Phase I study to stop the trial in case there 
are excessive DLTs as defined by updated posterior probabilities throughout the 
trial. At the end of the 28 day evaluation period after each cohort of patients is 
enrolled, new posterior probabilities will be calculated for each dose by the study 
statistician. The trial will be stopped if the posterior probability that the lowest dose 
is unacceptably toxic (> 25% of patients) is greater than 80%. 
  
Grade 3 or greater Infusion Related Reaction through Day 28 in association 
with any FT538 infusion in any Dose Cohort or in association with enoblituzumab 
in Dose Cohort 5 and 6 
The goal is to construct a boundary based on Grade 3 or greater infusion related 
reaction such that the probability of early stopping is at most 10% if the rate is 
equal to 5% and our sample size is at most 33. With these stipulations, the trial will 
be stopped and reviewed if 2/7, 3/16, 4/28 or 5 patients have events by Day 28. If 
the true probability of infusion related toxicity is 20%, there is an 89% chance of 
triggering the monitoring boundary. 
 
Early Death (Grade 5 Event) within 28 days after the last dose of FT538  
Enrollment will be suspended and reviewed by the study team with follow-up 
notification to the FDA and IRB of the findings before enrollment is restarted for 
any death within 28 days after the last dose of FT538 (21 days after Dose 2 of 
enoblituzumab in Cohorts 5 and 6) and not attributable to disease progression. 
15 Conduct of the Study 
15.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be 


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established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.  
15.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients. The study will 
only be conducted at sites where IRB approval has been obtained. The protocol, 
consent, written information given to the patients, safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB by the 
investigator.  
15.3 Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent to 
review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant decides 
to participate in the study, he/she will be asked to sign and date the consent 
document. Patients who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
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Appendix I – GOG PS Scale and NYHA Classification 
 
GOG 
Score 
Activity Level  
0 
Fully active, unrestricted activities of daily living  
1 
Ambulatory, but restricted in strenuous activity  
2 
Ambulatory, and capable of self care. Unable to work. Out of bed 
for greater than 50% of waking hours  
3 
Limited self care, or confined to bed or chair 50% of waking 
hours. Needs special assistance  
4 
Completely disabled, and no self care  
5 
Dead  
 
 
NYHA Class 
Patients with Cardiac Disease (Description of HF Related Symptoms) 
Class I (Mild) 
Patients with cardiac disease but without resulting in limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation 
(rapid or pounding heart beat), dyspnea (shortness of breath), or anginal pain 
(chest pain). 
Class II (Mild) 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain 
Class III (Moderate) 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Class IV (Severe) 
Patients with cardiac disease resulting in the inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is 
increased. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart 
and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
 
 


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Appendix II - Response Evaluation Criteria in Solid Tumors (RECIST) Quick 
Reference (CTEP) 
Eligibility 
 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
Measurable disease - the presence of at least one measurable lesion. If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter 20 mm using conventional techniques or 10 mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment.  
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
Methods of Measurement –  
 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen and pelvis. 
Head and neck tumors and those of extremities usually require specific protocols. 
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. 
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully 
and widely validated. Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers. Therefore, the utilization of 
such techniques for objective tumor response should be restricted to validation purposes in 
specialized centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained. 
 
Tumor markers alone cannot be used to assess response.  If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors). 
 


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Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  
 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference by which to characterize the 
objective tumor. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
 
Response Criteria 
Evaluation of target lesions 
* Complete Response 
(CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
* Progressive Disease 
(PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
 
Evaluation of non-target lesions 
* Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor marker 
level 
* Incomplete Response/    
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of tumor 
marker level above the normal limits 
* Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions (1)  
(1) Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
 
 


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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective progression 
even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
Confirmation 
 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study 
protocol  
Duration of overall response 
 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started. 
Duration of stable disease 
 
SD is measured from the start of the treatment until the criteria for disease progression are met, 
taking as reference the smallest measurements recorded since the treatment started.  


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 
The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval required 
between two measurements for determination of SD. This time interval should take into account 
the expected clinical benefit that such a status may bring to the population under study.  
Response review 
 
For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach.  
Reporting of results 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
 
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression).  Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
 
All conclusions should be based on all eligible patients. 
 
Sub-analyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these sub-analyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported.   
 
The 95% confidence intervals should be provided. 
https://ctep.cancer.gov/protocoldevelopment/docs/recist_guideline.pdf 
 
 
 


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Appendix III – Risks Associated with Cyclophosphamide and Fludarabine  
 
Warnings and precautions ascribed to cyclophosphamide (CY) include: 
• 
Myelosuppression, immunosuppression, bone marrow failure, and infections (see 
next section) 
• 
Urinary tract and renal toxicity including hemorrhagic cystitis, pyelitis, ureteritis, and 
hematuria 
− Urinary tract obstructions must be corrected prior to receipt of CY. 
• 
Cardiotoxicity including myocarditis, myopericarditis, pericardial effusion, arrythmias, 
and congestive heart failure, which may be fatal 
− Study participants should be closely monitored, especially those with risk factors 
for cardiotoxicity or pre-existing cardiac disease. 
• 
Pulmonary toxicity including pneumonitis, pulmonary fibrosis, and pulmonary veno-
occlusive disease leading to respiratory failure 
• 
Secondary malignancies 
• 
Veno-occlusive liver disease, which can be fatal 
• 
Embryo-fetal toxicity 
Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, 
nausea, vomiting, and diarrhea. 
For the complete safety profile of CY, as well as information regarding supportive care and 
management of associated toxicities, refer to the current local prescribing information. 
 
Warnings and precautions ascribed to fludarabine (FLU) include: 
• 
Severe bone marrow suppression, notably anemia, thrombocytopenia, and 
neutropenia (see below) 
• 
Transfusion-associated GvHD 
− Use only irradiated blood products for transfusions. 
• 
Severe CNS toxicity 
− Severe CNS toxicity was observed in patients treated at FLU doses of 96 mg/m2 
for 5-7 days. This toxicity was observed in ≤0.2% of patients treated at FLU 
doses of 25 mg/m2 
− Infections 
• 
• Renal insufficiency 
− The subject’s renal function should be monitored closely. 
• 
• Tumor lysis syndrome  
• 
• Embryo-fetal toxicity 
Adverse reactions occurring in >30% of subjects treated with FLU include myelosuppression 
(neutropenia, thrombocytopenia, and anemia), fever, infection, nausea and vomiting, fatigue, 
anorexia, cough, and weakness. 
 
For the complete safety profile of fludarabine, as well as information regarding supportive care 
and management of associated toxicities, refer to the current local prescribing information. 
 


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Some adoptive cell therapies delivered with supportive medications, such as CY and FLU for 
conditioning, have been reported to cause myelosuppression (neutropenia and/or 
thrombocytopenia), leukopenia, anemia, and in some cases, bone marrow failure. 
Hematologic cytopenias could be further compounded by other factors such as underlying 
disease, concurrent illnesses, and concomitant medications. Close monitoring of complete blood 
count for the development of cytopenias and infections is strongly recommended. Management 
of cytopenias and infections, including transfusion support, antimicrobial prophylaxis, and use of 
growth factors, should be done in accordance with standard institutional practice.


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Appendix IV – Management of Clinical Neurotoxicity 
Management of clinical neurotoxicity, i.e., encephalopathy syndrome, status epilepticus, and raised intracranial 
pressure, should follow current recommendations for CAR-T-cell therapies (Neelapu 2018; Table A-1, Table A-
2, and Table A-3) and/or institutional practice. 
  
Table A-1 
Recommendations for the Management of Encephalopathy Syndrome 
Grade 
Management  
Grade 1 
 
 Vigilant supportive care; aspiration precautions; IV hydration  
 Withhold oral intake of food, medicines, and fluids, and assess swallowing  
 Convert all oral medications and/or nutrition to IV if swallowing is impaired  
 Avoid medications that cause central nervous system depression  
 Low doses of lorazepam (0.25–0.5 mg IV every 8 hours) or haloperidol (0.5 mg IV every 6 hours) can be 
used, with careful monitoring, for agitated subjects  
 Neurology consultation  
 Fundoscopic exam to assess for papilloedema  
 MRI of the brain with and without contrast; diagnostic lumbar puncture with measurement of opening 
pressure; MRI spine if the subject has focal peripheral neurological deficits; CT scan of the brain can be 
performed if MRI of the brain is not feasible  
 Daily 30-minute EEG until toxicity symptoms resolve; if no seizures are detected on EEG, continue 
levetiracetam 750 mg every 12 hours  
 If EEG shows non-convulsive status epilepticus, treat as per algorithm in Table A-2  
 Consider anti-IL-6 therapy with tocilizumab 8 mg/kg a IV or siltuximab 11 mg/kg IV, if encephalopathy is 
associated with concurrent CRS  
Grade 2 
 
 Supportive care and neurological work-up as described for grade 1 encephalopathy  
 Tocilizumab 8 mg/kg a IV or siltuximab 11 mg/kg IV if associated with concurrent CRS  
 Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours if refractory to 
anti-IL-6 therapy, or for encephalopathy without concurrent CRS  
 Consider transferring subject to ICU if encephalopathy associated with Grade ≥2 CRS  
Grade 3 
 
