Clinical trial NCT04894994
Conditions: Advanced Melanoma
Keywords: Neoplasms Ipilimumab Antineoplastic Agents Immunological
Sponsor: RAPT Therapeutics, Inc.
Start date: 2021-09-03; Completion date: 2022-09-13
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This clinical trial is a Phase 2, open-label study to determine the anti-tumor activity of FLX475 in combination with ipilimumab in subjects with advanced melanoma previously treated with an anti-programmed cell death 1 (anti-PD-1) or anti-programmed cell death ligand 1 (anti-PD-L1) agent.

The study will be conducted starting with a safety run-in portion in which 6 eligible subjects will be enrolled and treated for at least one 3-week cycle to determine if the safety profile of FLX475+ipilimumab is acceptable to complete enrollment of the approximately 20-subject study.

Detailed description:

Arms: arm 1: Participants received FLX475 tablets orally and ipilimumab by IV infusions
Interventions: intervention 1: FLX475 intervention 2: Ipilimumab
Intervention descriptions: intervention 1: Tablet intervention 2: IV infusion

Protocol documents:
Prot_000.pdf: 
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Protocol FLX475-03 
 
 
 
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CLINICAL STUDY PROTOCOL 
Study Protocol 
Number: 
FLX475-03 
Study Protocol 
Title: 
Phase 2 Study of FLX475 in Combination with Ipilimumab in Advanced 
Melanoma 
Investigational 
Product Name: 
FLX475 (F003475) 
Indication: 
Advanced melanoma 
Phase: 
2 
IND Number: 
138286 
Sponsor: 
RAPT Therapeutics, Inc. 
561 Eccles Avenue 
South San Francisco, CA 94080 
Sponsor Contact: 
 
 
 
Date: 
Original Protocol:  October 1, 2020 
Amendment 1: October 19, 2020 
 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use guidances and all 
applicable local Good Clinical Practices (GCP) and regulations.  All 
required study documentation will be archived as required by regulatory 
authorities. 
 
CONFIDENTIALITY STATEMENT 
The following confidential information is the property of RAPT Therapeutics.  This protocol is provided for 
review by you, your staff, and Institutional/Ethics Review Board.  The information contained in this 
document is CONFIDENTIAL and, except to the extent necessary to obtain informed consent, may not be 
disclosed without permission by RAPT Therapeutics. 
 
 
 
 


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1 
CLINICAL PROTOCOL SYNOPSIS 
Investigational Product Name(s):  FLX475 
Study Protocol Title 
Phase 2 Study of FLX475 in Combination with Ipilimumab in Advanced Melanoma 
Sites 
Approximately 3−5 sites in the United States (US) 
Study Period and Phase of Development 
Phase 2 
Objectives 
Primary Objectives 
• To evaluate the objective response rate (ORR), defined as confirmed complete or partial 
response per RECIST 1.1, of FLX475 in combination with ipilimumab in subjects with 
advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the safety and tolerability of FLX475 in combination with ipilimumab in subjects 
with advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent 
 
Secondary Objectives 
• To evaluate the progression-free survival (PFS) of subjects with advanced melanoma treated 
with FLX475 in combination with ipilimumab who have been previously treated with an anti-
PD-1 or anti-PD-L1 agent  
• To evaluate the overall survival (OS) of subjects with advanced melanoma treated with 
FLX475 in combination with ipilimumab who have been previously treated with an anti-PD-1 
or anti-PD-L1 agent  
• To evaluate the objective response rate (ORR), defined as confirmed complete or partial 
response per iRECIST, of FLX475 in combination with ipilimumab in subjects with advanced 
melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the plasma concentrations of FLX475 when it is given in combination with 
ipilimumab 
• To assess the effects of FLX475 in combination with ipilimumab on pharmacodynamic (PD) 
markers relating to drug mechanism of action 
• To characterize the onset, magnitude, and duration of tumor control in subjects receiving 
FLX475 in combination with ipilimumab 
Number of Subjects 
Approximately 20 subjects 
Study Design:  
This clinical trial is a Phase 2, open-label study to determine the anti-tumor activity of FLX475 in 
combination with ipilimumab in subjects with advanced melanoma previously treated with an 
anti-PD-1 or anti-PD-L1 agent. 
The study will be conducted starting with a safety run-in portion in which 6 eligible subjects will 
be enrolled and treated for at least one 3-week cycle to determine if the safety profile of FLX475+ 


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ipilimumab is acceptable to complete enrollment of the approximately 20-subject study. Should the 
safety profile be deemed not acceptable for the 100 mg FLX475 PO QD and 3 mg/kg ipilimumab 
IV Q3W combination regimen, an alternative (lower) dose regimen of either or both drug(s) may 
be selected and tested in an additional 6-subject safety run-in phase. Ultimately at least 20 subjects 
should be treated and evaluated with a single combination dose regimen. 
 
Accrual to the study may be discontinued prior to completing enrollment, for reasons including, but 
not limited to, unacceptable safety, slow/insufficient enrollment, or changes in standard clinical 
practice. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria   
Subjects must meet all of the following inclusion criteria to be eligible to receive study treatment: 
 
1. All subjects must have pathologically confirmed advanced melanoma that is either Stage IV 
or unresectable Stage III. Subjects may have cutaneous, mucosal or unknown primary lesions 
of origin. Subjects with uveal primary are not eligible. 
2. Subjects must have had prior treatment with anti-PD-1 or anti-PD-L1 agents, with at least 
2 months of therapy followed by documented disease progression either while on these 
agents or after stopping therapy with these agents. Subjects must have discontinued anti-PD-
1 or anti-PD-L1 therapy at least 4 weeks prior to start of study treatment. Subjects who 
received prior treatment with anti-PD-1 or anti-PD-L1 agents in the adjuvant setting and 
whose disease recurred while on treatment, or within 6 months of completion of the 
treatment, are eligible.  
3. Men and women ≥ 18 years of age on day of signing informed consent. 
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1. 
(Subjects with stable ECOG PS of 2 due to non-cancer-related conditions may be permitted 
with the approval of the Sponsor’s medical monitor.) 
5. Subjects must have measurable disease per RECIST 1.1. 
6. Subjects with central nervous system (CNS) metastases must have all lesions adequately 
treated with stereotactic radiation therapy, craniotomy, Gamma Knife therapy, or whole brain 
radiotherapy, with no subsequent evidence of CNS progression. Subjects must not have 
required steroids for at least 14 days prior to start of study treatment. 
7. All acute toxic effects of any prior therapy have resolved to Grade 0 or 1 or to baseline level 
before the start of study treatment (except that up to Grade 2 alopecia, neurotoxicity, and 
bone marrow abnormalities may be permitted with Sponsor agreement, and subjects with 
immune-related endocrinopathies who are on stable doses of medications are permitted).  
8. Subjects must have adequate hematologic function as evidenced by all of the following at 
time of screening within 21 days prior to start of study treatment: absolute neutrophil count 
(ANC) ≥ 1500/µL; hemoglobin ≥ 8 g/dL; and platelets ≥ 100,000/µL. 
9. Human immunodeficiency virus (HIV)-infected subjects must be on anti-retroviral therapy 
(ART) and have well-controlled HIV infection/disease defined as: (a) CD4+ T cell count 
> 350 cells/mm3 at time of screening, (b) achieved and maintained virologic suppression 
defined as confirmed HIV RNA level <50 copies/mL or the lower limit of qualification 
(below the limit of detection) using the locally available assay at the time of screening and 
for at least 12 weeks prior to screening, (c) must have been on a stable anti-retroviral 
regimen, without changes in drugs or dose modification, for at least 4 weeks prior to start of 
study treatment (C1D1), and (d) the combination ART regimen must not contain any 
retroviral medications OTHER THAN abacavir, dolutegravir, emtricitabine, lamivudine, 
raltegravir, or tenofovir (due to potential CYP interactions, exceptions permitted only with 


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prior Sponsor clearance). 
10. Subjects must have adequate hepatic function as evidenced by all of the following at time of 
screening within 21 days prior to start of study treatment: total bilirubin ≤ 2.5 x Institutional 
Upper Limit of Normal (IULN) (except subjects with Gilbert’s syndrome); and AST and 
ALT both ≤ 5 x IULN. 
11. Subjects must have adequate kidney function as evidenced by serum creatinine ≤ 2.0 x IULN 
at time of screening within 21 days prior to start of study treatment. 
12. Subjects enrolled must be willing and able to provide tissue from a newly obtained core 
(minimum of 3 cores) or excisional (or skin punch) biopsy of a tumor lesion not previously 
irradiated (unless subsequent progression demonstrated).  In addition, subjects must be 
willing to provide a tumor biopsy (minimum of 3 cores, or excisional or skin punch) while on 
treatment at Cycle 2 Day 8 (± 7 days) and may be asked to provide additional biopsies at 
other timepoints such as the time of discontinuation due to progression. 
13. For women of childbearing potential, negative results on a serum pregnancy test within 2 
days prior to study registration and willingness to use an effective method of contraception 
(e.g., oral contraceptives, double-barrier methods such as a condom and a diaphragm, 
intrauterine device) from the start of study treatment (or 14 days prior to the initiation of 
study treatment for oral contraception) and for 120 days following the final dose of study 
treatment, or to abstain from sexual intercourse for this period of time. Note:  A female 
subject is considered to be of childbearing potential unless she has had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian 
failure (with serum estradiol and follicle-stimulating hormone levels within the 
institutional postmenopausal range and a negative result on serum or urine beta-human 
chorionic gonadotropin [β-HCG]) pregnancy test, or is postmenopausal (age ≥ 55 years 
with amenorrhea for ≥ 6 months). 
14. For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to abstain from heterosexual intercourse or use of a 
protocol-recommended method of contraception (e.g., partner use of oral contraceptives or an 
intrauterine device, or double-barrier methods such as a condom and a diaphragm) from the 
start of study treatment (or 14 days prior to the initiation of study treatment for oral 
contraception) to 120 days following the final dose of study treatment and to refrain from 
sperm donation from the start of study treatment to 120 days following the final dose of study 
treatment. Note:  A male subject is considered able to father a child unless he has had a 
bilateral vasectomy or a bilateral orchiectomy with confirmed azoospermia or has ongoing 
medical testicular suppression. 
15. Ability to swallow tablets without difficulty. 
16. Signed Informed Consent Form by the subject or his/her legal guardian.  
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible to receive study 
treatment: 
1. History of known antidrug antibodies or severe allergic, anaphylactic, or other infusion 
related reaction to a previous biologic agent. 
2. Any history of discontinuing prior treatment due to Grade 3–4 immune-related adverse 
events (irAEs) of colitis or pneumonitis. 
3. Prior treatment with ipilimumab or other CTLA-4 antagonists. 
4. Prior systemic anticancer therapy including any anti-PD-1 or anti-PD-L1 agents within 
4 weeks prior to start of study treatment. 
5. Active autoimmune disease requiring disease-modifying therapy at the time of screening. 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 


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therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment 
and is allowed. 
6. History of another malignancy that has progressed or has required active treatment within the 
past 2 years, unless it is clinically stable and does not require tumor-directed treatment. 
(Examples include the following: adequately treated local basal cell or squamous cell 
carcinoma of the skin; in situ cervical carcinoma; adequately treated papillary, noninvasive 
bladder cancer; asymptomatic prostate cancer without known metastatic disease and not 
requiring therapy or requiring only hormonal therapy, and with normal prostate specific 
antigen for ≥ 1 year prior to start of study treatment; or other adequately treated Stage 0, 1 or 
2 cancers currently in complete remission.) In addition, any other cancer treated with curative 
intent ≥ 2 years prior to screening with no evidence of disease is permitted. 
7. Significant cardiovascular disease, including myocardial infarction, arterial 
thromboembolism, or cerebrovascular thromboembolism within 6 months prior to start of 
study treatment, symptomatic dysrhythmias or unstable dysrhythmias requiring medical 
therapy, angina requiring therapy, symptomatic peripheral vascular disease, clinically 
significant history of syncope, New York Heart Association (NYHA) Class 3 or 4 congestive 
heart failure (Appendix 3), or chronic Grade 3 hypertension (diastolic blood pressure 
≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg). 
8. Significant screening electrocardiogram (ECG) abnormalities including atrial fibrillation 
(unstable or newly diagnosed), double (left and right) bundle branch block, second degree 
atrioventricular block type II, third-degree atrioventricular block, Grade ≥ 2 bradycardia, 
QTcF interval ≥ 450 msec, PR interval > 220 msec, or unstable cardiac arrhythmia requiring 
medication.  Chronic asymptomatic atrial fibrillation stably controlled with medications is 
permitted. 
9. Significant active gastrointestinal disease (e.g., malabsorption syndrome, resection of the 
stomach or small bowel, symptomatic inflammatory bowel disease, gastrointestinal 
perforation, or partial or complete bowel obstruction) that might impair absorption of study 
treatment. 
10. Evidence of an ongoing, uncontrolled systemic bacterial, fungal, or viral infection or an 
uncontrolled local infection requiring therapy at the time of start of study treatment.  
Note: Subjects with localized fungal infections of skin or nails are eligible. 
11. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman 
Disease. 
12. Known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known 
active Hepatitis C virus (defined as detection of HCV RNA [qualitative]) infection. 
13. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (at doses 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 14 days prior to the first dose of study treatment. Inhaled or topical steroids, 
and adrenal replacement doses of ≤ 10 mg daily prednisone or equivalent are permitted in the 
absence of active autoimmune disease. 
14. Prior allogeneic organ transplant. 
15. Females who are pregnant, breastfeeding, or expect to become pregnant within the projected 
duration of the study, starting with the screening visit through 120 days after the final dose of 
study treatment.  Males who plan to father children within the projected duration of the study, 
starting with the screening visit through 120 days after the final dose of study treatment. 
16. Radiotherapy within 14 days prior to start of study treatment.  Subjects must have recovered 
from all radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis. 


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17. Subjects currently receiving treatment with any medications that have the potential to 
prolong the QT interval and that cannot be either discontinued or substituted with a different 
medication prior to starting study treatment. (See Appendix 7) 
18. Subjects currently receiving treatment with strong cytochrome P450 (CYP)3A4 inhibitors or 
inducers should discontinue such treatment or be switched to a different medication prior to 
starting study treatment. (See Appendix 7) 
19. Current participation in another study of an investigational agent or device. 
20. Any illness, medical condition, organ system dysfunction, or social situation, including 
mental illness or substance abuse, deemed by the investigator to be likely to interfere with a 
subject’s ability to sign informed consent, adversely affect the subject’s ability to cooperate 
and participate in the study, or compromise the interpretation of study results. 
Test Product, Dose, and Mode of Administration: 
FLX475 for oral administration is provided as tablets.  All subjects will take 100 mg FLX475 (or 
lower dose if subsequently modified) orally with water once daily at approximately the same time 
each day at their assigned dose on a continual basis.  On days when ipilimumab is also 
administered (i.e., Day 1 of Cycles 1-4), FLX475 should be taken approximately 1 hour before the 
ipilimumab infusion. 
Ipilimumab 3 mg/kg will be administered as an IV infusion over 30 or 90 minutes (per institutional 
protocol) on Day 1 of every 3-week treatment cycle (i.e., every 21 days [±3 days] for up to 
4 doses), and approximately 1 hour after the Day 1 dose of FLX475. 
 