 Supportive care and neurological work-up as indicated for Grade 1 encephalopathy 
 ICU transfer is recommended  
 Anti-IL-6 therapy if associated with concurrent CRS, as described for Grade 2 encephalopathy and if not 
administered previously  
 Corticosteroids as outlined for Grade 2 encephalopathy if symptoms worsen despite anti-IL-6 therapy, or 
for encephalopathy without concurrent CRS; continue corticosteroids until improvement to Grade 1 
encephalopathy and then taper  
 Stage 1 or 2 papilloedema with CSF opening pressure <20 mmHg should be treated as per algorithm 
presented in Table A-3 
 Consider repeat neuroimaging (CT or MRI) every 2–3 days if subject has persistent grade ≥3 
encephalopathy 
Grade 4 
 
 Supportive care and neurological work-up as outlined for Grade 1 encephalopathy  
 ICU monitoring; consider mechanical ventilation for airway protection  
 Anti-IL-6 therapy and repeat neuroimaging as described for Grade 3 encephalopathy  
 High-dose corticosteroids continued until improvement to Grade 1 encephalopathy and then taper; for 
example, methylprednisolone IV 1 g/day for 3 days, followed by rapid taper at 250 mg every 12 hours for 2 
days, 125 mg every 12 hours for 2 days, and 60 mg every 12 hours for 2 days  
 For convulsive status epilepticus, treat as per algorithm in Table A-2  
 Stage ≥3 papilloedema, with a CSF opening pressure ≥20 mmHg or cerebral oedema, should be treated 
as per algorithm in Table A-3 
CAR, chimeric antigen receptor; CSF, cerebrospinal fluid; CRS, cytokine release syndrome; CT, computed tomography (scan); EEG, 
electroencephalogram; ICU, intensive care unit; IV, intravenous; MRI, magnetic resonance imaging. 
 a 
Maximum amount of tocilizumab per dose is 800 mg. 


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Table A-1 
Recommendations for the Management of Encephalopathy Syndrome 
Grade 
Management  
Reference: Neelapu 2018. 
 
Table A-2 
Recommendations for the Management of Status Epilepticus 
Status Epilepticus 
Type 
Management 
Non-convulsive 
status epilepticus  
 
 Assess airway, breathing, and circulation; check blood glucose  
 Lorazepam a 0.5 mg IV, with additional 0.5 mg IV every 5 minutes, as needed, up to a total 
of 2 mg to control electrographical seizures  
 Levetiracetam 500 mg IV bolus, as well as maintenance doses  
 If seizures persist, transfer to ICU and treat with phenobarbital loading dose of 60 mg IV  
 Maintenance doses after resolution of non-convulsive status epilepticus are as follows: 
lorazepam 0.5 mg IV every 8 hours for three doses; levetiracetam 1,000 mg IV every 12 
hours; phenobarbital 30 mg IV every 12 hours  
Convulsive status 
epilepticus  
 
 Assess airway, breathing, and circulation; check blood glucose  
 Transfer to ICU  
 Lorazepam a 2 mg IV, with additional 2 mg IV to a total of 4 mg to control seizures  
 Levetiracetam 500 mg IV bolus, as well as maintenance doses  
 If seizures persist, add phenobarbital treatment at a loading dose of 15 mg/kg IV  
 Maintenance doses after resolution of convulsive status epilepticus are: lorazepam 0.5 mg 
IV every 8 hours for three doses; levetiracetam 1,000 mg IV every 12 hours; phenobarbital 
1–3 mg/kg IV every 12 hours  
 Continuous electroencephalogram monitoring should be performed, if seizures are 
refractory to treatment  
ICU, intensive care unit; IV, intravenous. 
NOTE: All indicated doses of medication are for adult subjects.  
a 
Lorazepam is the recommended benzodiazepine because it is short-acting, compared with diazepam, and has been widely used in the 
management of seizures.  
Reference: Neelapu 2018. 
 
 
 
 


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Table A-3 
Recommendation for the Management of Raised Intracranial Pressure (ICP) 
Stage 
Management 
Stage 1 or 2 papilledema a with CSF 
opening pressure of <20 mmHg without 
cerebral edema  
 Acetazolamide 1,000 mg IV, followed by 250–1,000 mg IV every 12 hours 
(adjust dose based on renal function and acid-base balance, monitored 
1–2 times daily)  
Stage 3, 4, or 5 papilloedema, a with any 
sign of cerebral oedema on imaging 
studies, or a CSF opening pressure of  
≥20 mmHg  
 
 Use high-dose corticosteroids with methylprednisolone IV 1 g/day, as 
recommended for Grade 4 encephalopathy syndrome (Table A-1)  
 Elevate head end of the subject’s bed to an angle of 30 degrees  
 Hyperventilation to achieve target partial pressure of arterial carbon 
dioxide (PaCO2) of 28–30 mmHg, but maintained for no longer than 24 
hours  
 Hyperosmolar therapy with either mannitol (20 g/dL solution) or 
hypertonic saline (3% or 23.4%, as detailed below) 
 Mannitol: initial dose 0.5–1 g/kg; maintenance at  
0.25–1 g/kg every 6 hours while monitoring metabolic profile and 
serum osmolality every 6 hours, and withhold mannitol if serum 
osmolality is ≥320 mOsm/kg, or the osmolality gap is ≥40  
 Hypertonic saline: initial 250 mL of 3% hypertonic saline; maintenance 
at 50–75 mL/h while monitoring electrolytes every 4 hours, and 
withhold infusion if serum Na levels reach ≥155 mEq/L  
 For subjects with imminent herniation: initial 30 mL of 23.4% 
hypertonic saline; repeat after 15 minutes, if needed  
 If subject has ommaya reservoir, drain CSF to target opening pressure of 
<20 mmHg  
 Consider neurosurgery consultation and IV anesthetics for burst-
suppression pattern on electroencephalography  
 Metabolic profiling every 6 hours and daily CT scan of head, with 
adjustments in usage of the aforementioned medications to prevent 
rebound cerebral edema, renal failure, electrolyte abnormalities, 
hypovolemia, and hypotension  
CSF, cerebrospinal fluid; CT, computed tomography (scan); IV, intravenous. 
NOTE: All medication doses indicated are for adults.  
a 
Papilledema grading should be performed according to the modified Frisén scale. 
Reference: Neelapu 2018. 
 

ICF_001.pdf: 
Melissa A Geller, MD - University of Minnesota / Protocol Number CPRC# 2021LS103 (MT2021-27) 
Page 1 of 27   
 
Melissa Geller, MD 
Advarra IRB Approved Version 13 Oct 2023 
 
 
INFORMED CONSENT FORM 
AND 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
Sponsor / Study Title: 
 
Melissa A Geller, MD - University of Minnesota / 
“Intraperitoneal FT538 with Intravenous Enoblituzumab in 
Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal 
Cancer” 
 
Protocol Number: 
 
CPRC # 2021LS103 (MT2021-27) 
 
Principal Investigator: 
(Study Doctor) 
 
Melissa Geller, MD 
 
 
Telephone: 
 
612-626-3111 
612-273-3000 (24-Hour) 
 
Address: 
University of Minnesota 
420 Delaware St. SE 
Minneapolis, MN, 55455 
 
 
If your doctor is Dr. Geller, please note that she is interested in both your medical care and the 
conduct of this research study. You have the right to discuss this study with another person 
who is not part of the research team before deciding whether to participate in the research. 
 
Supported By: The research related expenses for this study are covered by National Institutes 
of Health (NIH) grants. 
 
Fate Therapeutics is supplying the FT538 cell product without cost for the purpose of this study.  
MacroGenics, Inc. is supplying enoblituzumab without cost for the purpose of this study.  
 
Financial Interest Disclosure: This research is supported in part by Fate Therapeutics. The 
University of Minnesota has licensed certain aspects of FT538, the cell product being tested in 
this study, to Fate Therapeutics. The University of Minnesota may benefit financially if the 
product is marketed in the future.  
 
The University of Minnesota has a financial interest in the FT538 cell treatment due to its 
license agreement with Fate Therapeutics, which is providing the FT538 for this study. This 
interest has been reviewed and managed by the University of Minnesota in accordance with its 
conflict of interest policies. If you would like further information about this interest, please 
contact Jon Guden, Associate Director, Conflict of Interest Program, at jguden@umn.edu 
 


Melissa A Geller, MD - University of Minnesota / Protocol Number CPRC# 2021LS103 (MT2021-27) 
Page 2 of 27   
 
Melissa Geller, MD 
Advarra IRB Approved Version 13 Oct 2023 
 
 
Key Information About This Research Study 
The following is a short summary to help you decide whether or not to be a part of this 
research study. More detailed information is listed later in this form. 
 
What is research? 
The study doctors are committed to your care and safety. There are important differences 
between research and treatment plans: 
• 
The goal of research is to learn new things in order to help groups of people in the 
future. Study doctors learn things by following the same plan with a number of 
participants. You, as an individual, may or may not be helped by participating in a 
research study; however, your participation helps answer the research questions. 
• 
The goal of routine (standard) treatment is to treat your cancer. Standard treatments 
are available from any doctor. 
Research and clinical care are often combined. One purpose of this consent document is to 
provide you clear information about the specific research activities of this study.  
This consent form is to help you decide if you want to participate in the research study.  
You should not join this research study until all your questions are answered. 
 
Why am I being asked to take part in this research study? 
You are invited to take part in this research study because you have ovarian, fallopian tube or 
primary peritoneal cancer that has returned (recurred) despite previous treatment.  
 
Things to Know Before Deciding To Take Part in a Research Study  
• 
If you elect to participate in this study, it may delay treatment with other options such 
as platinum based treatment if you are platinum sensitive at this time. 
• 
Someone will explain this research study to you. 
• 
You can ask all the questions you want before you decide. 
• 
Whether or not you take part is up to you. 
• 
You can choose not to take part. 
• 
You can agree to take part and later change your mind. 
• 
Your decision will not be held against you. 
 
Why is this research being done? 
Gynecological cancer that has returned (recurs) or re-grows (progresses) after surgery and/or 
drug therapy) rarely can be cured with standard treatments. 
 
A healthy immune system is designed to use the body’s own defenses to attack and kill foreign 
“invaders” such as bacteria and virus which cause infection. Cancer has a unique ability to turn 
off a body’s normal defenses allowing cancer cells to grow and spread without detection by the 
immune system. As more is learned, immunotherapy (treatment that stimulates the immune 
system to help it fight cancer), cell therapy (introducing healthy cells into the body to replace or 
repair damaged cells), and targeted therapies (treatment designed to attack certain types of 
cells) have become new approaches in addition to surgery, radiation therapy, and 
chemotherapy. 


Melissa A Geller, MD - University of Minnesota / Protocol Number CPRC# 2021LS103 (MT2021-27) 
Page 3 of 27   
 
Melissa Geller, MD 
Advarra IRB Approved Version 13 Oct 2023 
 
 
This study uses two investigational agents: FT538, a cell product that stimulates the immune 
system into action and enoblituzumab, a monoclonal antibody (mAb) that targets an antigen 
found on the surface of some solid tumor cancer cells.  
 
FT538 is a type of cell product made up of “natural killer” or NK cells. NK cells are a type of 
immune blood cell that are known to attack cancer cells. FT538 is produced by growing cells 
that come from a healthy human donor. The donor cells are treated with a process that turns 
them into a type of cell called an induced pluripotent stem cell, which means that these cells 
can be turned into any type of human cell. In this case, the cells are turned into NK cells which, 
once ready as FT538, are stored frozen until shipped to the study site where they are stored 
frozen until needed. 
 
FT538 is different from the NK cells in your body because FT538 has been changed through a 
process known as cell engineering. This type of cell engineering changes the coded blueprint of 
cells, known as DNA, affecting how the cells work in the body. Specifically: 
• A special protein called “hnCD16” has been added to FT538 so it can attach to a type of 
anti-cancer drug called monoclonal antibodies to help NK cells target and kill cancer 
cells.   
• Another protein called an “IL-15/IL-15 receptor complex” has also been added to FT538. 
This helps the NK cells stay alive.   
• Finally, FT538 has been engineered to remove a protein called “CD38.” CD38 is naturally 
present on NK cells. Removing CD38 allows certain monoclonal antibodies that target 
CD38, to kill the cancer cells, but not to kill FT538 cells. The removal of CD38 may also 
increase the activity of NK cells. 
 
FT538 is considered a xenotransplantation product because it comes in contact with cells of 
animal origin during the manufacturing process.  There are risks of taking a xenotransplantation 
product.  Refer to the sections “What are the risks of this study?  Is there any way being in this 
study could be bad for me? (Detailed Risks)” and “What Are My Responsibilities?” for more 
information. 
 
Enoblituzumab belongs to a group of drugs called monoclonal antibodies (mAB). Enoblituzumab 
targets cancer cells that make a lot of a protein called B7-H3. Another way to say it is that the 
cells "overexpress" the protein. B7-H3 is widely expressed by a number of different tumor 
types, including a majority of ovarian cancers. Very few normal cells express B7-H3. 
Enoblituzumab is thought to work by recognizing cancer cells that overexpress the B7-H3 
protein and directing the body’s immune system to kill those cells.  
 
Both of these agents are considered investigational. They are not approved by the United 
States (US) Food and Drug Administration (FDA) for general use; however, they each were 
developed based on similar therapies.  
 


Melissa A Geller, MD - University of Minnesota / Protocol Number CPRC# 2021LS103 (MT2021-27) 
Page 4 of 27   
 
Melissa Geller, MD 
Advarra IRB Approved Version 13 Oct 2023 
 
 
Up to 6 Dose Cohorts (study groups) will be tested. The first 4 Dose Cohorts will be FT538 
monotherapy (without enoblituzumab). Cohorts 5 and 6 will be FT538 plus enoblituzumab. You 
will be told the currently enrolling dose cohort as part of this consent discussion. 
 
The primary purpose of this study is to identify a safe dose of FT538 cells when given alone 
(monotherapy) and in combination with enoblituzumab. Another purpose of this study is to 
gain early information on many women who have disease stabilization or shrinkage by the time 
of the 1st disease reassessment.  
 
How long will I be in this study? 
Direct study participation is approximately 1 year; however, the most intensive study treatment 
is during the 1st 4 to 5 weeks with follow-up visits every 3 months through 1 year. 
 
At approximately 5 weeks the computed tomography (CT) scan of the chest, abdomen and 
pelvis is repeated. If your disease is stable or improved from your previous CT scan, you may be 
offered a second course of FT538 which would require signing a separate retreatment consent 
form. If no further study treatment is planned and your intraperitoneal (IP) catheter is still in 
place, it would be removed. 
 
If you are enrolled into Dose Cohort 5 or 6, enoblituzumab may continue as an intravenous 
infusion once every 3 weeks until it is no longer of benefit, you have unacceptable side effects, 
or decide to discontinue study treatment. A final study treatment visit is done approximately 4 
weeks after the last dose of enoblituzumab.  
 
Follow-up visits occur every 3 months for the 1st year. If you are continuing on enoblituzumab, 
follow-up visits will occur during a planned visit. Disease reassessments are done according to 
standard of care with the results documented on study case report forms.  
 
After 1 year, you will transfer to a long-term follow-up (LTFU) study to determine if there are 
any late effects of FT538. FT538 is an “engineered” cell product and the FDA recommends 
yearly follow-up for 15 years. You will sign a separate consent form for the LTFU study. 
Participation in the LTFU study is required for receiving study treatment on this study. 
 
What will I need to do to participate? 
If you are interested in this study, you will be asked to sign this consent form giving permission 
to formally evaluate you for this study. This is called screening and consists of the following 
routine evaluations: 
• Physical exam and medical history 
• Routine blood work including a CA125 level (a test requiring approximately 2 teaspoons 
of blood to determine the amount of the protein cancer antigen 125) 
• CT scan of your chest, abdomen and pelvis if not done in the previous few weeks 
• An echocardiogram of your heart to determine cardiac function 
• If you have shortness of breath or a history of lung issues, pulmonary function tests will 
be done 


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• If you had previous spread of the cancer to your brain or symptoms of possible spread, a 
CT or magnetic resonance imaging (MRI) of the brain will be done 
• Any other tests or procedures as determined by the study doctor based on your current 
or past medical history   
 
If you are eligible, a peritoneal port (a small chamber allowing access between the muscles and 
organs of the belly, or abdomen) and intraperitoneal catheter (a thin tube leading to the tissue 
of the abdomen) will be placed during an outpatient procedure in interventional radiology. It 
provides a painless way of withdrawing excessive fluid from the abdominal or peritoneal cavity 
and as a way to give the FT538 cells. The IP catheter will stay in place for at least 5 weeks. 
 
Occasionally, because of interior scarring from previous surgeries, the catheter cannot be 
inserted. If it cannot be placed, you would not be eligible to continue on this study. Other 
treatment options would be discussed with you. 
   
Study Treatment is given in the following order: 
• 
Cyclophosphamide and Fludarabine (CY/FLU) are given as IV (into a vein) infusions, one 
after the other, in the outpatient clinic for two days in a row. 
• 
FT538 is given as 3 weekly doses into the IP catheter with the 1st dose no sooner than 48 
hours (2 days) after the last CY/FLU dosing. Each cell infusion is given on the inpatient 
unit as a short stay.  
• 
If you are enrolled in Dose Cohort 5 or 6, Enoblituzumab is given as an intravenous 
(into a vein – IV) infusion in the outpatient clinic the day before the CY/FLU is started 
(although the schedule may be adjusted on an individual basis). It is given again 1 week 
after the last dose of FT538 and may continue every 3 weeks as long as it is of benefit. 
 
More detailed information about the study procedures can be found under “What happens if I 
say yes, I want to be in this research?” 
 
Is there any way that being in this study could be bad for me? 
You will have side effects from the study treatment given in this study.  
 
This study requires the placement of an intraperitoneal (IP) catheter into your abdomen to give 
the FT538 cells. There is risk associated with the penetration of the abdominal cavity during the 
IP catheter placement as it may expose new surfaces for the cancer cells to attach and grow, 
such as along the catheter track.   
 
Fludarabine and cyclophosphamide are common chemotherapy drugs given in this study to 
prepare for the FT538 cells by blunting your immune system to lessen the chance of a reaction 
to the FT538 cells. The drugs will lower your blood counts (white blood cells) increasing the risk 
of infection.  
 
In this study the FT538 is given into the abdomen through the IP catheter. In previous studies 
using similar cell products, abdominal pain and cramping was the most frequent complaint. 


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When FT538 is given as an IV (into a vein) infusion the most common side effects are chills and 
rarely, an allergic reaction. Signs of a reaction are flushing of the face, change in blood pressure 
and/or heart rate, difficulty breathing.  
 
If you are in Dose Cohort 5 or 6, the most common side effect of enoblituzumab (occurring in 
approximately 1 out of every 2 participants) is an infusion related reaction during or shortly 
after the study drug is given. Signs of a reaction include fever, chills, nausea, itching, difficulty 
breathing and/or low blood pressure. The infusion can be slowed and/or interrupted if signs 
occur and medications given to reduce the severity of the reaction.  
 