Safety Run-In and Enrollment:   
The first six subjects enrolled and treated at the recommended Phase 2 dose of FLX475 
(100 mg/dose QD) plus ipilimumab (3 mg/kg IV q3W, up to 4 doses) will be followed for at least 
one 3-week cycle (21 days) to monitor for any unacceptable (or dose-limiting) toxicities prior to 
enrolling additional subjects. 
After the first six subjects enrolled have completed the 3-week safety observation period, a Safety 
Review Committee (SRC) will be convened. The SRC members will comprise appropriate Sponsor 
and CRO representatives, including the Sponsor’s medical monitor or designee(s), safety officer or 
designee, and clinical trial managers (CTMs). Additional members may be added as needed (e.g. 
pharmacokinetic [PK] scientist and/or biostatistician). The SRC will carefully consider all available 
safety, laboratory, and PK information in consultation with the study investigators. After review of 
all available data, the SRC may recommend continued enrollment of the entire study (e.g. if no 
unacceptable toxicities are observed); dose reduction of either FLX475 and/or ipilimumab; or 
discontinuation of the study. Beyond the safety run-in phase, the SRC will continue to meet at least 
quarterly during the study to review accumulating safety data and may also recommend an 
amendment to the protocol to evaluate alternate study drug administration schedules or other 
changes in study design as may be appropriate based on emerging clinical data. 
Definition of Dose-Limiting Toxicity (DLT):  
Reference should be made to the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE), Version 5.0 (Appendix 1) for grading of the severity of AEs and 
laboratory abnormalities.  The safety profile of ipilimumab monotherapy has been well described 
(Yervoy® Package Insert; Hodi et al., 2010) and includes a significant number of immune-related 
adverse events (irAEs) to be taken into account when determining what might be either unexpected 
or unacceptable toxicity for the combination of FLX475 with ipilimumab.  Therefore, a DLT for 
this study will be defined as an AE or abnormal laboratory value assessed by the investigator as 
possibly, probably, or definitely related to study treatment, excluding toxicities clearly not related 
to study treatment, such as disease progression, environmental factors, unrelated trauma, etc. 


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occurring during Days 1–21 of Cycle 1 (“DLT Observation Period”), that meets any of the 
following criteria: 
• Grade 4 hematological laboratory abnormality lasting ≥ 7 days, except thrombocytopenia, or: 
◦ Grade 4 thrombocytopenia of any duration; or 
◦ Grade 3 thrombocytopenia associated with clinically significant bleeding 
• Nonhematological Grade 3 or 4 laboratory abnormalities: 
◦ Clinically significant medical intervention is required to treat the subject, or 
◦ The abnormality leads to hospitalization, or 
◦ The abnormality persists for >1 week, or 
◦ The abnormality results in a Drug-induced Liver Injury (DILI) 
◦ Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc. 
• 
Any Grade 4 non-hematologic AE of any duration, with the following exception: 
o Grade 4 diarrhea lasting 48–72 hours in subjects who have received suboptimal 
anti-diarrheal therapy 
• Grade 3 rash that does not resolve to Grade 1 or baseline level (whichever is higher) within 
14 days with adequate medical management 
• Grade 3 fever that does not resolve to Grade 1 or baseline level (whichever is higher) within 
14 days with adequate medical management 
• Grade 3 fatigue that does not resolve to Grade 2 or baseline level (whichever is higher) 
within 14 days with adequate medical management 
• Grade ≥ 3 creatinine increase 
• Grade 3 nausea, vomiting, colitis, or diarrhea requiring total parenteral nutrition or 
hospitalization (e.g., duration > 48 hours despite optimal management) that does not resolve 
to Grade 1 or baseline level (whichever is higher) within 14 days 
• Grade 2–3 uveitis, eye pain, or blurred vision that does not respond to topical therapy and 
does not improve to Grade 0 or 1 within 14 days 
• Grade ≥ 2 nonhematological toxicity requiring systemic immunosuppressive therapy.  This 
includes, but is not limited to, autoimmune diseases of the lung, heart, kidney, bowel, CNS, 
pituitary, or eye 
• Grade ≥ 2 endocrine toxicity requiring hormone replacement, with the exception of Grade 2 
adrenal insufficiency, thyroiditis and thyroid dysfunction (which are acceptable) 
• Grade ≥ 3 febrile neutropenia: 
◦ Grade 3 is defined as absolute neutrophil count (ANC) < 1000/mm3 with a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for 
more than 1 hour 
◦ Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C (101°F) 
or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated 
• QTcF interval ≥ 501 msec and > 60 msec prolongation from baseline (defined as the average 
QTcF value from pre-dose C1D1 ECGs), or associated with Torsades de pointes, 
polymorphic ventricular tachycardia, or serious arrhythmia 
• Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity; 
• Any treatment-related toxicity that causes the subject to discontinue treatment during Cycle 1 
• Any Grade 5 toxicity. 


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Duration of Treatment 
Subjects may continue to receive study therapy until the earliest of the following: subject 
withdrawal from study, confirmed progression of cancer, intolerable study-drug-related toxicity 
despite appropriate dose modification, the development of intercurrent illness that precludes 
continued study therapy, pregnancy or breastfeeding, substantial noncompliance with study 
procedures, completion of Treatment Phase comprising up to 35 treatment cycles for FLX475, or 
study discontinuation by Sponsor.  
Study Endpoints: 
Efficacy: 
The primary efficacy endpoint of the study is objective response rate (ORR), defined as the 
proportion of subjects who have best overall response of CR or PR as determined using 
RECIST 1.1 (Appendix 4) for subjects with melanoma.  
Other efficacy endpoints are as follows: 
• Overall Survival (OS), defined as the time from the date of start of treatment to the date of 
death from any cause.  Subjects who are lost to follow-up and those who are alive at the date 
of data cutoff will be censored at the date the subject was last known alive, or date of data 
cutoff, whichever occurs first. 
• Clinical Benefit Rate (CBR), defined as the proportion of subjects who achieve a CR, a PR, 
or durable SD duration of at least 6 months from start of study treatment. 
• Time to Response, defined as the interval from start of study treatment to the first 
documentation of CR or PR. 
• Duration of Response, defined as the interval from the first documentation of CR or PR to 
the earlier of the first documentation of PD or death from any cause.  
• Progression-free Survival (PFS), defined as the interval from the start of study treatment to 
the earlier of the first documentation of PD or death from any cause. 
 
Safety: 
The primary safety endpoint in the safety run-in portion of the study is safety and tolerability by 
the determination of AEs, including DLTs.  The following safety parameters will be characterized 
and summarized:  
• 
Treatment-emergent adverse events (TEAEs) and SAEs together with all other safety 
parameters   
• 
Number (%) of subjects who discontinue treatment due to TEAEs 
• 
Time to treatment failure due to toxicity, defined as the time from the date of start of 
treatment to the date that a subject discontinues study treatment due to TEAEs  
• 
Dose-limiting toxicity (defined in Section 10.4) 
• 
Laboratory abnormalities 
• 
Vital sign abnormalities 
• 
Adverse ECG findings 
 
Pharmacokinetics: 
Plasma concentrations of FLX475 will be determined with a validated bioanalytical method, and 
listed and summarized by time point. No PK parameters (e.g. Cmax and AUC) will be calculated. 
Pharmacodynamics: 
Changes in immune parameters, e.g., lymphocyte subpopulations and plasma cytokines or 
chemokines in peripheral blood or in tumor 


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Statistical Methods: 
Analysis Sets 
The following sets of data will be defined for this study: 
Full Analysis Set (FAS):  All subjects enrolled in the study.  The FAS will be used to 
summarize subject disposition, demographics and baseline data, cancer history, and exposure to 
study treatment.    
Safety Analysis Set:  All subjects who receive at least one dose of the investigational product, 
FLX475 (even a partial dose).  This set will be used for the analysis of all safety data, including 
adverse events, vital signs, and clinical laboratory data. 
Efficacy Eligible Set:  All subjects who receive at least one dose of FLX475 in combination 
with ipilimumab, have measurable disease at baseline per RECIST v1.1, and have at least one 
post-baseline scan or discontinue study treatment as a result of progressive disease, death, or a 
treatment-related adverse event before the first post-baseline scan.  This set will be used for 
sensitivity analysis of the primary efficacy endpoint, ORR.  
Efficacy Evaluable Set:  All subjects who complete at least one cycle of FLX475 in 
combination with ipilimumab and have a baseline and at least one post baseline on-study 
assessment of tumor response.  This set will serve as the primary basis for analysis of all 
efficacy endpoints, including ORR, DOR, PFS, and OS.    
As warranted by the data, efficacy may also be assessed in a Per-Protocol Population comprising 
all Efficacy Evaluable subjects who have no major protocol violations, as defined by the 
Sponsor prior to database lock.   
Pharmacokinetic (PK) Analysis Set:  All subjects who receive at least one dose of FLX475 in 
combination with ipilimumab, and have measurable plasma concentrations of FLX475. 
Pharmacodynamic (PD) Analysis Set:  All subjects who receive at least one dose of 
investigational product and have sufficient PD data to derive at least one PD measurement. 
Analysis Methods 
Evaluation of data will consist primarily of descriptive statistics, summary displays, and data 
listings.  Efficacy and safety data will be presented by treatment and tumor type.  
The number of subjects enrolled and discontinued from the study (by reason) will be presented.  
Demographic and baseline characteristics will be summarized for both the Safety Analysis Set 
and Efficacy Evaluable Set.  
 
The incidence of adverse events will be presented by system organ class, preferred term, and 
maximum toxicity grade for subjects.  Separate summaries will be provided for all adverse 
events, drug-related adverse events, serious adverse events, and adverse events leading to 
discontinuation of study treatment.  Hematology and clinical chemistry data will be summarized 
by worst-case toxicity grade shift relative to baseline.  Deaths will be listed by primary cause 
and date relative to last dose of study medication. 
 
Efficacy endpoints will be summarized using descriptive statistics, including mean, standard 
deviation, median, and range for continuous endpoints and frequency tables for categorical data.  
Estimates of ORR and other response proportions will be presented together with 95% 


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confidence intervals calculated using the Clopper-Pearson method.  Kaplan-Meier estimation 
will be used for the analysis of time-to-event endpoints, including DOR, PFS, and OS.   
 
Rationale for Sample Size 
The sample size of 20 subjects is considered adequate on clinical grounds to judge the safety of 
the combination therapy and obtain an initial estimate of its clinical efficacy.  The ORR for the 
combination therapy is hypothesized to exceed the value observed with ipilimumab 
monotherapy (10−15%, Long et al., 2017).  
 
To be considered evaluable, subjects must meet criteria for the Efficacy Evaluable Set (defined 
above), be evaluable as per RECIST v1.1 at 9 weeks, and should have no major protocol 
deviations.  Evaluability for tumor response will be based on the following: 
• Subjects who remain on study until the first evaluation (at 9 weeks) and are evaluated. 
• Subjects who withdraw from the study due to disease progression before the first evaluation 
(at 9 weeks) will be considered as subjects with early progression. 
• Subjects who died from malignant disease before the first evaluation (at 9 weeks) will be 
considered as subjects with early death. 
• Subjects with measurable disease, for whom all baseline target lesions have been assessed at 
least once after 9 weeks, with the same method of measurement used at baseline. 


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2 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
1 
CLINICAL PROTOCOL SYNOPSIS .....................................................................2 
2 
TABLE OF CONTENTS .......................................................................................11 
LIST OF IN-TEXT TABLES ..................................................................................................15 
LIST OF APPENDICES ..........................................................................................................15 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................16 
4 
ETHICS..................................................................................................................19 
4.1 
Institutional Review Boards/Independent Ethics Committees ........................19 
4.2 
Ethical Conduct of the Study ...........................................................................20 
4.3 
Subject Information and Informed Consent .....................................................20 
5 
INVESTIGATORS AND STUDY PERSONNEL ................................................22 
6 
INTRODUCTION .................................................................................................23 
6.1 
Background ......................................................................................................23 
6.1.1 
Immunotherapy for Cancer ..................................................................23 
6.1.2 
Ipilimumab ...........................................................................................24 
6.1.3 
FLX475 ................................................................................................24 
6.1.3.1 
Preclinical Experience with FLX475 ..........................................24 
6.1.3.1.1 
Non-clinical Pharmacology ..................................................24 
6.1.3.1.2 
Preclinical Pharmacokinetics ................................................24 
6.1.3.1.3 
Preclinical Toxicology ..........................................................25 
6.1.3.2 
Clinical Experience with FLX475 ..............................................26 
6.1.3.2.1 
FLX475-01: Phase 1 Healthy Volunteer Study ....................26 
6.1.3.2.2 
FLX475-02: Phase 1/2 Dose-Escalation and Expansion 
Study of FLX475 Alone and in Combination with 
Pembrolizumab in Advanced Cancer ...................................26 
6.1.4 
Dose Rationale for Combination Therapy ...........................................27 
6.1.4.1 
FLX475 .......................................................................................27 
6.1.4.2 
Ipilimumab ..................................................................................28 
6.2 
Risk-Benefit Assessment .................................................................................28 
6.3 
Study Rationale ................................................................................................29 
7 
STUDY OBJECTIVES ..........................................................................................31 
7.1 
Primary Objective ............................................................................................31 
7.2 
Secondary Objectives .......................................................................................31 
8 
INVESTIGATIONAL PLAN ................................................................................32 
8.1 
Overall Study Design and Plan ........................................................................32 
8.2 
Study Phases ....................................................................................................33 
8.2.1 
Pretreatment Phase ...............................................................................33 
8.2.2 
Treatment Phase ...................................................................................33 
8.2.3 
Follow-Up Phase ..................................................................................34 


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8.3 
Discussion of Study Design .............................................................................35 
9 
STUDY POPULATION ........................................................................................36 
9.1.1 
Inclusion Criteria .................................................................................36 
9.1.2 
Exclusion Criteria ................................................................................38 
9.1.3 
Replacement of Subjects ......................................................................39 
9.1.4 
Removal of Subjects from Therapy or Assessment .............................40 
10 
TREATMENTS .....................................................................................................41 
10.1 
Overview of Treatments Administered ............................................................41 
10.2 
FLX475 Administration ...................................................................................41 
10.2.1 
Dosing Plan ..........................................................................................41 
10.3 
Ipilimumab Administration ..............................................................................42 
10.4 
Dose-Limiting Toxicity and Stopping Criteria ................................................42 
10.5 
Dose Modifications for Toxicity ......................................................................44 
10.5.1 
FLX475 ................................................................................................44 
10.5.2 
Dose Modification for Ipilimumab ......................................................46 
10.6 
Identity of Investigational Products .................................................................54 
10.6.1 
FLX475 ................................................................................................54 
10.6.2 
Ipilimumab ...........................................................................................54 
10.6.3 
Supply, Packaging, and Labeling of Study Drug .................................54 
10.6.4 
Storage Conditions ...............................................................................54 
10.7 
Selection of Doses in the Study .......................................................................54 
10.8 
Selection of Dose and Timing for Each Subject ..............................................55 
10.9 
Blinding............................................................................................................55 
10.10 
Prior and Concomitant Therapy .......................................................................55 
10.10.1 
Recording of Prior and Concomitant Treatments and Procedures .......55 
10.10.2 
Drug-Drug Interactions ........................................................................56 
10.10.3 
Permitted Concomitant Therapies ........................................................56 
10.10.4 
Prohibited Concomitant Therapies and Drugs .....................................56 
10.10.5 
Rescue Medication and Supportive Care .............................................58 
10.11 
FLX475 Treatment Compliance ......................................................................58 
10.12 
Drug Accountability.........................................................................................59 
11 
STUDY PROCEDURES AND ASSESSMENTS .................................................61 
11.1 
Screening Assessments ....................................................................................61 
11.2 
Baseline Assessments ......................................................................................63 
11.3 
Efficacy Assessments .......................................................................................63 
11.3.1 
Tumor Imaging and Disease Assessment ............................................63 
11.3.1.1 
Timing of Tumor Imaging ..........................................................64 
11.3.1.2 
Disease Assessment by iRECIST ...............................................65 