More detailed information about the risks of this study can be found under “What are the risks 
of being in this study? Is there any way being in this study could be bad for me? (Detailed 
Risks)” and in the “What happens to the information collected for the research, including my 
health information?” section. 
 
Will being in this study help me in any way? 
There may be no benefit to you from participating in this research study. Your cancer may not 
shrink, or it may even get worse. Information learned from this study may benefit others with 
cancer through a better understanding of cancer and the immune system leading to future 
research. 
 
What happens if I do not want to be in this research? What are my alternatives? 
You do not have to be in this study.  
 
Your participation in this study is voluntary. You can decide not to be in the study and you can 
change your mind about being in the study at any time. There is no penalty to you, and you will 
not lose any benefits except for potential benefits having to do with the study. 
 
Other options may include: 
• Other investigational treatments at this institution or at another research center. 
• Continue platinum based therapy, if you are platinum sensitive. 
• No treatment at this time with comfort care only. This type of care helps manage pain, 
tiredness, appetite problems and other quality of life issues  caused by the cancer. It 
does not treat the cancer directly, but instead tries to improve how you feel. Comfort 
care tries to keep you as active and comfortable as possible. If you think you might 
prefer comfort care, please discuss this with your family, friends and your doctor. 
 
Your study doctor can provide you additional information, including the risks and benefits of 
each option. 
 
Detailed Information About This Research Study 
The following is more detailed information about this study in addition to the information listed 
above. 
 


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A study summary is found at the end of this document. 
 
How many people will be enrolled in this study? 
Enrollment will most likely include 19 participants including a minimum of 10 people treated at 
the best tolerated Dose Cohort. Up to 33 participants may be required if side effects are seen 
early in the study requiring the dose cohorts to expand to 3 participants each. 
 
What happens if I say “Yes, I want to be in this research”? 
If you are eligible and agree to take part in this study the following will occur: 
 
Peritoneal Port and Intraperitoneal Catheter must be placed before any study related 
treatment is started.  
 
A peritoneal port is a small reservoir or chamber that is surgically implanted under the skin to 
provide a painless way of withdrawing excess fluid or delivering anti-cancer drugs into the 
abdominal or peritoneal cavity over a period of weeks or longer. The port has a silicone rubber 
top that can be penetrated by a needle and an attached catheter that is designed to hang down 
into the abdominal cavity once it is placed inside the body. The port is placed underneath the 
skin and then sutured (stitched) to the ribs.  
 
The port and IP catheter are placed during an outpatient procedure in Interventional Radiology. 
Numbing medication and other medications will be used to reduce the pain. You will 
experience pain at the site of insertion until it heals.  
 
Occasionally, because of adhesions (internal scarring of tissue or organs) from previous 
surgeries, the catheter cannot be inserted. If it cannot be placed, you would not be eligible to 
continue on this study. Other treatment options would be discussed with you. 
 
Cyclophosphamide and Fludarabine (CY/FLU) are given as IV infusions, one after the other, in 
the outpatient clinic for two days in a row. Each infusion takes about 30 minutes, although 
fluids and medications are given before and after the infusion, so it will take longer than the 
1 hour study drug infusion time. 
 
FT538 is given as 3 weekly doses into the IP catheter with the 1st dose no sooner than 48 hours 
(2 days) after the last CY/FLU dosing. Each study treatment is given on the inpatient unit as a 
short stay. The FT538 is infused quickly (by gravity) followed by flushing of the tube with fluids. 
Depending on your dose, it may be given as one or more bags of cells. After the FT538 infusion, 
you will be asked to change positions every 15 minutes for 2 hours to distribute the cells 
throughout your abdomen.  
 
Three days after the 1st FT538 infusion only, you will have a clinic appointment with bloodwork.  
 
FT538 is given weekly in a manner identical to the first infusion, on Day 1, Day 8 and Day 15.  
 


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If you are assigned to Dose Cohort 5 or 6 (FT538 plus enoblituzumab): 
The first dose of enoblituzumab is given as an intravenous (into a vein – IV) infusion over 
approximately 2 hours in the outpatient clinic.  
 
A second dose is given approximately 1 week after your last FT538 infusion.  
 
As described in the next section, a repeat CT scan of the chest, abdomen and pelvis is done 
around this same time. If the CT scan shows stable or shrinking disease, enoblituzumab may 
continue once every 3 weeks as an outpatient IV infusion for up to 1 year unless unacceptable 
side effects occur or your disease worsens.  
 
Routine bloodwork and a clinic visit will occur with each study treatment. A final study treatment 
visit will be done approximately 4 weeks after your last dose of enoblituzumab for a routine 
exam and blood work to ensure there are no ongoing side effects.  
 
Visits and repeat CT scan after the 3rd FT538 infusion: 
After the last FT538 infusion you will return to clinic once a week for 4 weeks for a clinic visit, 
assessment of side effects, and routine blood work. If enoblituzumab is scheduled, the 
appointments will be scheduled on the same day if possible. 
 
Approximately 5 weeks after the 1st dose of FT538 infusion a repeat CT scan of the chest, 
abdomen and pelvis will be done. If it shows stable or shrinking disease, you may be offered a 
2nd study treatment course (identical to the 1st). If you plan on a 2nd course, your IP catheter 
will remain in place. If a second course of FT538 is not planned, your IP catheter will be removed 
as soon as the decision is made. 
 
Disease Re-Assessment and study visits through 1 year 
You will continue with routine follow-up imaging studies and CA-125 levels every 3 months. A 
follow-up visit is required at 3, 6, 9 and 12 months after the 1st FT538 infusion. If you are 
continuing on enoblituzumab, the follow-up visit will be aligned with one of those visits. 
 
Long-term follow-up after 1 year 
FT538 is a genetically engineered cell product and the FDA is recommending follow-up for up to 
15 years from the 1st dose. This follow-up can be done in person if you are receiving care at the 
University of Minnesota. Otherwise it can be done by phone, email or mail. You will be required 
to sign a separate consent for the long-term follow-up (LTFU) study. 
 
STUDY RELATED SAMPLE COLLECTION (RESEARCH RELATED): 
As this is a clinical research study, additional blood is collected for research related testing (70 ml 
or about 5 tablespoons) at key time points and up to 3 additional time points if felt important on 
an individual basis to learn about individual differences (for example, in the case of a very good 
disease response, unexpected side effects):   
• 
Before study treatment starts 
• 
Before the 1st dose of enoblituzumab if you are enrolled in Cohort 5 or 6 


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• 
Before the 1st CY/FLU study treatment 
• 
Before each FT538 infusion 
• 
At the clinic appointment approximately 3 days after the 1st dose of FT538 
• 
At each weekly visit after the FT538 infusion  
• 
At the 3, 6, 9, and 12 month follow-up visits (approximately 40 milliliters or about 3 
tablespoons) – if you have a worsening of your disease or start a new treatment, these 
samples may not be collected. 
 
Approximately 2 teaspoons of blood of additional blood will be collected around the time of 
your disease reassessment for to look for evidence of an immune response to FT538.  
 
In addition, approximately 2 teaspoons of blood is collected at the 3, 6, and 12 month follow-ups 
and sent to Fate Therapeutics as part of their long-term follow-up testing required by the FDA. 
These samples are stored frozen and shipped in batches to Fate Therapeutics for testing 
required on their products by the FDA. 
 
Participation in this study involves collection of blood that may result in a decrease in your 
overall hemoglobin level and may require a whole blood transfusion. Please speak to your study 
doctor if you have questions. 
 
The research blood samples will be analyzed to look at changes in your immune system over 
time, the effects of the study drugs (FT538, and if receiving, enoblituzumab), and how long the 
study drugs are present in your blood. Testing may include analysis of your genome (DNA), 
which is the “instruction book” for the cells in your body. Your samples may be tested to find out 
about mutations (permanent changes) and other possible changes to your genome. Testing will 
not be done to determine whether any of the mutations are inherited. 
 
Fluid will be collected from your abdomen through your IP catheter for research related analysis. 
Samples will be collected at the time your IP catheter is placed, prior to each FT538 infusion, and 
once a week until FT538 cells are no longer detected (approximately 2 weeks after the last FT538 
infusion) and at the catheter removal. If you have ascites (fluid pooling in your intraperitoneal 
space as a result of the cancer), these cells will be used. Otherwise, cells are obtained by an 
intraperitoneal (IP) washing where a small amount of normal saline is infused through your IP 
catheter. You then are asked to move around to distribute the fluid and then it is withdrawn 
through your IP catheter. Approximately ¼ cup of fluid is needed, but if more is available (as in 
the case of ascites), more will be collected. 
 
If feasible, a sample of tumor tissue will be taken by biopsy when your IP catheter is placed and 
at the time the IP catheter is removed. Your safety comes first - the biopsies are done only if 
tumor is easily accessible.  
 
At the time of study enrollment you are assigned a unique participant code that will be used 
instead of your name or other identifying information. The research samples are labelled with 
your unique code making it difficult for anyone looking at the sample to know it belongs to you.  


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Research related testing is primarily done at the University of Minnesota and M Health /Fairview 
laboratories; however, for specialized testing that cannot be done within the system, samples 
may be sent to outside laboratories, including Fate Therapeutics, and if receiving enoblituzumab, 
MacroGenics. Any samples sent outside of the system is labelled with the unique participant 
code assigned at enrollment. 
 
None of the research related testing results will affect your care or your participation in this 
study. Neither you nor your health insurance provider will be charged for the cost of research 
sample collection, processing, storage, and testing.  
 