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11.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments ...................................................................................66 
11.4.1 
Pharmacokinetic Assessments .............................................................66 
11.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments .........................................................................................66 
11.5 
Safety Assessments ..........................................................................................68 
11.5.1 
Adverse Events and Events of Clinical Interest ...................................68 
11.5.2 
Serious Adverse Events, Events of Clinical Interest, and Events 
Associated with Special Situations ......................................................71 
11.5.3 
Overdose ..............................................................................................72 
11.5.4 
Pregnancy, Contraception, and Breastfeeding .....................................72 
11.5.5 
Laboratory Measurements ...................................................................73 
11.5.6 
Vital Signs and Weight Measurements ................................................74 
11.5.7 
Physical Examinations .........................................................................75 
11.5.8 
Electrocardiograms ..............................................................................75 
11.6 
Schedule of Procedures/Assessments ..............................................................75 
11.6.1 
Appropriateness of Measurements .......................................................80 
11.6.2 
Completion/Discontinuation of Subjects .............................................80 
11.7 
Reporting of Adverse Events ...........................................................................80 
11.7.1 
Reporting of Serious Adverse Events ..................................................80 
11.7.2 
Reporting of Pregnancy and Breastfeeding .........................................81 
11.7.3 
Reporting of Events Associated with Special Situations .....................82 
11.7.3.1 
Reporting of Adverse Events Associated with Study Drug 
Overdose, Misuse, Abuse, or Medication Error .........................82 
11.7.4 
Expedited Reporting ............................................................................83 
11.7.5 
Regulatory Reporting of Adverse Events ............................................83 
11.8 
Confirmation of Medical Care by Another Physician .....................................83 
11.9 
Data Quality Assurance ...................................................................................83 
11.9.1 
Data Collection ....................................................................................83 
11.9.2 
Clinical Data Management ..................................................................84 
12 
STATISTICAL METHODS ..................................................................................85 
12.1 
General Statistical Considerations ...................................................................85 
12.1.1 
Rationale for Sample Size ....................................................................85 
12.1.2 
Statistical and Analytical Plans ............................................................86 
12.1.2.1 
Study Endpoints ..........................................................................86 
12.1.2.1.1 
Safety Endpoints ...................................................................86 
12.1.2.1.2 
Efficacy Endpoints ................................................................86 
12.1.2.2 
Pharmacokinetic and Pharmacodynamic Endpoints ...................87 
12.1.2.3 
Analysis Sets ...............................................................................87 
12.1.3 
Subject Disposition ..............................................................................88 


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12.1.4 
Demographic and Other Baseline Characteristics ...............................88 
12.1.5 
Prior and Concomitant Therapy ...........................................................88 
12.1.6 
Efficacy Analyses ................................................................................89 
12.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................90 
12.1.7.1 
Pharmacokinetic Analyses ..........................................................90 
12.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ......................................................................................90 
12.1.8 
Safety Analyses ....................................................................................90 
12.1.8.1 
Extent of Exposure ......................................................................91 
12.1.8.2 
Adverse Events ...........................................................................91 
12.1.8.3 
Laboratory Values .......................................................................91 
12.1.8.4 
Vital Signs ...................................................................................92 
12.1.8.5 
Electrocardiograms .....................................................................92 
12.1.9 
Interim Analysis ...................................................................................92 
13 
REFERENCE LIST ...............................................................................................93 
14 
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) ....................................................................................................96 
14.1 
Changes to the Protocol ...................................................................................96 
14.2 
Adherence to the Protocol ................................................................................96 
14.3 
Monitoring Procedures.....................................................................................96 
14.4 
Recording of Data ............................................................................................97 
14.5 
Retention of Records ........................................................................................98 
14.6 
Auditing Procedures and Inspection ................................................................98 
14.7 
Handling of Study Drug ...................................................................................98 
14.8 
Publication of Results ......................................................................................99 
14.9 
Disclosure and Confidentiality ........................................................................99 
14.10 
Termination of the Study .................................................................................99 
14.11 
Subject Insurance and Indemnity ...................................................................100 
15 
APPENDICES .....................................................................................................101 


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LIST OF IN-TEXT TABLES 
Table 1 
Study Treatments .......................................................................................41 
Table 2 
Dose Modification Guidelines for FLX475-Related Toxicity ...................46 
Table 3 
Infusion Reaction Treatment Guidelines for Ipilimumab ..........................48 
Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Ipilimumab ................................50 
Table 5 
Clinical Laboratory Tests ...........................................................................74 
Table 6 
Schedule of Procedures/Assessments in Study FLX475-03 ......................76 
Table 7 
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease in Subjects Receiving FLX475 and Ipilimumab ........................111 
 
LIST OF APPENDICES 
Appendix 1 
Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0.............................................................................................................102 
Appendix 2 
Eastern Cooperative Oncology Group Performance Status Scale ...........103 
Appendix 3 
New York Heart Association (NYHA) Cardiac Disease Classification ..104 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST) ......................105 
Appendix 5 
Description of the Modified Response Evaluation Criteria in Solid 
Tumors 1.1 for Immune-based Therapeutics (iRECIST) Process for 
Assessment of Disease Progression .........................................................106 
Appendix 6 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 112 
Appendix 7 
Prohibited Medications and Therapies.....................................................115 
Appendix 8 
Anti-PD-(L)1 Refractory Definition ........................................................118 
Appendix 9 
Summary of Changes ...............................................................................119 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADL 
Activities of daily living 
AEs 
Adverse events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma time-concentration curve 
BCG 
Bacillus Calmette–Guérin 
β-hCG 
Beta-human chorionic gonadotropin 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CBR 
CCL17 
CCL22 
CCR4 
Clinical benefit rate (CR + PR + durable SD ≥23 weeks) 
C-C motif chemokine ligand 17 
C-C motif chemokine ligand 22 
C-C chemokine receptor type 4 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendment 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CPI 
Checkpoint inhibitor 
CR 
Complete response 
CRA 
Clinical research associate 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
CV 
Cytotoxic T lymphocyte-associated antigen 4 
Curriculum vitae  
DLT 
Dose-limiting toxicity 
DM 
Diabetes mellitus 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EU 
European Union 


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FAS 
FDA 
Full Analysis Set 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use  
iCPD 
Confirmed radiographic progression 
iCR 
Immune-based complete response 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio  
iPR 
Immune-based partial response 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
iRECIST 
Modified RECIST for immunotherapies 
iSD 
Immune-based stable disease 
ITT 
Intent-to-treat data set 
iUPD 
Immune-based unconfirmed progressive disease 
IV 
Intravenous 
K-M 
Kaplan-Meier 
LDH 
Lactase dehydrogenase 
mAb 
Monoclonal antibody(ies) 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
Modified Response Evaluation Criteria In Solid Tumors 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NCI 
National Cancer Institute 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease; pharmacodynamics 
PD-1 
PFS 
Programmed cell death protein 1 
Progression-free survival 
PG 
Pharmacogenomics 
PI 
Principal investigator 
PO 
By mouth 
PR 
Partial response 


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PK 
Pharmacokinetics 
PS 
Performance status 
PT 
Preferred term, prothrombin time 
PTT 
Partial thromboplastin time 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QD 
Once daily 
RBC 
Red blood cell 
RECIST 
RO 
Response Evaluation Criteria In Solid Tumors 
Receptor Occupancy 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
SOPs 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reactions 
T1DM 
Type 1 diabetes mellitus 
t½ 
Terminal half-life 
TEAEs 
Teff 
Treatment-emergent adverse events 
Effector T cell 
TEMAV 
Treatment-emergent markedly abnormal laboratory values  
TME 
Tumor microenvironment 
Treg 
Regulatory T cell 
TTR 
Time to response 
UA 
Urinalysis 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO DD 
World Health Organization Drug Dictionary 
 


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4 
ETHICS 
4.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) E6 (Good Clinical Practice), Section 3, and any local regulations.  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(e.g., change in contract research associate(s) [CRAs], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
Sponsor before study start and the release of any study treatment to the site by the Sponsor or 
its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
Sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
Sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the Sponsor at the time of each periodic report.  
The investigator(s) or the Sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required. 
At the end of the study, the Sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  The definition of the end of the study is the date of the data cutoff for the 
final analysis or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.  The Sponsor should also provide the IRB/IEC with a 
summary of the study’s outcome. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given. 


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4.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
Sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following: 
• Principles of the World Medical Association Declaration of Helsinki 2013 
• ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
• Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312 
• European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any European Union (EU) country.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, 
to the Competent Authorities of all involved EU member states.   
• Other applicable regulatory authorities’ requirements or directives 
 
4.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator or designee must 
explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to the subject is read and explained to 
him/her, and after the subject has orally consented to the his/her participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject (or legal guardian) will be asked to sign an 
ICF at the Screening Visit before any study-specific procedures are performed.  No subject 
can enter the study before his/her informed consent has been obtained. 


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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the Sponsor or designee and 
kept on file according to local procedures at the site.   
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented. 
With regard to the biomarker assessments described in Section 11.4.2, an informed consent 
for collection of samples during the study for gene analysis will be included in the study-
specific ICF or will be prepared separately.   


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5 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of RAPT 
Therapeutics (the Sponsor) at approximately 3−5 investigational sites in the US. 
The name, telephone, and fax numbers of the medical monitor and other contact personnel at 
the Sponsor and of the contract research organization (CRO) are listed in the Investigator 
Study File provided to each site. 


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6 
INTRODUCTION 
6.1 
Background 
6.1.1 
Immunotherapy for Cancer 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis, 2010).  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis 
in various malignancies.  In particular, the presence of CD8+ T cells and the ratio of CD8+ 
effector T cells (Teff) to FoxP3+ regulatory T cells (Treg) correlates with improved prognosis 
and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic 
cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma (Dudley, et al., 2005; 
Hunder, et al., 2008). 
The cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) receptor serves as 
negative regulator of anti-tumor immunity.  The normal function of CTLA-4, expressed on 
the cell surface of activated T cells under healthy conditions, is to mediate immune 
homeostasis, including prevention of autoimmune reactions.  CTLA-4 is a homolog of cluster 
of differentiation 28 (CD28) that binds to CD80 and CD86 on the surface of antigen-
presenting cells, outcompeting CD28, and serves as an “off switch” or “checkpoint” to 
immune activation (Walunas, et al., 1994; Sansom, 2000). 
The recent use of antibodies (known as checkpoint inhibitors, or CPIs) to block immune 
checkpoints such as CTLA-4  and the programmed cell death 1 protein (PD-1) has resulted in 
meaningful anti-tumor immune responses in multiple types of cancer (Pardoll, 2012, 
Sharma and Allison, 2015, Shin and Ribas, 2015).  However, only a minor subset of patients 
experiences deep and durable responses to these treatments.  Because activated immune 
responses are naturally controlled from running unchecked and causing autoimmunity not 
only by these suppressive checkpoint signals, but also by immunosuppressive cells such as 
Treg and suppressive myeloid cells, more effective anti-tumor immunotherapy treatments may 
also need to address the accumulation of Treg in and around tumors which can inhibit 
cytotoxic (effector) T cells (Teff) from killing tumor cells (Fridman, et al., 2017). 
Treg are recruited into tumors by small secreted protein signals called chemokines – 
specifically C-C motif chemokine ligand 17 (CCL17, or Thymus and activation-regulated 
chemokine) and C-C motif chemokine ligand 22 (CCL22, macrophage-derived chemokine) – 
produced by tumor cells and other cells in the tumor microenvironment (TME).  These 
chemokines serve as a “homing signal” to Treg by binding to their cognate receptor, 
C-C-chemokine receptor type 4 (CCR4), which is expressed on nearly all human Treg 
(Curiel, et al., 2004, Li, et al., 2013).  Thus, specifically blocking the CCR4-mediated 
“homing signal” from tumors to Treg could prevent the accumulation of these 
immunosuppressive cells and enable the immune system to elicit a more robust anti-tumor 
response, particularly when combined with other immune modulating agents such as CPIs. 