There may be some leftover cells from the samples collected for research purposes. With your 
permission, after analysis for this study is completed we would like to store any leftover samples 
for future analysis as new research tests become available. They will not be used for studies 
other than ones to learn about the immune system and/or cancer. You will be asked to indicate 
your decision about future use of leftover samples at the end of this document. 
 
New findings  
Any new important information that is discovered during the study which may influence your 
willingness to continue participation in the study will be provided to you. 
 
What are my responsibilities? 
Because FT538 is a xenotransplantation product, you are also expected to have certain 
responsibilities in the future.  These future responsibilities may include, but are not limited to, 
having regular check-ups and telling your doctor or other healthcare providers about receiving 
a xenotransplantation product in the event of unexplained illnesses.  You and your family 
members and intimate contacts should not donate blood, sperm, or other body fluids or 
tissues.  If needed, ask the study doctor or a member of the study staff to help you discuss this 
with your family members and intimate contacts, or if you have any questions. 
 
What happens if I say “Yes” but I change my mind later? 
If you take part in this research study, and want to leave, you should let a member of the 
research team or your study doctor know. Your choice not to be in this study will not affect 
your right to any present or future medical care.  
 
If you leave the study before the planned final visit, you may be asked by the study doctor to 
have some tests or procedures for your safety.  
 
The study doctor may stop your participation in this study at any time without your consent for 
reasons including the following: 
• 
It appears being in the study may be harmful to you; 
• 
There is a change in the research and/or the risk profile that requires your re-consent 
and you refuse to sign the updated consent form; 
• 
If the study is stopped early. 
 


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If you end participation in this study early, the information about you, test results, and 
laboratory samples that were collected while you were participating in the study may still be 
used. Follow-up information will still be requested unless you withdraw consent.  
 
What are the risks of being in this study? Is there any way being in this study could be bad for 
me? (Detailed Risks) 
 
Risks of being in this study: 
You will experience side effects. You may experience all, some, or none of these side effects 
and the side effects may vary in severity. The severity may be mild, moderate, or severe, up to 
and including death. Also, there is always the risk of a rare or previously unknown side effect 
occurring. 
 
This multi-day study therapy may trigger or worsen underlying conditions such as a fast and 
irregular heartbeat (atrial fibrillation/flutter), chronic obstructive pulmonary disease (COPD), or 
may make management of chronic conditions such as hypertension (high blood pressure) or 
diabetes more difficult during study therapy. 
 
The University Of Minnesota has been doing studies with NK cells similar to this study for 
several years including by intraperitoneal administration; however this is an early study of 
FT538 in humans and the 1st as an intraperitoneal infusion, so its side effects are not well 
documented. 
 
Other drugs will be given to make side effects less serious and uncomfortable or your study 
doctor may delay or alter the planned study treatment. Many side effects go away shortly after 
the study drugs are stopped, but in some cases side effects can be serious, long-lasting or 
permanent, even fatal. 
 
Cyclophosphamide (CY) and fludarabine (FLU) are commonly used chemotherapy drugs and are 
available without being on a research study. 
 
Risks Related to Cyclophosphamide (CY) 
CY may cause side effects, as described below.   
Common Side Effects - occurring in more than 30 out 100 participants receiving this drug 
• Low blood counts: Your white and red 
blood cells and platelets may temporarily 
decrease. This can put you at increased risk 
for infection, anemia, and/or bleeding. 
• Poor appetite 
• Nausea and vomiting (more common with 
larger doses) 
• Temporary hair loss  
• Discoloration of the skin or nails 
Less Common Side Effects - occurring in about 10 to 29 participants receiving this drug 
• Loss of fertility 
• Diarrhea 
• Mouth sores 
• Bladder problems and bleeding 
(hemorrhagic cystitis) 


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Serious, but uncommon, side effects of CY include:  
• Increased risk of developing other cancers, such as bladder cancer, acute leukemia (a 
type of blood cancer), lymphoma (a type of lymph node cancer), thyroid cancer, and/or 
sarcoma (a type of cancer that can start in the soft tissue, bone, or other tissue).  
• Liver problems, which can be fatal 
• Heart failure, which can be fatal 
• Inflammation of the lung  
 
CY may cause rare and unexpected side effects other than those described here. Tell the study 
doctor if you have any unusual problems while receiving this study drug.  
 
Risks Related to Fludarabine (FLU) 
FLU may cause side effects, as described below.   
Common Side Effects (occurring in more than 30% of participants) 
• Fever 
• Infection 
• Weakness 
• Cough 
• Nausea and vomiting 
• Poor appetite 
• Low blood counts. Your white and red 
blood cells and platelets may temporarily 
decrease. This can put you at increased risk 
for infection, anemia, and/or bleeding. 
Less Common Side Effects (occurring in about 10%-29% of participants) 
• Chills 
• Fatigue 
• Pain 
• Sweating 
• Numbness and tingling of hands and feet 
• Shortness of breath (lung problems) 
• Diarrhea 
• Rash (skin reactions) 
• Swelling 
• Taste changes, metallic taste 
 
Serious, but uncommon, side effects of FLU include:  
• An increased risk of infection (such as herpes, fungal infection, and a type of pneumonia 
that occurs in people with weakened immune systems called Pneumocystis carinii) due 
to suppression of the immune system   
• Severe side effects involving the brain and other parts of the nervous system, which 
were seen at doses higher than the dose you will receive in this study     
• Hemolytic anemia (destruction of red blood cells)   
• A rare condition called transfusion-associated graft-versus-host disease (also called 
GvHD), which occurs when immune cells in a blood transfusion attack cells in the body 
causing fever, rash, liver problems, and abdominal pain and diarrhea. If you require a 
blood transfusion while on this study, you will receive only blood transfusions that have 
received radiation treatment to reduce the risk of transfusion-associated GvHD. 
• Tumor lysis syndrome (also called TLS) can happen when cancer cells have broken down 
and byproducts of that breakdown have entered the bloodstream. Symptoms may 
include weakness, low blood pressure, muscle cramps, and decreased urination. TLS can 
lead to kidney damage and/or other organ damage. In addition to cancer treatment, 
many factors including the type and extent of the cancer, as well as treatments given to 


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an individual, can contribute to TLS. Let the study doctor know immediately if you 
develop these symptoms.   
 
FLU may cause rare and unexpected side effects other than those described here. Tell the study 
doctor if you have any unusual problems while receiving this study drug.  
 
Risks of FT538 
FT538 has not been widely used in humans and has only been given as an intravenous (IV - into 
a vein) infusion.  
 
In this study, the FT538 is given directly into the abdominal space through an IP catheter. This 
is the first time that FT538 is being given as an intraperitoneal infusion, and therefore the risks 
are not known. In previous studies using similar cell products given intraperitoneally (IP), 
abdominal cramping was the most frequent complaint. You will be given acetaminophen 
(Tylenol®) and diphenhydramine (Benadryl®) before the FT538 infusion and every 4 hours 
afterwards as needed. In some situations abdominal pain and cramping has required stronger 
oral or intravenous pain control. 
 
Risks of FT538 based on intravenous (IV) infusion are listed below: 
 
The potential risks of FT538 based on IV infusion include those related to how FT538 may work 
in the body and how the body may react to FT538. The potential side effects listed below are 
based on laboratory studies and knowledge of similar cell therapies. 
• 
An infusion related (allergic) reaction during or shortly after the FT538 cell infusion. 
There is a potential risk for an allergic reaction during intravenous (IV) infusion. The 
reaction with IV infusion may be mild (skin irritation/rash) to life-threatening (difficulty 
breathing/swelling of the face and throat). Please seek treatment immediately and tell 
the study doctor and research team if you have any of these symptoms, or any other 
side effects, during the study. 
• 
Cytokine release syndrome (CRS) is a serious systemic (whole body) inflammation 
response. CRS is seen with other types of cell therapies, but is not typically seen with NK 
cell therapies. Signs of CRS include fever, nausea, headache, rash, rapid heartbeat, low 
blood pressure, and trouble breathing. Most patients who develop CRS have a mild 
reaction, but sometimes, the reaction may be severe or life threatening. CRS is treated 
with supportive care and steroids. 
• 
Tumor lysis syndrome (also called TLS) can happen when cancer cells have broken 
down and byproducts of that breakdown enter the bloodstream. Symptoms may include 
weakness, low blood pressure, muscle cramps, and decreased urination. TLS can lead to 
kidney damage and/or organ damage. In addition to cancer treatment, many factors can 
contribute to TLS, including the type and extent of a patient’s cancer, as well as 
treatments given to a patient. Let your study doctor know immediately if you are unable 
to urinate. 
• 
Effect on the nervous system have been seen with other types of cell products, but is 
not a common risk of NK cell therapies. Neurotoxicity (when substances alter normal 


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activity of the nervous system) symptoms observed with other cell therapies include 
confusion, delirium, and sometimes seizures and cerebral edema (swelling) that could 
lead to death. You will be monitored for changes in your mental status before and at 
every clinic visit after FT538. 
• 
Reaction to DMSO (dimethyl sulfoxide) is a common ingredient in cell therapy products. 
Some people have a negative reaction to DMSO. If you have had a previous reaction 
related to DMSO, you will not be eligible to take part in this study. Because of the very 
small volume of the cell infusion and it is given into your abdominal space, no reaction is 
expected. DMSO may cause side effects like coughing, flushing, rash, chest tightness, 
wheezing, nausea, vomiting, and high or low blood pressure. 
• 
There is an increased risk of infection. FT538 contains cells from human donors and 
may transmit infectious diseases or infectious agents, such as viruses, bacteria, or other 
pathogens, and/or other non-infectious agents, which may also cause side effects.  The 
master cell bank from which FT538 is manufactured has been extensively tested to 
reduce the risk of disease infection.  However, these tests do not completely eliminate 
this risk.  For some infectious agents, there are no routine tests to predict or prevent 
their presence. 
 