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6.1.2 
Ipilimumab 
Ipilimumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) with 
high specificity of binding to the CTLA-4 receptor, thus inhibiting its interaction with CD80 
and CD86.  Ipilimumab has an acceptable preclinical safety profile and is approved as an 
intravenous (IV) immunotherapy for several advanced malignancies either as monotherapy, 
or in combination with the anti-PD-1 monoclonal antibody, nivolumab 
(Yervoy® Package Insert).   
6.1.3 
FLX475 
FLX475, also known as F003475, is an orally available, potent and selective small-molecule 
antagonist of CCR4.  In preclinical models of cancer, it has been shown to inhibit the 
recruitment of Treg into tumors, and to improve tumor control and eradication in combination 
with CPIs.   
6.1.3.1 
Preclinical Experience with FLX475 
6.1.3.1.1 
Non-clinical Pharmacology 
FLX475 potently inhibits CCL22- and CCL17-induced CCR4-mediated chemotaxis with 
excellent selectivity over other chemokine receptors.  Daily oral dosing of FLX475 
(10 mg/kg) in preclinical models reduced migration of Treg to subcutaneous Pan02 tumors in 
mice by over 75%.  The tumors had a corresponding 3-fold increase in numbers of activated 
CD8+ T cells.  In the CT26 syngeneic subcutaneous mouse tumor model, FLX475 (10 mg/kg 
PO) or an antagonistic anti-PD-L1 antibody had minimal tumor growth inhibition when used 
alone.  However, median survival was greater with the combination of FLX475 and 
anti-PD-L1 compared to anti-PD-L1 alone (40.5 days vs 26.5 days, respectively).  
Additionally, FLX475 enhanced the efficacy of an agonistic anti-CD137 antibody.  
Treatment of animals with anti-CD137 alone resulted in 4 out of 10 tumor-free animals, 
whereas FLX475 combined with anti-CD137 resulted in 7 out of 10 tumor-free animals.  In 
the EMT6 breast tumor model, FLX475 (10 mg/kg PO) enhanced the tumor growth 
inhibition of anti-CTLA-4 antibody treatment resulting in delayed tumor growth.  The 
combination of anti-CTLA-4 treatment and FLX475 resulted in 3 of 10 tumor free animals 
compared to 0 of 10 tumor free animals treated with anti-CTLA-4 alone.  Taken together, 
these data suggest that FLX475 may inhibit recruitment of Treg to tumors and augment the 
immune response in tumors.  Furthermore, FLX475 may enhance the therapeutic efficacy of 
immune checkpoint inhibitors or other immune modulating agents.  For more details on 
non-clinical studies, refer to the FLX475 Investigator’s Brochure. 
Consistent with the observation that CCR4 is not associated with any immune activation 
pathways, FLX475 did not stimulate secretion of cytokines (IFN-γ, TNF-α, IL-2, IL-6, IL-4, 
or IL-10) from PBMC in vitro at doses up to 5 µM. 
6.1.3.1.2 
Preclinical Pharmacokinetics 
FLX475 has been given orally and intravenously to mice, rats, dogs, and monkeys and was 
absorbed and bioavailable in all species tested.  Following single and repeated doses in mice 




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6.1.3.2 
Clinical Experience with FLX475 
6.1.3.2.1 
FLX475-01: Phase 1 Healthy Volunteer Study 
FLX475 has been studied in a Phase 1, first-in-human, randomized, double-blind, placebo-
controlled trial in the Netherlands examining the safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) of both single and repeat dosing of FLX475 in healthy volunteers 
(van Marle et al., 2018). Seven cohorts of 8 subjects each (6 drug, 2 placebo) were 
administered single doses ranging from 5 mg to 1000 mg.  Six cohorts were administered 
daily doses of FLX475 for 14 days ranging from 25 mg to 150 mg, including two cohorts 
evaluating a 300 mg loading dose administered on Day 1.  
FLX475 was well-tolerated, with no significant laboratory abnormalities or dose-limiting 
clinical adverse events.  Dose-dependent increases in exposure were observed with low 
peak-to-trough ratios and a half-life of approximately 72 hours.  Daily dosing without a 
loading dose demonstrated approximately 4–5x accumulation of FLX475 over 14 days.  The 
tablet formulation of FLX475 to be used in the oncology study was shown to provide 
equivalent exposure as the capsule formulation used in the healthy volunteer (HV) study, 
suggesting the HV PK data are applicable to the planned study in cancer patients.  In 
addition, there was no significant effect of food on the bioavailability or PK profile of 
FLX475 tablets.  A receptor occupancy (RO) PD assay using study subject peripheral blood 
Treg demonstrated a tight PK/PD relationship, suggesting that doses of approximately 75 mg 
PO QD and above are sufficient to maintain target drug exposure above the IC90 for human in 
vitro Treg migration.  
The most common adverse events reported were transient low-grade headache and 
gastrointestinal symptoms (e.g. loose stool, abdominal discomfort, vomiting) that were 
considered not, unlikely, or possibly related to study medication.  Asymptomatic transient 
Grade 1 and 2 prolongations in QTc interval were occasionally observed during dose 
escalation. An increased number of QTc interval increases were observed at the highest dose 
cohorts which achieved mean Cmax values approximately 3–5-fold greater than the target 
therapeutic exposure level.  There was no notable increase in QTc interval prolongation 
events observed at dose levels and exposures within the target exposure range for clinical 
efficacy. 
6.1.3.2.2 
FLX475-02: Phase 1/2 Dose-Escalation and Expansion Study of 
FLX475 Alone and in Combination with Pembrolizumab in Advanced 
Cancer 
FLX475-02 is on ongoing study examining the safety and preliminary anti-tumor activity of 
FLX475 as monotherapy and in combination with pembrolizumab (Keytruda®) in subjects 
with several types of advanced cancer (Powderly et al., 2020). Phase 1 dose escalation has 
been completed for both FLX475 monotherapy and FLX475 + pembrolizumab combination 
therapy, and a recommended Phase 2 dose of 100 mg QD for FLX475 has been selected, 
based on the cumulative PK, PD, and safety data for both FLX475 monotherapy and 
combination therapy. 


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In Part 1a of the FLX475-02 study (Phase 1 dose escalation of FLX475 monotherapy), 
19 subjects with advanced cancer have been treated in four dose escalation cohorts with daily 
dosing of FLX475 at 25 mg (3 subjects), 50 mg (3 subjects), 75 mg (7 subjects), and 100 mg 
(6 subjects). PK, PD, and safety findings have been consistent with what was observed in the 
healthy volunteer study. While one dose-limiting clinical adverse event of asymptomatic QTc 
prolongation (> 500 ms and > 60 ms prolongation from baseline) was observed in each of the 
75 mg and 100 mg monotherapy dose escalation cohorts, both in subjects with confounding 
factors (including an elevated and increasing QTc at baseline in one, and hypokalemia in the 
other), no monotherapy maximum tolerated dose (MTD) was defined as no dose was 
determined to have exceeded the MTD. Preliminary PK data demonstrated that all 6 subjects 
in the 100 mg cohort achieved or exceeded the target minimum FLX475 drug exposure level 
of 130 ng/mL after 1 week of dosing. Available PD (RO) data suggested all subjects 
achieved target RO levels of 75% or more (see Section 6.1.4.1 for dose rationale). Based on 
the results of the healthy volunteer study, it was expected that additional dose escalation 
beyond 100 mg (e.g. 125 mg and beyond) was unnecessary to improve target drug exposure 
and RO, and would likely eventually exceed an MTD due to QTcF prolongation observed. 
Therefore 100 mg was chosen as the recommended Phase 2 dose (RP2D) for FLX475 
monotherapy.  
In Part 1b of the FLX475-02 study (Phase 1 dose escalation of FLX475 + pembrolizumab 
combination therapy), 18 subjects with advanced cancer have been treated in three dose 
escalation cohorts with standard-dose pembrolizumab plus daily dosing of FLX475 at 50 mg 
(3 subjects), 75 mg (4 subjects), and 100 mg (11 subjects). PK, PD, and safety findings have 
been consistent with what was observed in the healthy volunteer study (FLX475-01) and in 
Part 1a of FLX475-02. PK of FLX475 was similar between monotherapy and combination 
therapy cohorts. Preliminary PK data demonstrated that all evaluable subjects in the 100 mg 
combination cohort achieved or exceeded the target minimum FLX475 drug exposure level 
of 130 ng/mL after 1 week of dosing. Available PD (RO) data suggested all evaluable 
subjects in the 100 mg combination cohort achieved target RO levels of 75% or more. No 
new or unexpected treatment-emergent adverse events (TEAEs) were observed with the 
combination of FLX475 + pembrolizumab, i.e. all TEAEs observed were similar to those 
previously observed with either FLX475 monotherapy or pembrolizumab monotherapy 
alone.  Finally, no DLTs were observed in all DLT-evaluable subjects , including at the 
highest combination dose of 100 mg FLX475 and therefore 100 mg FLX475 PO QD + 
200 mg pembrolizumab IV Q3 weeks was selected as the RP2D for combination therapy, as 
additional dose escalation would be unnecessary to improve target drug exposure and RO, 
and would likely eventually exceed an MTD due to predicted QTcF prolongation at higher 
exposures. 
6.1.4 
Dose Rationale for Combination Therapy 
6.1.4.1 
FLX475 
FLX475 administered to mice at a dose of 10 mg/kg orally QD resulted in maximal 
inhibition of in vivo Treg migration into tumors (refer to the FLX475 Investigator’s Brochure 
for details).  The average plasma concentration of FLX475 in these mice was 
 
at trough.  This concentration is approximately equal to the IC90 




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experience in healthy volunteers and in subjects with advanced cancer to date 
(Section 6.1.3.2.2), only asymptomatic and reversible QTcF prolongation has been observed 
as a dose-related effect of FLX475, and a daily oral dose of 100 mg FLX475 has been chosen 
as the recommended Phase 2 dose of FLX475 to be used in subjects with advanced cancer, 
both as monotherapy, and in combination with pembrolizumab. 
Thus, based on the available preclinical, non-clinical, and clinical data, the risk-benefit 
profile of FLX475 is judged acceptable for this proposed Phase 2 study in subjects with 
advanced melanoma. No significant safety findings have been observed [Section 6.1.3.2] that 
would alter the risk-benefit profile of this proposed phase 2 study testing FLX475 
combination therapy with ipilimumab in subjects with advanced or metastatic melanoma. 
Because the proposed mechanism of action of FLX475 is the specific CCR4-mediated 
inhibition of recruitment of Treg into tumors, and not a global inhibition or depletion of Treg 
activity, it is not expected that FLX475 will result in significant autoimmunity or generalized 
immune activation.  Consistent with this hypothesis, no clinical or histopathologic signs of 
cytokine release, autoimmunity, or inflammation were observed in non-clinical studies or in 
healthy volunteers or cancer subjects to date. 
The safety profile of ipilimumab has been well described, and does include immune-
mediated toxicity (Yervoy® Package Insert).  Based on its proposed mechanism of action, 
FLX475 is not expected to significantly enhance immune-mediated toxicity when 
administered with ipilimumab.  Consistent with this, no overlapping toxicity with 
pembrolizumab has been observed to date. However, signs and symptoms of immune-
mediated toxicity (e.g., autoimmunity) will be closely monitored in the clinic and appropriate 
supportive care measures will be administered as indicated.  
As part of a safety run-in, the first six subjects on study will be treated with both the 
recommended Phase 2 dose of FLX475 (100 mg PO QD) and the approved dose of 
ipilimumab (3 mg/kg IV) and observed for a minimum of one cycle of treatment (21 days) 
for any unacceptable toxicities (dose-limiting toxicities or DLTs as described in 
Section 10.4) prior to enrolling additional subjects. A DLT can be observed in no more than 
one of the first six subjects during the first cycle of treatment before enrollment of the 
remainder of the study subjects can continue. If a treatment-related DLT is observed during 
the first cycle of treatment in more than one of the first six (or fewer) subjects, dose 
modification of either or both drugs will be considered by the Safety Review Committee 
prior to continuing enrollment, potentially in an additional safety run-in. 
6.3 
Study Rationale 
This Phase 2 study will evaluate safety and clinical efficacy, in addition to PK and potential 
changes in the TME of FLX475 in combination with ipilimumab in subjects with advanced 
melanoma.  Ipilimumab is an approved treatment for advanced melanoma with a reported 
best overall response rate (ORR) ranging from 10.9% in previously-treated patients 
(Hodi, et al., 2010) to 19% in previously untreated patients (Larkin, et al., 2015), thus there 
remains room for clinical improvement. 


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The primary hypothesis of this study is that FLX475 administration may block the 
CCR4-mediated recruitment of Treg into tumors, thus increasing the intratumoral Teff:Treg 
ratio and favoring an anti-tumor immune response when given in combination with 
ipilimumab, thus increasing the clinical activity of ipilimumab.  The study design will first 
examine the safety of the combination of FLX475 and ipilimumab as part of a safety run-in 
phase, and will also examine the degree of anti-tumor activity (clinical responses) in subjects 
with advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent. Based 
upon available clinical data, the ORR of ipilimumab monotherapy in such subjects is 
expected to be approximately 14% (Long, et al., 2017).  Thus an ORR of >20−30% with the 
combination of FLX475 and ipilimumab in this study would provide preliminary clinical 
evidence in support of the clinical hypothesis. 


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7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
The primary objectives of the study are: 
• To evaluate the objective response rate (ORR), defined as confirmed complete or partial 
response per RECIST 1.1, of FLX475 in combination with ipilimumab in subjects with 
advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the safety and tolerability of FLX475 in combination with ipilimumab in 
subjects with advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 
agent 
 
7.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the progression-free survival (PFS) of subjects with advanced melanoma 
treated with FLX475 in combination with ipilimumab who have been previously treated 
with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the overall survival (OS) of subjects with advanced melanoma treated with 
FLX475 in combination with ipilimumab who have been previously treated with an anti-
PD-1 or anti-PD-L1 agent 
• To evaluate the objective response rate (ORR), defined as confirmed complete or partial 
response per iRECIST, of FLX475 in combination with ipilimumab in subjects with 
advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the plasma concentrations of FLX475 when it is given in combination with 
ipilimumab 
• To assess the effects of FLX475 in combination with ipilimumab on PD markers relating to drug 
mechanism of action 
• To characterize the onset, magnitude, and duration of tumor control in subjects receiving FLX475 
in combination with ipilimumab 
 


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8 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan 
This clinical trial is a Phase 2, open-label study to determine the anti-tumor activity of 
FLX475 in combination with ipilimumab in subjects with advanced melanoma previously 
treated with an anti-PD-1 or anti-PD-L1 agent. 
The study will be conducted starting with a safety run-in portion in which 6 eligible subjects 
will be enrolled and treated for at least one 3-week cycle to determine if the safety profile of 
FLX475+ ipilimumab is acceptable to complete enrollment of the approximately 20-subject 
study.  Should the safety profile be deemed not acceptable for the 100 mg FLX475 PO QD 
and 3 mg/kg ipilimumab IV Q3W combination regimen, an alternative (lower) dose regimen 
of either or both drug(s) may be selected and tested in an additional 6-subject safety run-in 
phase. Ultimately at least 20 subjects should be treated and evaluated with a single chosen 
combination dose regimen. 
Accrual to the study may be discontinued prior to completing enrollment, for reasons 
including, but not limited to, unacceptable safety, slow/insufficient enrollment, or changes in 
standard clinical practice.  For each subject, the study consists of the following: screening 
period, treatment phase, and long-term follow-up: 
• Screening visit within 21 days of enrollment into the Treatment Phase 
• Treatment Phase comprising up to a maximum of 4 cycles (4 doses) of ipilimumab and 
up to 35 treatment cycles (2 years) of FLX475, unless another intervening reason for 
discontinuation occurs.  Each treatment cycle is 3 weeks in duration.  Treatment beyond 
35 cycles may be considered only if it is felt to be in the best interests of the subject by 
the investigator and upon Sponsor agreement (if feasible). 
• End-of-treatment visit within 90 days after the final dose of study treatment 
• Posttreatment survival follow-up phase 
 
The definition of the end of the study is the date of the data cutoff for the final analysis or last 
subject/last visit, including discontinuation from the study for any reason, whichever occurs 
later. 
The study will start with a safety run-in phase. The first six subjects enrolled and treated at 
the recommended Phase 2 dose of FLX475 (100 mg/dose QD) plus ipilimumab (3 mg/kg IV 
q3W, up to 4 doses) will be followed for at least one 3-week cycle (21 days) to monitor for 
any unacceptable (or dose-limiting) toxicities prior to enrolling additional subjects. 
After the first six subjects enrolled have completed the 3-week safety observation period, a 
Safety Review Committee (SRC) will be convened.  The SRC members will comprise 
appropriate Sponsor and CRO representatives, including the Sponsor’s medical monitor or 
designee(s), safety officer or designee, and clinical trial managers (CTMs).  Additional 


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members may be added as needed (e.g. PK scientist and/or biostatistician). The SRC will 
carefully consider all available safety, laboratory, and PK information in consultation with 
the study investigators.  After review of all available data, the SRC may recommend 
continued enrollment of the entire study (e.g. if no unacceptable toxicities are observed); 
dose reduction of either FLX475 and/or ipilimumab; or discontinuation of the study.  Beyond 
the safety run-in phase, the SRC will continue to meet at least quarterly during the study to 
review accumulating safety data and may also recommend an amendment to the protocol to 
evaluate alternate study drug administration schedules or other changes in study design as 
may be appropriate based on emerging clinical data. 
8.2 
Study Phases 
8.2.1 
Pretreatment Phase 
The Pretreatment Phase will last no longer than 21 days and will include a Screening Period 
to establish protocol eligibility and disease characteristics and Baseline to confirm eligibility 
and establish disease characteristics prior to treatment.  See the Schedule of 
Procedures/Assessments in Table 6 for complete details. 
Screening Period 
Screening will occur from Day -21 to Day -1.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 4.3.  Repeated laboratory evaluation to establish 
eligibility is not allowed unless discussed and agreed upon with the Sponsor.   
Procedures to be followed when obtaining both approval to screen a subject and approval to 
enroll (i.e. register) a subject after screening are detailed in Section 11. 
Baseline Period 
Baseline assessments must be performed on Cycle 1 Day 1 prior to administration of the first 
dose of study drug(s). 
Subjects who complete the baseline assessments and meet all of the criteria for 
inclusion/exclusion (Sections 9.1.1 and 9.1.2) will begin the Treatment Phase. 
8.2.2 
Treatment Phase 
The Treatment Period for each subject will begin at the start of dosing and will end with the 
completion of the End-of-Treatment Visit, which will occur within 90 days after the final 
dose of study treatment.   
The following conditions apply: 
• Subjects will receive study treatment with FLX475 and ipilimumab (first four (4) cycles) 
or FLX475 alone (Cycle 5 and beyond) as continuous 3-week (21-day) cycles.  Treatment 


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cycles will be counted continuously regardless of dose interruptions (i.e. all study visits 
are anchored to Cycle 1 Day 1).  Subjects will undergo safety and efficacy assessments as 
defined in the Schedule of Procedures/Assessments (Table 6).  Subjects will continue to 
receive study treatment for a maximum of 2 years (35 cycles) or until subject withdrawal 
from the study, confirmed progression of cancer, intolerable study treatment-related 
toxicity despite appropriate dose modification and supportive treatment, the development 
of intercurrent illness that precludes continued study treatment, pregnancy or 
breastfeeding, substantial noncompliance with study procedures, loss to follow-up, or 
study termination by the Sponsor, whichever occurs first.  Treatment beyond 35 cycles 
may be considered only if it is felt to be in the best interests of the subject by the 
investigator and upon Sponsor agreement (if feasible). 
• Subjects who discontinue ipilimumab prior to receiving the planned four doses due to 
toxicity may continue treatment with FLX475 alone.  
 
For subjects who have radiological disease progression (PD) by Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1 as determined by the investigator, the investigator will decide 
in consultation with the Sponsor’s medical monitor whether the subject can continue to 
receive study treatment until repeat, confirmatory imaging is obtained using modified 
RECIST for immunotherapies (iRECIST) for subject management (see Appendix 5 for 
details).  The investigator’s decision is based on the subject’s overall clinical condition.   
8.2.3 
Follow-Up Phase 
Unless they withdraw consent or are lost to follow-up, subjects who discontinue study 
treatment will be followed for acquisition of safety information for 90 days after the final 
dose of study treatment (or 30 days following cessation of study treatment if the subject 
initiates new anticancer therapy, whichever occurs first).  Subjects will also be followed for 
long-term collection of information regarding further therapies for cancer and overall 
survival (OS).  
If a subject discontinues study treatment and does not consent to continued follow-up, the 
investigator must not access confidential records that require the subject’s consent.  
However, an investigator may consult public records to establish survival status, as well as 
for OS (until death or loss to follow-up).   
During the Follow-up Phase, subjects will be treated by the investigator according to the 
prevailing local standard of care.  Subjects will be followed at approximately 3- to 6-month 
intervals for survival and all subsequent anticancer treatments received.  Long-term 
follow-up information will be collected during routine clinic visits, other study site contact 
with the subjects, or via telephone or e-mail with the subject/caregiver or referring 
physician’s office.  These data will be collected in the source documents (e.g., subject 
medical record) and recorded onto a specific eCRF.  The information will be recorded unless 
not permitted because of confidentiality.  The Sponsor may choose to discontinue survival 
follow-up following completion of the primary study analysis when appropriate, e.g., when 
only a minimal number of subjects remain in follow up. 


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If a subject becomes unavailable for follow-up (e.g., misses scheduled assessment, telephone 
contact), the investigator or designee will make every attempt to contact the subject to 
determine his or her status.  All attempts at contact will be recorded in the subject’s medical 
notes.  A subject may be considered lost to follow-up after a minimum of two attempts to 
contact the subject (e.g. by email or telephone) have been unsuccessful.  
All subjects who discontinue study treatment prior to PD will undergo tumor imaging at the 
time of treatment discontinuation (± 4-week window).  If previous tumor imaging was 
obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory.  For subjects who discontinue study treatment without 
documented PD, every effort should be made to continue monitoring disease status by tumor 
imaging using the same imaging schedule used during study treatment (every 9 weeks ± 
1 week in Year 1 or every 12 weeks ± 1 week beyond Year 1) until the start of a new 
anticancer treatment, PD, pregnancy, death, withdrawal of consent, loss to follow-up, or 
termination of the study, whichever occurs first. 
For subjects who discontinue study treatment due to documented PD, no tumor imaging is 
required during follow-up if the investigator elects not to implement iRECIST. 
8.3 
Discussion of Study Design 
This multicenter, nonrandomized, single arm, open-label, Phase 2 study was designed to 
evaluate the safety and activity of FLX475 in combination with ipilimumab in subjects with 
previously treated advanced melanoma.  The study utilizes a safety run-in phase to confirm 
that the previously determined Phase 2 dose of FLX475 and the approved dose of ipilimumab 
are acceptable to be used in combination.  The entire Phase 2 study will be used to evaluate 
the level of response to this novel combination.  Ipilimumab will be used as a comedication 
since it is an approved checkpoint inhibitor with activity in patients with advanced 
melanoma. 


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9 
STUDY POPULATION 
The target population is composed of adult subjects with adequate performance status and 
organ function who have advanced melanoma previously treated with anti-PD-1 or anti-
PD-L1. 
9.1.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible to receive study 
treatment: 
1. All subjects must have pathologically confirmed melanoma that is either Stage IV or 
unresectable Stage III. Subjects may have cutaneous, mucosal or unknown primary 
lesions of origin. Subjects with uveal primary are not eligible. 
2. Subjects must have had prior treatment with anti-PD-1 or anti-PD-L1 agents, with at least 
2 months of therapy followed by documented disease progression either while on these 
agents or after stopping therapy with these agents. Subjects must have discontinued anti-
PD-1 or anti-PD-L1 therapy at least 4 weeks prior to start of study treatment. Subjects 
who received prior treatment with anti-PD-1 or anti-PD-L1 agents in the adjuvant setting 
and whose disease recurred while on treatment or within 6 months of completion of the 
treatment are eligible.  
3. Men and women ≥ 18 years of age on day of signing informed consent. 
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 
1.(Subjects with stable ECOG PS of 2 due to non-cancer-related conditions may be 
permitted with the approval of the Sponsor’s medical monitor.) 
5. Subjects must have measurable disease per RECIST 1.1. 
6. Subjects with central nervous system (CNS) metastases must have all lesions adequately 
treated with stereotactic radiation therapy, craniotomy, Gamma Knife therapy, or whole 
brain radiotherapy, with no subsequent evidence of CNS progression. Subjects must not 
have required steroids for at least 14 days prior to registration. 
7. All acute toxic effects of any prior therapy have resolved to Grade 0 or 1 or to baseline 
level before the start of study treatment (except that up to Grade 2 alopecia, 
neurotoxicity, and bone marrow abnormalities may be permitted with Sponsor agreement, 
and subjects with immune-related endocrinopathies who are on stable doses of 
medications are permitted).  
8. Subjects must have adequate hematologic function as evidenced by all of the following at 
time of screening within 21 days prior to start of study treatment: absolute neutrophil 
count (ANC) ≥ 1500/µL; hemoglobin ≥ 8 g/dL; and platelets ≥ 100,000/µL. 
9. Human immunodeficiency virus (HIV)-infected subjects must be on anti-retroviral 
therapy (ART) and have well-controlled HIV infection/disease defined as: (a) CD4+ T 
cell count >350 cells/mm3 at time of screening, (b) achieved and maintained virologic 
suppression defined as confirmed HIV RNA level <50 copies/mL or the lower limit of 
qualification (below the limit of detection) using the locally available assay at the time of 


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screening and for at least 12 weeks prior to screening, (c) must have been on a stable anti-
retroviral regimen, without changes in drugs or dose modification, for at least 4 weeks 
prior to start of study treatment (C1D1), and (d) the combination ART regimen must not 
contain any retroviral medications OTHER THAN abacavir, dolutegravir, emtricitabine, 
lamivudine, raltegravir, or tenofovir (due to potential CYP interactions, exceptions 
permitted only with prior Sponsor clearance). 
10. Subjects must have adequate hepatic function as evidenced by all of the following at time 
of screening within 21 days prior to start of study treatment: total bilirubin ≤ 2.5 x 
Investigational Upper Limit of Normal (IULN) (except subjects with Gilbert’s 
syndrome); and AST and ALT both ≤ 5 x IULN. 
11. Subjects must have adequate kidney function as evidenced by serum creatinine ≤ 2.0 x 
IULN at time of screening within 21 days prior to start of study treatment. 
12. Subjects enrolled must be willing and able to provide tissue from a newly obtained core 
(minimum of 3 cores) or excisional (or skin punch) biopsy of a tumor lesion not 
previously irradiated (unless subsequent progression demonstrated).  In addition, subjects 
must be willing to provide a tumor biopsy (minimum of 3 cores, or excisional or skin 
punch) while on treatment at Cycle 2 Day 8 (± 7 days) and may be asked to provide 
additional biopsies at other timepoints such as the time of discontinuation due to 
progression. 
13. For women of childbearing potential, negative results on a serum pregnancy test within 
2 days prior to study registration and willingness to use an effective method of 
contraception (e.g., oral contraceptives, double-barrier methods such as a condom and a 
diaphragm, intrauterine device) from the start of study treatment (or 14 days prior to the 
initiation of study treatment for oral contraception) and for 120 days following the final 
dose of study treatment, or to abstain from sexual intercourse for this period of time. 
Note:  A female subject is considered to be of childbearing potential unless she has had 
a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone 
levels within the institutional postmenopausal range and a negative result on serum or 
urine beta-human chorionic gonadotropin [β-HCG]) pregnancy test, or is 
postmenopausal (age ≥ 55 years with amenorrhea for ≥ 6 months). 
14. For male subjects of childbearing potential having intercourse with females of 
childbearing potential, willingness to abstain from heterosexual intercourse or use of a 
protocol-recommended method of contraception (e.g., partner use of oral contraceptives 
or an intrauterine device, or double-barrier methods such as a condom and a diaphragm) 
from the start of study treatment (or 14 days prior to the initiation of study treatment for 
oral contraception) to 120 days following the final dose of study treatment and to refrain 
from sperm donation from the start of study treatment to 120 days following the final 
dose of study treatment. Note:  A male subject is considered able to father a child unless 
he has had a bilateral vasectomy or a bilateral orchiectomy with confirmed 
azoospermia or has ongoing medical testicular suppression. 
15. Ability to swallow tablets without difficulty. 
16. Signed Informed Consent Form by the subject or his/her legal guardian.  


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9.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible to receive study 
treatment: 
1. History of known antidrug antibodies or severe allergic, anaphylactic, or other infusion 
related reaction to a previous biologic agent. 
2. Any history of discontinuing prior treatment due to Grade 3–4 immune related adverse 
events (irAEs) of colitis or pneumonitis. 
3. Prior treatment with ipilimumab or other CTLA-4 antagonists. 
4. Prior systemic anticancer therapy including any anti-PD-1 or anti-PD-L1 agents within 
4 weeks prior to start of study treatment. 
5. Active autoimmune disease requiring disease-modifying therapy at the time of screening. 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed. 
6. History of another malignancy that has progressed or has required active treatment within 
the past 2 years, unless it is clinically stable and does not require tumor-directed 
treatment. (Examples include the following: adequately treated local basal cell or 
squamous cell carcinoma of the skin; in situ cervical carcinoma; adequately treated 
papillary, noninvasive bladder cancer; asymptomatic prostate cancer without known 
metastatic disease and not requiring therapy or requiring only hormonal therapy, and with 
normal prostate specific antigen for ≥ 1 year prior to start of study treatment; or other 
adequately treated Stage 0, 1 or 2 cancers currently in complete remission.) In addition, 
any other cancer treated with curative intent ≥ 2 years prior to screening with no evidence 
of disease is permitted. 
7. Significant cardiovascular disease, including myocardial infarction, arterial 
thromboembolism, or cerebrovascular thromboembolism within 6 months prior to start of 
study treatment, symptomatic dysrhythmias or unstable dysrhythmias requiring medical 
therapy, angina requiring therapy, symptomatic peripheral vascular disease, clinically 
significant history of syncope, New York Heart Association (NYHA) Class 3 or 4 
congestive heart failure (Appendix 3), or chronic Grade 3 hypertension (diastolic blood 
pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg). 
8. Significant screening electrocardiogram (ECG) abnormalities including atrial fibrillation 
(unstable or newly diagnosed), double (left and right) bundle branch block, second degree 
atrioventricular block type II, third-degree atrioventricular block, Grade ≥ 2 bradycardia, 
QTcF interval ≥ 450 msec, PR interval > 220 msec, or unstable cardiac arrhythmia 
requiring medication.  Chronic asymptomatic atrial fibrillation stably controlled with 
medications is permitted. 
9. Significant active gastrointestinal disease (e.g., malabsorption syndrome, resection of the 
stomach or small bowel, symptomatic inflammatory bowel disease, gastrointestinal 
perforation, or partial or complete bowel obstruction) that might impair absorption of 
study treatment. 


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10. Evidence of an ongoing, uncontrolled systemic bacterial, fungal, or viral infection or an 
uncontrolled local infection requiring therapy at the time of start of study treatment.  
Note: Subjects with localized fungal infections of skin or nails are eligible. 
11. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman 
Disease. 
12. Known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known 
active Hepatitis C virus (defined as detection of HCV RNA [qualitative]) infection. 
13. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (at doses 
exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 14 days prior to the first dose of study treatment. 
Inhaled or topical steroids, and adrenal replacement doses of ≤ 10 mg daily prednisone or 
equivalent are permitted in the absence of active autoimmune disease. 
14. Prior allogeneic organ transplant. 
15. Females who are pregnant, breastfeeding, or expect to become pregnant within the 
projected duration of the study, starting with the screening visit through 120 days after 
the final dose of study treatment.  Males who plan to father children within the projected 
duration of the study, starting with the screening visit through 120 days after the final 
dose of study treatment. 
16. Radiotherapy within 14 days prior to start of study treatment.  Subjects must have 
recovered from all radiation-related toxicities, not require corticosteroids, and not have 
had radiation pneumonitis. 
17. Subjects currently receiving treatment with any medications that have the potential to 
prolong the QT interval and that cannot be either discontinued or substituted with a 
different medication prior to starting study treatment. (See Appendix 7) 
18. Subjects currently receiving treatment with strong cytochrome P450 (CYP)3A4 inhibitors 
or inducers should discontinue such treatment or be switched to a different medication 
prior to starting study treatment. (See Appendix 7) 
19. Current participation in another study of an investigational agent or device. 
20. Any illness, medical condition, organ system dysfunction, or social situation, including 
mental illness or substance abuse, deemed by the investigator to be likely to interfere 
with a subject’s ability to sign informed consent, adversely affect the subject’s ability to 
cooperate and participate in the study, or compromise the interpretation of study results. 
 