There may be other risks that are unknown which could range from mild to serious, and even 
fatal. The use of NK cell products like FT538 is investigational.  
 
Risks Related to Xenotransplantation Products 
FT538 is considered a xenotransplantation product because it comes in contact with cells of 
animal origin (mouse cell) during the manufacturing process.  Risks of receiving a 
xenotransplantation product may include, but are not limited to, developing infections from 
agents that may be associated with cells of animal origin, transmitting these infectious agents 
to others, and the growth of tumors.  The animal cells, which come into contact with the FT538 
cells during the manufacturing process, originate from a master cell bank that has been 
extensively tested to reduce these risks.  However, these tests do not completely eliminate this 
risk.  The likelihood and timing for developing a condition or illness from xenotransplantation 
products is unknown.  If you have any questions about the risks involved in receiving a 
xenotransplantation product, ask the study doctor or a member of the study staff. 
 
FT538 has been genetically engineered (the structure of the NK cell has been changed from the 
state in which NK cells naturally exist in your body) using virus-based technology. The long-term 
risks of the genetic engineering and the viruses used to make these changes are not known. As 
a result, the FDA requires long-term follow-up at least once a year for up to 15 years. Of 
interest is the development of cancer, new or worsening neurologic disorders, new or 
worsening autoimmune (immune reactions) or rheumatologic (of the immune system) disorder, 
or new blood disorder. Details of the long-term follow-up study are provided in a separate 
consent form. 
 
 


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Risks of Enoblituzumab (Dose Cohorts 5 and 6 only) 
General risks associated with drugs similar to enoblituzumab: 
• Infusion reactions: These are generally temporary reactions. They usually happen during 
or within hours after getting the study drug. A mild to moderate reaction can cause a 
fever, chills, nausea, vomiting, headache, confusion, seizures, muscle stiffness, rash, or 
itching. A more severe infusion reaction can also cause low blood pressure, and difficulty 
breathing. They can be life threatening, cause hospitalization, or rarely may cause death.   
• Immune-related side effect: A possible side effect of the test drug is that your immune 
system may attack other, healthy parts of your body. This is known as an autoimmune 
reaction. This reaction can affect many different organs in your body. If you have a 
reaction, you may require treatment with high-dose steroids or hospitalization. Patients 
who have received other drugs that affect the immune system have experienced the 
following types of side effects: 
o Pneumonitis (inflammation in the lungs): Symptoms may include shortness of 
breath, chest pain, and/or cough. 
o Colitis (inflammation of the colon): This may lead to tears or holes in your colon 
(large intestine). Symptoms may include diarrhea or more frequent bowel 
movements, black or tarry stools (that may have blood or mucous), and/or severe 
abdominal pain. 
o Hepatitis (inflammation of the liver): Symptoms include yellowing of your skin or 
the whites of your eyes. You might have nausea or vomiting, abdominal pain, and 
feel less hungry than usual. Other signs include fevers or chills, dark urine, and/or 
bleeding or bruising more easily than usual. 
o Hormone gland problems (including thyroid, pituitary [pituitary gland is a gland in 
the brain that produces hormones], adrenal and pancreas): If you have hormone 
gland problems, you might feel a rapid heartbeat, have changes in weight, or 
increased sweating. You may feel hungrier or thirstier than usual. You may need to 
use the toilet more often. Other possible side effects are hair loss, feeling cold, 
constipation, deeper voice, muscle aches, dizziness or fainting, and/or unusual 
headaches. 
o Kidney problems: Symptoms may include changes in the amount or color of your 
urine, swelling of ankles, and/or loss of appetite. 
o Encephalitis (inflammation of the brain): You may feel headache, fever, tiredness, 
and confusion. You might have memory problems, weakness, see or hear things that 
are not there, uncontrolled muscle movements, and/or stiff neck. 
o Skin problems, including Stevens-Johnson syndrome (SJS) and toxic epidermal 
necrolysis (TEN): Inflammation of the skin so you may have widespread peeling of 
the skin, itching, and redness. More severe inflammation of the skin may involve the 
inside of your mouth, the surface of your eye, genital areas, and/or may  cause the 
top layer of your skin to peel from all over your body, which may cause severe, 
potentially life-threatening, infection. 
o Myocarditis (inflammation of the heart muscle): Inflammation of the heart muscle 
may cause difficulty pumping your blood throughout your body. This can result in 


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chest pain, shortness of breath, swelling of the legs, fast or irregular heartbeat 
and/or dizziness or fainting. 
o Problems in other organs: You might have changes in eyesight, severe muscle or joint 
pain or weakness, and/or low red blood cells (anemia). 
 
Enoblituzumab  
As of April 2021, 349 adult participants had received enoblituzumab at doses up to 15.0 mg/kg, 
which is the dose given in this study.  
 
So far, the most important safety risk that has been identified with enoblituzumab is infusion-
related reaction (IRR), including reactions known as cytokine release syndrome (CRS). IRRs are 
effects due to a drug that may occur during or shortly after an infusion. Signs and symptoms of 
an infusion-related reaction may include: 
• fever 
• chills 
• nausea 
• vomiting 
• headache 
• muscle stiffness 
• rash 
• itching 
• low blood pressure 
• difficulty breathing 
 
IRRs can be life threatening and, in rare cases, may cause death. For all adult studies, IRRs 
(including CRS) have occurred in 48% of participants receiving study treatment with 
enoblituzumab. Most of the infusion-related reactions observed in participants receiving 
enoblituzumab have been mild to moderate in severity with 6 % of participants having more 
severe infusion-related reactions (including two who experienced life-threatening IRR events). 
These participants, some of whom were hospitalized for these reactions, recovered after 
receiving treatment with steroids, antihistamines and intravenous fluids. 
 
The following were the most common side effects that were considered related to 
enoblituzumab administration and were seen in at least 1 of 10 adult participants. These side 
effects have been generally mild or moderate. 
• infusion related reactions (described above) 
• fatigue  
• nausea  
• chills  
• vomiting  
 
 


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Eleven (11) participants have experienced serious side effects that were considered related to 
enoblituzumab. Serious side effects that occurred in 3 or more participants included: 
• IRRs 
 
Risks of the Peritoneal Port and Intraperitoneal (IP) Catheter Placement and Use 
Rarely, a complication can occur at the time of IP catheter placement due to the bowel being 
stuck to the abdominal wall from scar tissue formed during prior surgery. The risks of 
placement of the IP catheter include infection, bleeding and damage to surrounding organs 
such as the bowel. If the interventional radiologist does not feel that they can safely place the 
catheter, the procedure will be terminated and you will not be able to receive study treatment 
under this study. Sometimes these IP catheters are placed and they do not function well, but 
this is uncommon. 
 
There is a risk that cancer cells that are located within the peritoneum could spread to 
surrounding tissues such as the abdominal wall. This risk is associated with the penetration of 
the abdominal cavity during the IP catheter placement as it exposes new surfaces for the cancer 
cells to attach. Implantation of cancerous cells within surgical incisions, along biopsy needles 
and drainage catheter tracts is a recognized mechanism for the spread of cancer. Instances of 
this happening have been reported in the literature. Spread of cancer cells is a potential hazard 
of all invasive procedures in the case of any malignancy. Although this is thought to be a rare 
event, placement of an IP catheter in your abdomen may put you at risk for tumor cells 
spreading to surrounding tissues. 
 
The plan is to keep the IP catheter in place until around Day 36 (after the repeat CT scan of the 
chest, abdomen, and pelvis) or once it is determined that you will not be retreated. The primary 
risk associated with keeping an IP catheter in for any period of time is localized skin infection. 
Although this risk is rare (less than 1%) it would require antibiotic treatment. Very rarely, the 
catheter becomes plugged. The catheter would be removed early if it posed a risk or was not 
functional.  
 
General Risks of Intraperitoneal Infusions and Washings 
• 
abdominal discomfort due to the infusion of fluids into the abdominal area 
• 
fever 
• 
infection within the abdomen 
 
Risks of Intraperitoneal Biopsy 
The biopsies will be done in Interventional Radiology (where the IP catheter is placed) and will 
only be done if tumor cells are easily accessible. Risks may include: 
• 
You will have an injection of a local anesthetic to numb the area where the biopsy will 
be taken – it stings for a moment before the area goes numb. After that you only feel 
mild to moderate pressure as the biopsy is taken. 
• 
Slight risk of bleeding which usually requires no treatment – overall of all types of 
ultrasound/CT guided biopsies 1-2 participants out of 1,000 experience bleeding. 
• 
Slight risk of infection 


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• 
The biopsy site may be uncomfortable for a day or two 
 
Risks of Routine Tests and Procedures 
Risks of Blood Collection 
Risks of having blood drawn for routine blood tests and research purposes include: 
• 
pain at the site of the needle stick 
• 
tenderness and/or bruising at the site of blood collection  
• 
dizziness, light-headedness, rarely fainting 
• 
very rarely, infection at the site of the needle stick 
 
Risks of a chest, abdomen, pelvis CT scan or Positron Emission Tomography (PET)/CT 
A CT scan is a computerized x-ray picture of your internal organs. You may feel some discomfort 
or anxiety when lying inside of the CT scanner.  
 