9.1.3 
Replacement of Subjects 
Any subjects in the safety run-in phase who do not receive at least 80% of planned doses in 
Cycle 1 due to reasons other than DLT, or who stop treatment prior to completing evaluation 
for the initial 3 weeks of therapy (DLT Observation Period) due to PD or refusal to 
participate further for reasons other than DLT, will be replaced at that dose level to permit 
full evaluation of the safety run-in.  See Section 10.4 for the definition of a DLT. 


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9.1.4 
Removal of Subjects from Therapy or Assessment 
Discontinuation of study treatment does not represent withdrawal from the study. 
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons, but should inform or 
discuss with the Sponsor’s medical monitor prior to doing so (when feasible).  The subject 
may decide to discontinue study treatment or withdraw from the study at any time for any 
reason. 
The reason for discontinuation of FLX475, ipilimumab, or both will be documented.  If a 
subject discontinues study treatment, the subject will enter the Follow-Up Phase and 
complete protocol-specified End-of-Treatment and Follow-up visits, procedures, and survival 
follow-up, unless the subject withdraws consent.  The investigator should confirm whether a 
subject will discontinue study treatment but agree to continue protocol-specified, post-
treatment study visits, procedures, and survival follow-up, or whether the subject withdraws 
consent or is lost to follow-up.  If a subject withdraws consent, the date will be documented 
in the source documents.  The investigator, or designee, will complete the appropriate eCRF, 
indicating the primary reason for discontinuation.  In addition, the date of final dose of study 
treatment(s) will be recorded on the appropriate eCRF. 
All subjects who discontinue study treatment without having PD will continue to undergo 
tumor assessments using the same imaging schedule used during the Treatment Phase 
(i.e., every 9 weeks [±1 week] in Year 1 or every 12 weeks [±1 week] beyond Year 1) until 
the start of a new anticancer treatment, disease progression, pregnancy, or the end of the 
study, whichever occurs first, unless the subject withdraws consent, is lost to follow-up, or 
dies.   
All subjects will be followed for survival until death, except for those subjects who withdraw 
consent or are lost to follow-up, or the Sponsor chooses to halt survival follow-up after 
completion of the primary study analysis. 


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10 
TREATMENTS 
10.1 
Overview of Treatments Administered 
Subjects will take FLX475 orally once daily (QD) starting on Day 1 of Cycle 1.  See 
Section 10.2.1 for details of the planned dose administration schema. 
Subjects will also receive ipilimumab.  Ipilimumab 3 mg/kg will be administered IV Q3W 
for up to four doses. 
The treatments to be used in this study are outlined in Table 1. 
Table 1 
Study Treatments 
Study 
Treatment 
Formulation 
 
Dose Levels 
Route of 
Administration 
Sourcing 
FLX475  
Tablets 
 
100 mg (with 
possible dose 
reduction to 
75, 50, or 
25 mg) qd 
Oral 
Provided 
centrally by 
the Sponsor 
Ipilimumab 
Solution for 
infusion 
 
3 mg/kg Q3W 
IV infusion 
Provided by  
the site 
IV = intravenous, Q3W = once every 3 weeks, qd = once daily. 
 
10.2 
FLX475 Administration 
All subjects will take FLX475 orally once daily on a continual basis.  On days when 
ipilimumab is also administered (i.e., Day 1 of Cycles 1−4), FLX475 should be taken 
approximately 1 hour before the ipilimumab infusion.   
The dose administration schema for FLX475 is provided below, along with instructions for 
dose modification. 
10.2.1 
Dosing Plan 
As noted in Section 6.1.4, the recommended Phase 2 dose of FLX475 of 100 mg PO QD has 
been selected both for monotherapy and for combination therapy with pembrolizumab in 
study FLX475-02. Therefore, this same dose will be used in this study in combination with 
ipilimumab. Should the safety run-in safety data suggest that the 100 mg of FLX475 dose is 
not acceptable in combination with ipilimumab, a lower dose (e.g. 75 or 50 mg PO QD) may 
be chosen to be used after evaluation in a new safety run-in cohort of six subjects. In the 
event of a change in FLX475 dose, additional subjects may be enrolled to ensure that a 
minimum of 20 subjects are treated at the chosen combination dose regimen. 
After all subjects in the safety run-in phase have completed the 3-week safety observation 
period, a Safety Review Committee (SRC) will be convened.  The SRC members will be 
composed of appropriate Sponsor and CRO representatives, including the Sponsor’s medical 


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monitor or designee(s), safety officer or designee, and clinical trial managers (CTMs).  
Additional members may be added as needed (e.g., PK scientist, and/or biostatistician).  The 
SRC will carefully consider all available safety, laboratory, and PK information in 
consultation with the study investigators.  After review of all available data, and if the safety 
profile of the combination therapy is deemed acceptable, the SRC will recommend 
continuation of the study and enrollment of the remainder of the subjects. If the safety profile 
of the combination regimen is not deemed to be acceptable (e.g. DLT observed in > 1 of 
6 subjects), the SRC may recommend de-escalation of FLX475 to a lower dose (e.g. 75 or 
50 mg PO QD); de-escalation of ipilimumab to a lower approved dose (e.g. 1 mg/kg); delay, 
or termination of dosing.  Beyond the safety run-in, the SRC will continue to meet at least 
quarterly during the study to review accumulating safety data and may also recommend an 
amendment to the protocol to evaluate alternate study drug administration schedules or other 
changes in study design as may be appropriate based on emerging clinical data.  
10.3 
Ipilimumab Administration 
Ipilimumab 3 mg/kg will be administered as an IV infusion over 30 or 90 minutes (per 
institutional protocol) on Day 1 of the first four 3-week treatment cycles (i.e., 21 days 
[± 3 days]) after all procedures and assessments have been completed, including any 1 hour 
post-FLX475 dose procedures, approximately 1 hour after the Day 1 dose of FLX475.   
The investigational staff should make every effort to ensure that the infusion duration be as 
close to 30 or 90 minutes as possible.  However, given the variability of infusion pumps from 
site to site, a window between -5 minutes and + 10 minutes is permitted. 
Ipilimumab should be prepared and administered per standard institutional protocol and the 
approved label instructions. 
10.4 
Dose-Limiting Toxicity and Stopping Criteria 
The safety profile of ipilimumab monotherapy has been well described 
(Yervoy® Package Insert) and includes a significant number of immune-related adverse events 
(irAEs) to be taken into account when determining what might be either unexpected or 
unacceptable toxicity for the combination of FLX475 with ipilimumab.  Therefore, a DLT 
for this study will be defined as an AE or abnormal laboratory value assessed by the 
investigator as possibly, probably, or definitely related to study treatment, excluding 
toxicities clearly not related to study treatment, such as PD, environmental factors, unrelated 
trauma, etc.  occurring during Days 1–21 of Cycle 1 (“DLT Observation Period”), that meets 
any of the following criteria:  
• Grade 4 hematological laboratory abnormality lasting ≥ 7 days, except thrombocytopenia, 
or: 
◦ 
Grade 4 thrombocytopenia of any duration; or 
◦ 
Grade 3 thrombocytopenia associated with clinically significant bleeding 


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• Nonhematological Grade 3 or 4 laboratory abnormalities: 
◦ 
Clinically significant medical intervention is required to treat the subject, or 
◦ 
The abnormality leads to hospitalization, or 
◦ 
The abnormality persists for >1 week, or 
◦ 
The abnormality results in a Drug-induced Liver Injury (DILI) 
◦ 
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc. 
• Any Grade 4 non-hematologic AE of any duration, with the following exception: 
• Grade 4 diarrhea lasting 48–72 hours in subjects who have received suboptimal 
anti-diarrheal therapy 
• Grade 3 rash that does not resolve to Grade 1 or baseline level (whichever is higher) 
within 14 days with adequate medical management 
• Grade 3 fever that does not resolve to Grade 1 or baseline level (whichever is higher) 
within 14 days with adequate medical management 
• Grade 3 fatigue that does not resolve to Grade 2 or baseline level (whichever is higher) 
within 14 days with adequate medical management 
• Grade ≥ 3 creatinine increase  
• Grade 3 nausea, vomiting, colitis, or diarrhea requiring total parenteral nutrition or 
hospitalization (e.g., duration >48 hours despite optimal management) that does not 
resolve to Grade 1 or baseline level (whichever is higher) within 14 days 
• Grade 2–3 uveitis, eye pain, or blurred vision that does not respond to topical therapy and 
does not improve to Grade 0 or 1 within 14 days 
• Grade ≥ 2 nonhematological toxicity requiring systemic immunosuppressive therapy.  
This includes, but is not limited to, autoimmune diseases of the lung, heart, kidney, 
bowel, CNS, pituitary, or eye 
• Grade ≥ 2 endocrine toxicity requiring hormone replacement, with the exception of 
Grade 2 thyroiditis and thyroid dysfunction (which are acceptable) 
• Grade ≥ 3 adrenal insufficiency 
• Grade ≥ 3 febrile neutropenia: 
◦ 
Grade 3 is defined as absolute neutrophil count (ANC) < 1000/mm3 with a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) 
for more than 1 hour 




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• For any clinically-significant organ-related Grade 4 TEAE (neurologic, pulmonary, 
cardiac, gastrointestinal, genitourinary, renal, hepatic, cutaneous) at least possibly related 
to FLX475, discontinue drug use permanently (unless it is determined by the investigator, 
in consultation with the Sponsor’s medical monitor, to be in the subject’s best interest to 
continue treatment, at a reduced dose). 
• For subjects with average Grade 2 or 3 QTcF prolongation at doses of 75 mg or greater 
(measured at times other than during the up to 6-hour period immediately following an 
FLX475 dose when a threshold of Grade 3 QTcF prolongation should be used), interrupt 
treatment with FLX475 until resolution to Grade 0 or 1 or to the pretreatment severity 
grade, then resume treatment at 50 mg.  Subjects with average Grade 2 or 3 QTcF 
prolongation while at the 50 mg or lower dose level of FLX475 (measured at times other 
than during the up to 6-hour period immediately following an FLX475 dose when a 
threshold of Grade 3 QTcF prolongation should be used) should be permanently 
discontinued from FLX475 treatment (unless it is determined by the investigator, in 
consultation with the Sponsor’s medical monitor, to be in the subject’s best interest to 
continue treatment either at 50 mg or at a reduced dose of 25 mg).  Any subjects with 
observed QTcF prolongation of potential significance should have the ECG repeated for 
confirmation and electrolytes assessed and replaced as needed prior to action with study 
drug being taken. Any subjects with observed Grade 4 QTcF prolongation (including 
symptomatic/serious arrhythmia) should be treated appropriately and permanently 
discontinued from FLX475 treatment (unless it is later determined by the investigator, in 
consultation with the Sponsor’s medical monitor, to be in the subject’s best interest to 
continue treatment). 
• The investigator may interrupt treatment with FLX475 for any other AE considered 
unacceptable for the individual subject, and treatment may be resumed at the previous 
lower dose level when resolved to Grade 0 or 1 or to pretreatment severity grade. 
• If no lower dose level exists to which the subject may de-escalate, FLX475 should be 
discontinued. 
 
Other dose modifications may be acceptable but should be implemented at the investigator’s 
discretion in consultation with the Sponsor’s medical monitor, considering the subject’s 
condition and the clinical benefit to the subject of continuing treatment at the current dose.  If 
the subject requires a dose modification for an AE, then FLX475 administration should be 
interrupted, as necessary (and upon consultation with the Sponsor’s medical monitor), until 
the AE resolves or stabilizes to an acceptable degree (generally to CTCAE Grade 0 or 1 or to 
pretreatment severity grade).  Thereafter, treatment with FLX475 may be reinstituted at the 
previous lower dose level.  Subsequent reductions to successively lower dose levels can be 
made, if needed, as shown in Table 2.  More frequent laboratory monitoring may be required.  
Once the dose of study treatment has been reduced, it may not be increased at a later date 
without approval from the Sponsor’s medical monitor. (Note that AEs known to be 
associated with ipilimumab may not require interruption or modification of FLX475 dosing.) 


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Table 2 
Dose Modification Guidelines for FLX475-Related Toxicity 
Treatment-Related 
Toxicitya,b 
Management 
Dose Adjustment 
Grade 1 or Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c or Grade 3d, e 
First occurrence 
Interrupt FLX475 until resolved to 
Grade 0–1 or tolerable Grade 2 (or 
baseline) 
Reduce FLX475 dose by 
1 level (or if no lower dose 
level exists, discontinue 
drug) 
Second occurrence 
(same toxicity or new 
toxicity) 
Interrupt FLX475 
Discuss with Sponsor 
Grade 4f: Discontinue Study Treatment 
Note:  For grading see CTCAE version 5.0 (Appendix 1).  Collect all CTC grades of adverse events, decreasing 
and increasing grade.   
BMI = body mass index, CTCAE = Common Terminology Criteria for Adverse Events. 
a 
An interruption of study treatment for more than 21 days will require Sponsor`s approval before treatment 
can be resumed.   
b 
Initiate optimal medical management for nausea, vomiting, hypothyroidism and/or diarrhea prior to any 
study treatment interruption or dose reduction.   
c 
Applicable only to Grade 2 toxicities judged by the subject or physician to be intolerable. 
d 
For Grade 3 toxicity, investigator will decide the probability of the event being related to 1 or both drugs 
and as to whether dose modification of either or both drugs is required. 
e 
For asymptomatic laboratory abnormalities, such as Grade ≥ 3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor. 
f 
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
 
10.5.2 
Dose Modification for Ipilimumab 
Adverse events associated with ipilimumab exposure may represent an immunologic etiology 
and may affect more than one body system simultaneously.  These immune-related AEs 
(irAEs) may occur shortly after the first dose or several months after the final dose of 
ipilimumab.  Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs are reversible and can be 
managed with interruptions of ipilimumab, administration of corticosteroids, and/or other 
supportive care.  Suspected irAEs should be adequately evaluated to confirm etiology or 
exclude other causes.  Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation.  Based on the severity of irAEs, ipilimumab 
should be withheld or permanently discontinued, and corticosteroids administered.  
Ipilimumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Note that modification of dosing of ipilimumab (e.g. withholding or discontinuation) due to 


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potential/likely ipilimumab toxicity (e.g. irAE) does not require similar modification of 
FLX475 dosing unless there is evidence of concurrent FLX475-related toxicity.  
Thorough dose modification and toxicity management guidelines for irAEs associated with 
immunotherapies including ipilimumab have been published and should be followed 
(Brahmer, et al., 2018). Criteria for dose delay, modification, or discontinuation of 
ipilimumab are described below. Additional guidance regarding dose modification for 
ipilimumab can be found in Section 2.3 of the approved label (Yervoy® Package Insert). 
Table 3 shows treatment guidelines, including premedications, for subjects who experience 
an infusion reaction associated with the administration of ipilimumab. Examples of some of 
the most common irAEs are provided in Table 4. 
Ipilimumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistical reasons not related to study treatment.  Ipilimumab 
should be restarted within 3 weeks of the scheduled interruption, unless otherwise discussed 
with the Sponsor.  The timing of restarting ipilimumab should be discussed with and agreed 
to by the Sponsor’s medical monitor.  The reason for interruption should be documented in 
the subject's eCRF. 