A PET scan helps doctors see changes due to certain disease in organs and tissues inside your 
body. A PET scan may cause you to feel “closed in” while lying in the scanner. However, the 
scanner is open at both ends and an intercom allows you to talk with doctors and staff. If you 
feel ill or anxious during scanning, doctors and/or technicians will give comfort or the scanning 
will be stopped. The PET scan exposes your body to radiation. The radioactive solution does not 
remain in your system for a long period of time. However, you should wait 2 hours before 
holding an infant or getting close to a pregnant woman to avoid exposing them to radiation. 
You should drink fluids after the scan to help remove the solution from your system. 
 
You will be exposed to ionizing radiation during the scanning to evaluate your disease status. 
The scientific unit of measurement for radiation dose is the millisievert (mSv). The average 
amount of radiation received from natural sources of radiation by a Minnesota resident in one 
year is 3 mSv. Each CT scan of the chest, abdomen and pelvis would expose you to 18 mSv 
radiation. This is equal to approximately 5.6 years of background radiation. If you have a PET/CT 
each exposure is 25 mSv and equal to approximately 8.3 years of background radiation. 
Exposure to radiation may increase your lifetime risk of developing a 2nd cancer. If you have 
additional questions, you may ask your study doctor. 
 
Your disease re-assessment study may be done with CT contrast (a chemical substance to allow 
a better view of what is being scanned). Your study doctor can tell you if the dye is necessary 
for your procedure. The contrast material (dye) that is injected into your body may cause you to 
get a metallic taste in your mouth and to feel warm. Rarely, it causes nausea and vomiting. You 
may develop a skin rash or itchiness if you're allergic to the contrast. A life-threatening allergic 
reaction can also happen, but this is rare. Tell your study doctor about any sensitivities to 
medications, or any kidney problems you have. IV contrast can increase the risk of kidney 
failure if you're dehydrated or have a pre-existing kidney problem. 
 
Risks of MRI 
During the MRI, you may feel mild vibrations throughout your body. The machine will produce a 
loud knocking noise. This is normal. You will be given earplugs to protect your ears. Some 


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people, especially those who tend to feel uncomfortable in small or closed spaces, may feel 
“closed in” and become anxious while in the scanner. The scanner has an intercom, which will 
allow you to speak to the staff during the procedure. If you feel ill or anxious during scanning, 
tell the MRI staff and the scanning will be stopped if you wish. The magnetic field used in MRI 
scanning may harm people who have metal in their bodies (pacemakers, neurostimulators, 
certain clips, or staples from surgery). It may cause problems with devices, such as pacemakers. 
If you have metal in your body or a pacemaker, you should not have an MRI. 
 
Risks of Echocardiogram (ECHO) 
There are no known risks from an echocardiogram (ECHO) because the test uses only sound 
waves to evaluate your heart.  These high-frequency sound waves have not been shown to 
have any harmful effects. 
 
Risks of Ultrasound used for the IP catheter placement and removal 
There is little risk associated with ultrasound – there is no ionizing radiation exposure 
associated with ultrasound imaging. Ultrasound waves can heat the tissues slightly. In rare 
cases, it can also produce small pockets of gas in body fluids or tissues (cavitation). 
 
Risks of Pulmonary Function tests 
You may have some coughing or experience some shortness of breath after the pulmonary 
function test, but there is no pain associated directly with these tests. 
Other Risks: 
• 
Risks of Genetic Research - The risks to you and your family from genetic research on 
the blood samples are very low. The unique participant code assigned at study 
enrollment is used instead of your name or other identifying information making it 
difficult for anyone looking at the sample to know it belongs to you. Testing is done in 
batches (more than 1 participant at a time) and no research results will be placed in 
your medical record. 
• 
Because this study involves the use of your identifiable, personal information, there is a 
chance that a loss of confidentiality will occur. There are procedures in place to lessen 
the possibility of this happening (see “What happens to the information collected for 
the research, including my health information?” section below). 
 
Reproductive Risks: If you are able to become pregnant (pre-menopausal and have a uterus 
and ovaries) the following applies to you: 
• You must have a negative pregnancy test within 14 days of the study treatment start as 
pregnant women cannot take part in this study.  
• You must agree to use a highly effective form of contraception for at least 12 months 
after the last dose of cyclophosphamide or at least 4 months after the last dose of 
FT538.  
o If you receive enoblituzumab and continue it for more than 12 months after the last 
dose of cyclophosphamide, effective contraception must be used for the duration of 
enoblituzumab study treatment.  


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According to the World Health Organization and the United States Center for 
Disease Control and Prevention, the most effective forms of birth control include 
complete abstinence, surgical sterilization (both male and female), intrauterine 
devices (IUDs), and the contraceptive implant. The next most effective forms of birth 
control include injectables, oral contraceptive pills, the contraceptive ring, or the 
contraceptive patch. Acceptable, but least effective, methods of birth control 
include male condoms (with or without spermicide) and female condoms. 
 
Will it cost me anything to participate in this research study? 
FT538 is provided at no cost by Fate Therapeutics for the purpose of this study. If you are 
assigned to enoblituzumab, MacroGenics will provide this study drug without cost. The cost of 
processing and testing any samples collected for research is paid for by study funds.  
 
You and/or your insurance company will be billed for any standard medical care given during 
this research study. This means your insurance company will be billed for the placement and 
removal of the intraperitoneal catheter, the cyclophosphamide and fludarabine, outpatient 
clinic visits, the hospitalizations, routine medical care, all laboratory tests done for standard 
safety assessment, and assessments that are done for your medical care. You will be 
responsible for any copays your insurance normally issues for these visits/procedures. 
 
Compensation for Participation 
You will not receive any monetary compensation for your participation in this study. 
 
What happens to the information collected for the research, including my health 
information? 
The researchers will do their best to make sure that your private information is kept confidential. 
Information about you will be handled as confidentially as possible but participating in research 
may involve a loss of privacy and has a potential for breach of confidentiality. Study data will be 
physically and electronically secured. As with any use of electronic means to store data, there is a 
risk of breach of data security. 
 
Overview 
If you participate in this study, your information, including your health information, will be used 
and shared for purposes of conducting this research. As described later in this Consent Form, 
your information may also be used and shared for publishing and presenting the research 
results, future research. If you sign and date this Consent Form, you are giving permission to 
use and share your health information for these purposes and you are giving permission to any 
health care providers who are treating you to share your medical records with us. 
 


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What health information will be made available? 
Health information about you to be used and shared for the research includes those items 
checked by the research team below: 
☒ Your medical records, which may include records from hospital and clinic visits, 
emergency room visits, immunizations, medical history and physical exams, 
medications, images and imaging reports, progress notes, psychological tests, 
electroencephalography (EEG), electrocardiogram (ECG), and echocardiogram (ECHO) 
reports, laboratory and pathology reports, dental records and/or financial records. 
These records may be used and shared for as long as this research continues. 
 
☒ Information collected as part of this research study, including research procedures, 
research visits, and any optional elements of the research you agree to, all as described 
in this Consent Form. This information might not be part of your medical record, and 
may include things like responses to surveys and questionnaires, and information 
collected during research visits described in this Consent Form. 
 
What about more sensitive health information? 
Some health information is so sensitive that it requires your specific permission. If this research 
study requires any of this sensitive information, the boxes below will be marked and you will be 
asked to initial to permit this information to be made available to the research team to use and 
share as described in this Consent Form. 
☐ My drug & alcohol abuse, diagnosis & treatment records ______ (initial) 
☒ My HIV/AIDS testing records  ______ (initial) 
☐ My genetic testing records  ______ (initial) 
☐ My mental health diagnosis/treatment records  ____ (initial) 
☐ My sickle cell anemia records  _______ (initial) 
 
Who will access and use my health information? 
If you agree to participate in this study, your information will be shared with: 
• 
The University of Minnesota research team and any institutions or individuals 
collaborating on the research with us; 
• 
The study doctor and study staff may share your information with representatives of the 
University of Minnesota and M Health. These people may use your information to 
provide oversight and administrative support for the research, conduct evaluations and 
reviews, and perform other activities related to the conduct of the research; 
• 
The University of Minnesota and representatives of this institution and its affiliates, 
including those that have responsibilities for monitoring or ensuring compliance, such as 
the Quality Assurance Program of the Human Research Protection Program. 
• 
The research sponsor(s), any affiliates, partners or agents of the sponsor(s) involved in 
the research, organizations funding the research, and any affiliates, partners or agents 
of the funding organization(s) involved in the research; 
• 
Organizations who provide accreditation and oversight for research and the research 
team, and others authorized by law to review the quality and safety of the research 


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(such as U.S. government agencies like the Food and Drug Administration, the Office of 
Human Research Protections, the Office of Research Integrity, or government agencies 
in other countries); and 
• 
Advarra IRB, the independent external Institutional Review Board that is responsible for 
the review of this study. 
 
Fate Therapeutics (and MacroGenics if you receive enoblituzumab) will be provided copies of 
any serious adverse event reports as they occur with direct identifiers removed.  
 
How will my information be used in publications and presentations? 
Your health data will be used to conduct and oversee the research. We may publish the results 
of this research in scientific, medical, academic or other journals or reports, or present the 
results at conferences. Information that makes it easy to identify you (such as your name and 
contact information, social security number (SSN) and medical records number) will not be part 
of any publication or presentation. If you have an extremely unique or rare condition that is not 
shared by many others, it is possible that some people may be able to determine your identity 
even without these identifiers. 
 