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Table 3 
Infusion Reaction Treatment Guidelines for Ipilimumab 
NCI CTCAE Grade 
Treatment 
Premedication for 
Subsequent Doses of 
Ipilimumab 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 h 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate.  Otherwise ipilimumab 
administration will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
permanently discontinue study 
treatment. 
Subject may be 
premedicated 1.5 h 
(± 30 minutes) prior to 
infusion of ipilimumab 
with: 
Diphenhydramine 50 mg 
orally (or equivalent 
dose of antihistamine). 
 
Acetaminophen 
500−1000 mg orally (or 
equivalent dose of 
antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication for 
Subsequent Doses of 
Ipilimumab 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Permanently discontinue study 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 
CTCAE = Common Terminology Criteria for Adverse Events, version54.0, IV = intravenous, NCI = National Cancer 
Institute, NSAID = nonsteroidal anti-inflammatory drug. 
 


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Table 4 
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated 
with Ipilimumab 
Immune-related 
Adverse Event 
Toxicity Grade 
or Conditions 
(CTCAE v5.0) 
Action Taken with 
Ipilimumab 
irAE Management with 
Corticosteroids and Other 
Therapies 
Monitoring and Follow-up 
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 0 or 1 and continue to taper over at least 4 weeks. 
For situations where ipilimumab has been withheld, ipilimumab can be resumed after AE has improved to Grade 0 or 1 and corticosteroid has 
been tapered.  Ipilimumab should be permanently discontinued if AE does not resolve within 12 weeks of final dose or corticosteroids cannot be 
reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.   
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid.  Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Rash/Inflammatory 
Dermatitis 
Grade 2 
Consider withholding and 
monitor; if not resolved, 
interrupt until Grade 1 
Treat with topical emollients, 
oral antihistamines, and 
medium- to high-potency 
topical corticosteroids. 
Consider initiating prednisone 
(or equivalent) at 1 mg/kg, 
tapering over at least four 
weeks.  
Monitor for improvement, and for 
progression of Grade 4 rash to 
severe cutaneous adverse reaction. 
Consult with dermatology. 
Consider discontinuing ipilimumab 
if skin irAE does not resolve to 
Grade 1 or less. 
Grade 3 or 4 
Withhold, consult 
dermatology to determine 
appropriateness of resuming 
Treat with topical emollients, 
oral antihistamines, and 
medium- to high-potency 
topical corticosteroids. 
Initiate IV methylprednisolone 
(or equivalent) at 1−2 mg/kg, 
tapering over at least four 
weeks.  
Pneumonitis 
Grade 2 
Withhold 
Administer corticosteroids 
(initial dose of 1–2 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor subjects for signs and 
symptoms of pneumonitis. 
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging.  
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently discontinue 


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Immune-related 
Adverse Event 
Toxicity Grade 
or Conditions 
(CTCAE v5.0) 
Action Taken with 
Ipilimumab 
irAE Management with 
Corticosteroids and Other 
Therapies 
Monitoring and Follow-up 
Add prophylactic antibiotics 
for opportunistic infections 
Diarrhea / Colitis 
Grade 2 
Withhold until symptoms 
recover to Grade 1; can 
consider permanently 
discontinuing 
Administer corticosteroids 
(initial dose of 1–2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Subjects with diarrhea/colitis 
should be advised to drink 
liberal quantities of clear fluids.  
If sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Monitor subjects for signs and 
symptoms of enterocolitis (i.e., 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation (i.e., 
peritoneal signs and ileus). 
Subjects with Grade ≥ 2 diarrhea 
suspecting colitis should consider 
GI consultation and performing 
endoscopy to rule out colitis.  
Grade 3 or 4 
Permanently discontinue 
AST / ALT 
elevation or 
Increased bilirubin 
Grade 2 
Withhold 
Administer corticosteroids 
(initial dose of 0.5–1 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returns to 
baseline level or is stable) 
Grade 3 or 4 
Permanently discontinue 
Administer corticosteroids 
(initial dose of 1–2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withhold until glucose 
control obtained with 
reduction to no greater than 
Grade 1 toxicity 
Initiate insulin replacement 
therapy for subjects with 
T1DM. 
Administer antihyperglycemic 
in subjects with hyperglycemia.  
Monitor subjects for hyperglycemia 
or other signs and symptoms of 
diabetes 


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Immune-related 
Adverse Event 
Toxicity Grade 
or Conditions 
(CTCAE v5.0) 
Action Taken with 
Ipilimumab 
irAE Management with 
Corticosteroids and Other 
Therapies 
Monitoring and Follow-up 
Hypophysitis 
Grade 2 
Consider holding until 
stabilized on replacement 
hormones 
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Consider holding until 
stabilized on replacement 
hormones or permanently 
discontinuea 
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
Monitor for signs and symptoms of 
thyroid disorders 
Grade 3 or 4 
Consider holding until 
symptoms return to baseline 
or permanently discontinuea 
Hypothyroidism 
Grade 2−4 
Continue 
Initiate thyroid replacement 
hormones (e.g., levothyroxine 
or liothyroinine) per standard 
of care 
Monitor for signs and symptoms of 
thyroid disorders 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1–2 mg/kg or 
equivalent) followed by taper 
Monitor changes of renal function 
Grade 3 or 4 
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
Withhold, consider 
discontinuation if Grade 2 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinue 


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Immune-related 
Adverse Event 
Toxicity Grade 
or Conditions 
(CTCAE v5.0) 
Action Taken with 
Ipilimumab 
irAE Management with 
Corticosteroids and Other 
Therapies 
Monitoring and Follow-up 
All other immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
 
 
Grade 3 
Withhold or discontinue 
based on the type of event.  
Events that require 
discontinuation include but 
are not limited to:  
Guillain-Barre Syndrome, 
encephalitis 
Based on type and severity of 
AE administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 4 or 
recurrent Grade 
3 
Permanently discontinue 
 
 
NOTE:  For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of ipilimumab is required, ipilimumab may be resumed when the AE 
improves to Grade ≤ 2 and is controlled with hormonal replacement therapy or metabolic control is achieved (in the case of T1DM). 
AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTCAE = Common Terminology Criteria for Adverse Events:  
GI = gastrointestinal, irAE = immune-related adverse event, IV = intravenous, T1DM = Type 1 diabetes mellitus. 
a 
Withholding or permanently discontinuing ipilimumab is at the discretion of the investigator or treating physician. 
 




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permitted as needed. Subjects will take FLX475 once daily.  Each 3-week treatment period is 
considered to be 1 treatment cycle, based on administration of ipilimumab.   
The dose of ipilimumab used in this study, 3 mg/kg mg as an IV infusion Q3W for a 
maximum of 4 doses, is the approved dosage in unresectable or metastatic melanoma. 
Additional dosage regimens of 10 mg/kg and 1 mg/kg are also approved in other clinical 
settings. 
10.8 
Selection of Dose and Timing for Each Subject 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.  Fasting is not required for FLX475 administration. 
FLX475 tablets are to be taken with water orally once a day at approximately the same time 
each day in every 3-week cycle (21 days) from Cycle 1 Day 1 onward.   
Ipilimumab will be administered at a dose of 3 mg/kg as a 30- or 90-minute IV infusion (per 
institutional protocol), Q3W, on Day 1 of each 3-week (21-day) cycle for cycles 1−4, 
approximately 1 hour after the FLX475 dose and after the 1-hour post-FLX475 dose 
assessments have been completed. 
Dose modifications may be acceptable for toxicity but should be implemented at the 
investigator’s discretion in consultation with the Sponsor’s medical monitor after considering 
the subject’s condition and the clinical benefit to the subject of continuing treatment at the 
current dose. 
See Section 10.5 for details pertaining to the guidelines for dose modifications in this study. 
10.9 
Blinding 
The study will not be blinded to the investigator or the subject.  However, any independent 
radiologists reading the tumor assessment images for response/progression, if used, will be 
blinded per standard procedures. 
10.10 
Prior and Concomitant Therapy 
10.10.1 
Recording of Prior and Concomitant Treatments and Procedures 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medications taken by the subject 
within 30 days before the first dose of study treatment.  The dates and doses of the most 
recent CPI administered (e.g. anti-PD-1 or anti-PD-L1 therapy) prior to study entry should be 
recorded even if beyond 30 days before the first dose of study treatment.  Prior antibiotic 
usage (type, dose, and duration) for up to 6 months prior to study entry should also be 
recorded, if the information is readily available. 
All prior medications (including over-the-counter medications) administered within 30 days 
before the first dose of study treatment and any concomitant therapy administered to the 




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receive study treatment requires the mutual agreement of the investigator, the Sponsor, and 
the subject. 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Investigational agents other than ipilimumab or FLX475 
• Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary non-target lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of study treatment and during 
participation in the study.  Examples of live vaccines include, but are not limited to:  
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid 
vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed.   
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have an immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.   
 
Note: Inhaled steroids are allowed for management of asthma or seasonal allergies.  The use 
of prophylactic corticosteroids to prevent allergic reactions (e.g., IV contrast dye or 
transfusions) is permitted.   
Subjects who, in the investigator’s judgment, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  If a subject receives 
additional anticancer therapies, this will be judged to represent evidence of PD, and study 
treatment will be discontinued.  These subjects should complete all End-of-Treatment 
assessments and continue to be followed for survival in the Follow-up Phase unless they 
withdraw consent or are lost to follow-up. 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.   
All concomitant medication will be recorded on the eCRF, including all prescription, over-
the-counter products, herbal supplements, and IV medications and fluids.  If changes occur 
during the study period, documentation of drug dosage, frequency, route, and date should 
also be included on the eCRF. 


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Concomitant medications administered up to 90 days after the final dose of study treatment 
(or 30 days following cessation of study treatment if the subject initiates new anticancer 
therapy, whichever occurs first) should be recorded for SAEs and events of clinical interest 
(ECIs) as defined in Section 11.5.2. 
10.10.5 
Rescue Medication and Supportive Care 
Subjects should receive appropriate supportive care measures for an AE as deemed necessary 
by the treating investigator.  Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are outlined along with the dose modification guidelines 
in Section 10.5.2.  Where appropriate, these guidelines include the use of oral or IV treatment 
with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Several courses of steroid tapering may be 
necessary, as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
an attempt should be made to rule out other causes, such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care.  The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
ipilimumab (or FLX475).  It may be necessary to perform conditional procedures such as 
bronchoscopy, endoscopy, or skin photography as part of the evaluation of the event. 
Note:  If, after evaluation, the event is determined to be not related to ipilimumab (or 
FLX475), the investigator does not need to follow the treatment guidance.   
10.11 
FLX475 Treatment Compliance 
FLX475 tablets will be self-administered by participating study subjects, except on study 
visit days when FLX475 should only be administered by clinic staff after pre-dose 
procedures and assessments have been completed.  Subjects will be provided with dosing 
instructions at the start of their participation in the study and at the time of any dosing 
modifications (e.g., dose reduction due to AE), and will be encouraged by study site 
personnel to take the study medication according to the instructions for the duration of the 
study.  A diary card will be provided for subjects to record their adherence to the oral 
medication, which will be reviewed by qualified site personnel during study visits.  Subjects 
will be instructed to bring the assigned bottles of study medication to the site staff at each 
study visit, whether empty or not.  At the completion of each treatment cycle and at other 
times when the study drug dispensed might be returned (e.g., in the case of a dose reduction), 
the returned study medication will be checked for any unused study drug, and a tablet count 
will be performed for any remaining study medication.  This information will be recorded in 
the appropriate eCRF for each treatment cycle.  
FLX475 plasma concentration measurements over the course of the study may also be used 
to assess subject compliance.  Any events of non-compliance to the protocol will be 
documented in the study records. 


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10.12 
Drug Accountability 
FLX475 will be self-administered in this study.  A diary card will be provided to each subject 
to record all dose administration information at home.  On Day 1 of each cycle, FLX475 will 
be self-administered in the clinic, after a new supply of study treatment has been dispensed 
for that cycle, for drug accountability purposes.   
The disposition of all FLX475 supplies should be documented from the time of receipt at the 
site through subject dispensing and return.  The investigator and the study staff (or if 
regionally required, the head of the medical institution or the designated pharmacist) will be 
responsible for the accountability of all FLX475 (dispensing, inventory, and record keeping) 
following the Sponsor’s instructions and adherence to GCP guidelines as well as local or 
regional requirements. 
[As ipilimumab will not be provided by the Sponsor, but instead will come from local 
pharmacy supplies, local site staff should track the supplies of ipilimumab administered as 
part of study treatment in the event an issue or adverse event arises in a subject during the 
course of the study that requires an investigation and/or safety or regulatory reporting. At 
minimum, pharmacy logs should contain the following information: subject ID, date vial(s) 
administered, vial number, vial batch number, and expiration date.] 
Under no circumstances will the investigator allow the study treatments provided by the 
Sponsor (i.e., FLX475) to be used other than as directed by this protocol.  Study drug will not 
be dispensed to any individual who is not enrolled in the study.   
The site must maintain an accurate and timely record of the following:  receipt of FLX475, 
dispensing of FLX475 to the subject, collection and reconciliation of unused FLX475 that are 
either returned by the subjects or shipped to site but not dispensed to subjects, and return of 
reconciled FLX475 to the Sponsor or (where applicable) destruction of reconciled study 
treatments at the site.  This includes but may not be limited to: (a) documentation of receipt 
of FLX475, (b) FLX475 dispensing/return reconciliation log, (c) FLX475 accountability log, 
(d) all shipping service receipts, (e) documentation of returns to the Sponsor, and (f) 
certificates of destruction for any destruction of FLX475 that occurs at the site.  All forms 
will be provided by the Sponsor or designee.  Any comparable forms that the site wishes to 
use must be approved by the Sponsor. 
The study drug and inventory records must be made available, upon request, for inspection 
by a designated representative of the Sponsor or a representative of a health authority (e.g., 
FDA, Medicines and Healthcare products Regulatory Agency).  As applicable, all unused 
FLX475 and empty and partially empty containers from used FLX475 supplies are to be 
returned to the investigator (or if regionally required, the head of the medical institution or 
the designated pharmacist) by the subject and, together with unused study treatments that 
were shipped to the site but not dispensed to subjects, are to be destroyed on-site during the 
study and at the conclusion of the study, unless the site cannot destroy on-site and requests to 
ship the returned and unused study treatments to the Sponsor’s designated depot.  Site 
destruction Standard Operating Procedures (SOPs) must be reviewed and approved by 
Sponsor to ensure proper destruction will occur.  Upon completion of drug accountability and 


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reconciliation procedures by the site’s personnel and documentation procedures by the 
Sponsor’s personnel, study treatments that are to be returned to the Sponsor’s designated 
central or local depot(s) must be boxed, sealed, and shipped back to the central or local 
depot(s) following all local regulatory requirements.  In some regions, FLX475 may be 
removed from the site and hand delivered to the central or local depot by Sponsor 
representatives.  Where FLX475 supplies are approved for destruction at the site, destruction 
will occur following the site’s standard procedures and certificates of destruction or 
equivalent documentation of destruction will be provided to the Sponsor. 
Drug accountability will be reviewed by Sponsor representatives during site visits and at the 
completion of the study. 
Refer to Section 14.7 of the protocol for further details pertaining to the handling of study 
drug.   