Optional Consent for Future Use of Identifiable Data or Specimens 
At the completion of this research study, we would like to store and be able to use and share 
your identifiable research related samples and/or health information with researchers at the 
University or affiliated hospitals for other research. Any research that involves identifiable 
information will be reviewed by an Institutional Review Board (IRB), which is the committee 
that provides ethical and regulatory oversight of research at the University, prior to use. 
Because these specimens and/or health information are identifiable, we are asking your 
permission to store, use and share these for other research. 
 
We may not ask for your consent before using or sharing your identifiable specimens or data. 
You will not receive any results or financial benefit from the future research done on your 
specimens or data. We may share your identifiable specimens or data with outside researchers 
who will use them for future research. Samples are labelled with your unique study code 
assigned at study enrollment and information such as the date of collection/study day that can 
be linked back to your health information through a master study list. 
 
If you leave the study, you can ask to have the data collected about you removed or the 
samples destroyed. You can also ask us to remove information that identifies you from the data 
or samples. This may not be possible if your samples and data have already been shared. 
 
Do I have to sign and date this Authorization and give my permission to make my 
information, including my health information, available for use and sharing? 
No, you do not have to sign and date this Authorization. But if you do not sign and date it, you 
will not be able to participate in this research study. Treatment available outside of the study, 
payment for such treatment, enrollment in health insurance plans and eligibility for benefits 
will not be impacted by your decision about signing and dating this Authorization. 


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Does my permission for making my health information available for use and sharing ever 
expire? 
No, there is no expiration date. 
 
May I cancel my permission for making my health information available for use and sharing? 
Yes. You may cancel your permission at any time by writing to the study doctor at the address 
on the first page of this Form. If you cancel your permission, you will no longer be in the 
research study. You may also want to ask someone on the research team if canceling will affect 
any research-related study treatment. If you cancel your permission, any health information 
about you that was already used and shared may continue to be used and shared for the 
research study and any optional elements of the study to which you agree in this Authorization. 
 
What happens to my health information after it is shared with others? 
When we share your information with others as described in this Authorization, privacy laws 
may no longer protect your information and there may be further sharing of your information. 
 
Will I be able to look at my records? 
It is possible that the research team may not allow you to see the information collected for this 
study. However, you may access any information placed in your medical records after the study 
is complete. 
 
What will be done with my data and specimens when this study is over? 
We will use and may share data and/or specimens for future research. They may be shared with 
researchers/institutions outside of University of Minnesota. This could include for profit 
companies. We will not ask for your consent before using or sharing them. We will remove 
identifiers from your data and/or specimens, which means that nobody who works with them 
for future research will know who you are. Therefore, you will not receive any results or 
financial benefit from future research done on your specimens or data. No results from 
research related testing will be placed in your medical record. 
 
Research samples may be sent to an outside laboratory for testing (including to Fate 
Therapeutics and MacroGenics, if you are assigned to enoblituzumab) that cannot be routinely 
performed at the University of Minnesota and M Health/Fairview laboratories. No information 
to directly identify you will be provided on these samples. 
 
Will I receive research test results? 
No, individual tests results will not be shared with participants. Research related testing is not 
done in real-time like laboratory work for medical care. Instead the samples are stored frozen 
and tested in batches at a future date. 
 
Whom to contact about this study: 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study such as: 
• Whom to contact in the case of a research-related injury or illness; 


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• Payment or compensation for being in the study, if any; 
• Your responsibilities as a research participant; 
• Eligibility to participate in the study; 
• The study doctor’s or study site’s decision to withdraw you from participation; 
• Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this 
consent document. 
 
If you seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in this research study. 
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
• 
By mail:  
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Drive, Suite 600 
Columbia, MD 21044 
• 
or call toll free:        877-992-4724 
• 
or by email:              adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00065732. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You may search this Web site at any time. 
 
This research has also been reviewed and approved by an IRB within the Human Research 
Protections Program (HRPP) at the University of Minnesota. To share feedback privately with 
the University of Minnesota HRPP about your research experience, call the Research 
Participants’ Advocate Line at 612-625-1650 (Toll Free: 1-888-224-8636) or go to 
z.umn.edu/participants. You are encouraged to contact the HRPP if: 
• 
Your questions, concerns, or complaints are not being answered by the research team. 
• 
You cannot reach the research team. 
• 
You want to talk to someone besides the research team. 
• 
You have questions about your rights as a research participant. 
• 
You want to get information or provide input about this research. 
 
Will I have a chance to provide feedback after the study is over? 
The University of Minnesota HRPP may ask you to complete a survey that asks about your 
experience as a research participant. You do not have to complete the survey if you do not 


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want to. If you do choose to complete the survey, your responses will be anonymous. If you are 
not asked to complete a survey, but you would like to share feedback, please contact the study 
team or the University of Minnesota HRPP. 
 
What happens if I am injured while participating in this research? 
In the event that this research activity results in an injury, treatment will be available, including 
first aid, emergency treatment and follow-up care as needed. Care for such injuries will be 
billed in the ordinary manner to you or your insurance company. If you think that you have 
suffered a research-related injury, let the study doctor know right away. By signing and dating 
this document, you will not lose any of your legal rights or release anyone involved in the 
research from responsibility for mistakes. 
 
Optional Storing of Leftover Samples for Future Research: 
Once the research associated with this study there may be some leftover blood, ascites/IP 
washings, and tumor cells collected for research purposes. With your permission we would like 
to store them after the study ends for future analysis as new things are learned including about 
the immune system and cancer. Leftover samples may be sent to laboratories outside of the 
University of Minnesota if specialized testing cannot be performed locally. There is no cost to 
you or your insurance company for long-term storage. If you agree to storage now and later 
change your mind, you may contact a member of the research team and request that any 
remaining identifiable samples be destroyed. 
 
Use of Identifiable Research Related Samples and/or Health Information 
Please indicate whether you will allow the identifiable research related samples and/or health 
information to be used for future research by putting your initials next to one of the following 
choices: 
 
_____ (initials)  NO, my identifiable research related samples and/or health information 
may not be used for future research. They may be used for this study 
only. 
_____ (initials)  YES, my identifiable research related samples and/or health information 
may be used for other future research studies. 
 


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Signature Block: 
 
Your signature documents your permission to take part in this research. You will be provided 
with a copy of this signed and dated document. 
 
 
 
 
 
 
Signature of Participant 
Date 
 
 
 
 
Printed Name of Participant 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
Date 
 
 
 
 
Printed Name of Person Obtaining Consent 
 
 
STUDY SUMMARY 
 
All participants receive: 
CY/FLU - a two day course of outpatient IV (into a vein) chemotherapy with the common anti-
cancer drugs cyclophosphamide (CY) and fludarabine (FLU) or CY/FLU for short. 
 
    FT538 is a NK cell product given after the CY/FLU once a week for 3 weeks in a row as a short 
infusion through the IP catheter. 
 
 
 
Participants enrolled in Dose Cohort 5 or Dose Cohort 6: 
     Enoblituzumab is given as an IV (into a vein) infusion before CY/FLU and approximately 1 
week before FT538. Enoblituzumab may continue every 3 weeks until disease progression or 
unacceptable side effects 
 


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STUDY TREATMENT PLAN: 
This is an early in human study for each of the investigational products (FT538 and 
enoblituzumab) and a 1st in human study for the combination. For this reason, the U.S. Food 
and Drug Administration (FDA) requires a very careful approach to study treatment. Up to 6 
Dose Cohorts will be tested in this study. The dose levels of FT538 match those being tested in 
other ongoing FT538 studies using intravenous (IV) administration. You will be told which 
cohort is enrolling when you are told about this study: 
 
DOSE 
COHORT 
STUDY TREATMENT PLAN 
1 
Low dose of FT538 by IP infusion once a week for 3 weeks  
2 
Medium dose of FT538 by IP infusion once a week for 3 weeks 
3 
Medium high dose of FT538 by IP infusion once a week for 3 weeks 
4 
High dose of FT538 by IP infusion once a week for 3 weeks 
5 
Enoblituzumab by IV infusion before CY/FLU and FT538 (at 1 Dose Cohort 
drop from the highest Dose Cohort from 1-4) with the option to continue 
enoblituzumab every 3 weeks after the FT538 is completed. 
6 
Enoblituzumab by IV infusion before CY/FLU and FT538 (at highest Dose 
Cohort from 1-4) with the option to continue enoblituzumab every 3 weeks 
after the FT538 is completed. 
 
ENROLLMENT PLAN: 
Participants are enrolled and receive the study treatment in this study according to rules for 
moving from one Dose Cohort to the next. 
 
Start with 1 participant per Dose Cohort until the first unacceptable side effect or Dose Cohort 
6 is reached. A minimum of 4 weeks pass from the 1st FT538 infusion of a current participant to 
observe for late side effects and the enrollment of the next participant. 
If the 1st four Dose Cohorts are completed no unacceptable side effect, the 5th participant 
receives enoblituzumab plus FT538 at one Dose Cohort below the highest level tested (Dose 
Cohort 3 FT538 dose). Dose Cohort 6 is enoblituzumab plus FT538 at the highest level tested 
(Dose Cohort 4 FT538 dose). 
 
At the 1st unacceptable side effect, the current Dose Cohort is expanded to 3 participants and a 
minimum of 3 participants are enrolled into all future Dose Cohorts with using a more extensive 
list of unacceptable side effects. A minimum of 14 days must past between the 1st and 2nd 
participant in a Dose Cohort and a new Dose Cohort cannot be assigned until a minimum of 4 
weeks pass from the 3rd participant’s 1st FT538 infusion. 
 
Enrollment continues until 33 participants are treated or 10 participants in a row are treated at 
the same dose level.