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11 
STUDY PROCEDURES AND ASSESSMENTS 
Complete information pertaining to all procedures and evaluations is provided in the 
Schedule of Procedures/Assessments in Table 6. 
11.1 
Screening Assessments 
The study center should confirm enrollment availability and obtain approval for screening 
from the Sponsor prior to obtaining informed consent and initiation of screening.  The 
approval to screen is requested by sending the appropriate screening approval form to the 
Sponsor or designee.  The Sponsor or designee will approve the subject for screening and a 
unique subject identification number will be assigned and documented on the form.  This 
number is used to identify the subject throughout the clinical study and must appear on all 
study related documentation and communications, including the enrollment authorization 
form used to approve enrollment of the subject.  Subjects who fail to meet screening criteria 
may only be rescreened upon prior approval from the Sponsor. 
The purpose of the Screening Period is to ensure that each subject meets all the specified 
inclusion (Section 9.1.1) and none of the exclusion criteria (Section 9.1.2).  Screening will 
occur within 21 days before start of study treatment.  Before performing any procedures or 
assessments, the nature of the study and the potential risks associated with the trial will be 
explained to all subjects and written informed consent will be obtained from them (or their 
legal guardian).  Once signed informed consent is obtained, the following procedures and 
evaluations will be performed/recorded: 
• Demographics/Baseline characteristics 
• Physical examination, including height, weight, and vital sign measurements 
• 12-Lead ECG (triplicate) 
• Blood, urine, and tissue samples for laboratory tests and tumor biomarkers, as indicated 
on Table 6 
• Serum pregnancy test (female subjects who are premenopausal or amenorrheic for 
< 12 months) 
• Tumor assessment (data collected before obtaining informed consent may be used if the 
data was collected within 28 days before start of study treatment) 
• Adverse events 
• Prior and concomitant drugs/therapy 
 
Demography information will include date of birth (or age), sex, and race/ethnicity.   


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Baseline characteristics will include ECOG PS (Appendix 2), NYHA cardiac disease 
classification (Appendix 3), and cancer staging at the time of initial diagnosis.  The subjects’ 
medical and surgical histories, including those for their underlying cancer, will be obtained 
during the Screening Phase, along with a record of prior and concomitant medications. 
Physical examinations (comprehensive or symptom-directed) will be performed as specified 
in the Schedule of Procedures/Assessments (Table 6).  The physical examination should 
include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and 
lungs), abdomen, limbs, skin, and a complete neurological examination.  Documentation of 
the physical examination will be included in the source documentation at the investigational 
site.  Significant findings present before the signing of informed consent will be recorded on 
the appropriate eCRF.  Changes from Screening in physical examination findings that meet 
the definition of an AE will be recorded on the Adverse Events eCRF. 
Subjects must have measurable disease according to RECIST 1.1 (Appendix 4) as defined in 
Eligibility Criteria (Section 9).  Subjects must also fulfill the medical and physical 
characteristics identified in the inclusion criteria and not otherwise meet any of the exclusion 
criteria.  Subjects who successfully complete the Screening process will be registered for the 
study and start study treatment within 21 days of initial screening.  If judged to be ineligible, 
the reason(s) for screening failure will be described in the "Subject Screening Log" to the 
extent possible.   
See the Schedule of Procedures/Assessments (Table 6) for a complete list of Screening 
assessments. 
Subjects may be eligible to enroll once all screening assessments and procedures are 
completed and results indicate that all eligibility criteria are met.  
Enrollment (i.e. registration) of a subject into the study will be performed according to the 
following procedure:  
• To initiate enrollment of a subject, the study center will email a completed Subject 
Enrollment Approval Form to the Sponsor or designee.  
• The Sponsor or designee will review the subject’s information and notify the site of any 
additional information required or enrollment approval.  Within one business day of 
receipt from the study center, the study Sponsor will complete the Subject Eligibility 
Form (Enrollment Authorization Form) to approve enrollment. 
• The Sponsor will return the approved Subject Eligibility Form (Enrollment Authorization 
Form) to the study center via fax/email.  Subjects are only considered enrolled once the 
Sponsor’s medical monitor or designee approves the subject enrollment.  The enrollment 
date will be the date of start of study treatment. 
• The investigator or designee is responsible for ensuring that the confirmation of 
enrollment approval from the Sponsor or its designee has been received prior to 
administration of study treatment on Day 1. 


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11.2 
Baseline Assessments 
The following assessments will be performed on Cycle 1 Day 1 prior to the start of study 
treatment: 
• Physical examination and vital sign measurements 
• ECOG performance status 
• 12-Lead ECG 
• Blood and urine samples for laboratory tests, PK assessments, and tumor biomarkers, as 
indicated on Table 6 
• Pregnancy test (female subjects who are premenopausal or amenorrheic for < 12 months) 
• Adverse events 
• Concomitant drugs/therapy 
 
11.3 
Efficacy Assessments 
11.3.1 
Tumor Imaging and Disease Assessment 
RECIST 1.1 will be used as the primary measure for assessment of tumor response and 
progression, date of PD, and as a basis for all protocol guidelines related to disease status 
(e.g., discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant, to enable a broader sampling of tumor burden.   
Investigator-determined response assessments will be performed at each assessment time 
point and recorded on the eCRF.  Tumor assessments for progression may also be performed 
by the investigator using iRECIST; this assessment will be performed following treatment 
discontinuation (Appendix 5). 
It is strongly preferred that tumor imaging be acquired by CT.  For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice.  The same imaging modality (and ideally the same 
scanner) and image-acquisition protocol (including use or nonuse of contrast) should be used 
consistently for each subject across all time points throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging.  Note: for the 
purposes of assessing tumor imaging, the term “investigator” refers to the local investigator 
at the site or the radiological reviewer located at the site or at an offsite facility. 
• In general, imaging should include the chest (CT), and abdomen and pelvis (CT or MRI) 
• Imaging should include other known or suspected sites of disease 


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• If brain imaging is indicated, MRI is strongly preferred.  However, CT imaging will be 
acceptable if MRI is medically contraindicated.  The brain scan (MRI pre- and post-
gadolinium or CT with contrast) will be performed at Screening and as clinically 
indicated thereafter, and within a target of 1 week but no more than 2 weeks following 
achievement of a CR.  For subjects with a history of protocol-eligible, treated brain 
metastases, a brain scan will be required at Screening (for all such subjects) and at all 
tumor assessment time points (for subjects treated for brain metastases within 6 months 
prior to C1D1). 
• Clinically assessed/visible lesions (including at minimum those being used as target 
lesions for disease assessment) should be followed by clinical caliper assessment and 
digital medical photography using standard equipment (including ruler) and light settings. 
The timing of cutaneous lesion photographs should follow the same schedule as imaging 
scans. Images should be archived per local site practice as part of the subject’s medical 
record. 
 
11.3.1.1 
Timing of Tumor Imaging 
Screening 
Initial tumor imaging at Screening must be performed within 21 days prior to Cycle 1, Day 1.  
The investigator must review screening images to confirm that the subject has measurable 
disease per RECIST 1.1.  Historical CT or MRI scans performed within 28 days before the 
start of study treatment, but before the signing of informed consent, may be used as screening 
scans, provided they meet minimum standards for RECIST assessment.   
Confirmation of measurable disease based on RECIST 1.1 using local assessment at 
Screening will be used to determine subject eligibility.   
During Treatment 
The first imaging assessment during study treatment should be performed 9 weeks (±7 days) 
from Cycle 1, Day 1.  Subsequent tumor imaging should be performed every 9 weeks 
(±7 days) or more frequently if clinically indicated for the first year of treatment.  After 
1 year, subjects who continue to receive study treatment will have imaging performed every 
12 weeks (±7 days) .  The timing of tumor imaging should follow calendar days and should 
not be adjusted for delays in cycle starts.  Tumor imaging should continue to be performed 
until PD is identified by the investigator (unless the investigator elects to continue treatment 
and follow iRECIST), the start of new anticancer treatment, withdrawal of consent, loss to 
follow-up, death, 2 years of study treatment, or termination of the study by the Sponsor, 
whichever occurs first.   
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed.  Subjects will then return to regularly scheduled imaging, starting with 
the next scheduled imaging time point.  Subjects who receive additional imaging for 


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confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Per iRECIST, investigator-assessed PD in the clinically stable subjects should be confirmed 
by the investigator 4 to 8 weeks after the first radiologic evidence of PD.  A subject with 
unconfirmed PD may continue to receive study treatment at the discretion of the investigator 
until progression is confirmed by the investigator, provided the subject has met the 
conditions detailed in Section 11.3.1.2.  Subjects who have confirmatory imaging do not 
need to undergo the next scheduled tumor imaging assessment if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable.  Subjects who have confirmed PD by iRECIST, as assessed by the investigator, will 
discontinue study treatment.  Exceptions are detailed in Section 11.3.1.2. 
End of Treatment and Follow-up Tumor Imaging 
Subjects who discontinue study treatment for a reason other than PD, tumor imaging should 
be performed at the time of treatment discontinuation (±4-week window).  If previous 
imaging was performed within 4 weeks prior to the date of discontinuation, then imaging at 
treatment discontinuation is not mandatory.  For subjects who discontinue study treatment 
due to documented PD, this is the final required tumor imaging if the investigator elects not 
to implement iRECIST. 
For subjects who discontinue study treatment without documented PD, every effort should be 
made to continue monitoring disease status during the Follow-up Phase by tumor imaging 
using the same imaging schedule used during the Treatment Phase (i.e., every 9 weeks 
[±1 week] for the first year and every 12 weeks [±1 week] thereafter) until the start of a new 
anticancer treatment, PD, pregnancy, death, withdrawal of consent, loss to follow-up, or 
termination of the study, whichever occurs first.   
11.3.1.2 
Disease Assessment by iRECIST 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs.  iRECIST will be used by the investigator to assess solid 
tumor response and progression, and make treatment decisions.  When clinically stable, 
subjects should not be discontinued until progression is confirmed by the investigator, in 
conjunction with the local radiologist, according to the rules outlined in Appendix 5.  This 
allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response.  This data will 
be captured in the clinical database. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  


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• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care 
 
Any subject deemed clinically unstable should discontinue study treatment at first radiologic 
evidence of PD as assessed by the investigator, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST. 
If the investigator decides to continue treatment, the subject may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per investigator assessment.   
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
subject continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, subjects will be discontinued from study treatment. 
If a subject has confirmed radiographic progression (iCPD) as defined in Appendix 5, study 
treatment should be discontinued; however, if the subject is achieving a clinically meaningful 
benefit, an exception to continue study treatment may be considered following consultation 
with the Sponsor.  In this case, if study treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in Section 11.3.1.1.  
A description of the adaptations and iRECIST process is provided in Appendix 5, with 
additional details in the iRECIST publication (Seymour, et al., 2017).  A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 7 in Appendix 5. 
11.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments 
11.4.1 
Pharmacokinetic Assessments 
Plasma concentrations of FLX475 will be measured.  
Blood samples for PK analysis will be collected as specified in the Schedule of 
Procedures/Assessments in Table 6.  In addition, blood samples may be drawn at the 
investigator’s discretion, e.g., during the occurrence of a clinically significant AE potentially 
related to study treatment.  Study sites must have appropriately trained staff and adequate 
equipment for procuring and processing specimens.  Instructions for the collection, handling, 
and shipping procedures of PK samples will be provided in the laboratory manual.   
See Sections 12.1.2.2 and 12.1.7 for more details. 
11.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Blood samples for analysis of whole blood or serum biomarkers will be collected as specified 
in Appendix 6 and in the Schedule of Procedures/Assessments in Table 6.  Blood samples 


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may also be drawn at the investigator’s discretion, e.g., during the occurrence of a clinically 
significant AE potentially related to study treatment. 
Biomarker discovery and/or validation may be performed to identify blood or tumor 
biomarkers that may be useful to predict subject response to study treatment, evaluation of 
response-related and/or safety-related outcomes as well as for potential use in diagnostic 
development (if optional subject consent for sample banking is provided).  Blood samples 
may undergo enzyme-linked immunosorbent assay-based analyses or multiplex bead-based 
immunoassay, and/or DNA/RNA analysis, but not limited to, in an effort to identify 
biomarkers.  In addition, biomarkers identified in other clinical studies of study treatment 
may also be assessed in samples collected from subjects enrolled in this study.  The decision 
to perform biomarker analysis may be based on the clinical outcome of this study and/or the 
signals observed in other clinical studies or other information available at that time. 
Pharmacodynamic and Pharmacokinetic/Pharmacodynamic: 
Immunophenotyping:  Blood samples will be obtained for T/B/NK and T cell panels as 
specified in the Schedule of Procedures/Assessments in Table 6. 
Plasma concentration data for FLX475 from the study may be used to explore 
PK/pharmacodynamic relationships for effects of FLX475 in combination with ipilimumab 
on objective response rate (ORR), other efficacy-related parameters including progression-
free survival (PFS) and OS, and AEs/dose reduction.  Exploratory/graphical analyses will be 
conducted for PK/pharmacodynamic evaluations and, if possible, may be followed by model-
based analyses. 
Any pharmacodynamic analyses may be detailed in a separate analysis plan and the results 
provided in a stand-alone report. 
Pharmacogenetic/Pharmacogenomic (PG) Assessments 
All subjects enrolled in the study will provide a core biopsy (minimum of 3 cores) or 
excisional (or skin punch) biopsy of a tumor lesion prior to starting treatment and on Cycle 2 
Day 8 (±7 days) (minimum of 3 cores).  Optionally, additional biopsies may be obtained at 
clinically significant time points (e.g., early disease response or upon PD) with subject 
consent.   
Tissue from the biopsy of tumor lesions will be collected for potential assessment of 
mutations and other genetic alterations or genes or proteins that may be important in the 
development and progression of cancer as well as in response to study treatment for potential 
use in diagnostic development.  Genetic alterations in selected molecular targets may be 
explored based on their potential involvement in tumor biology.  Immune cell profiling and 
molecular targets and factors involved in immune checkpoint axis, such as PD-1 or PD-L1 
levels, markers of Treg/Th1/Th2 phenotype, and inflammatory status, may also be explored.  
Appropriate technology/methodologies will be used based on the amount of tumor tissue 
available. 


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A blood sample may be collected for potential pharmacogenomic analysis from all enrolled 
subjects (in accordance with regional or local laws).  Variation in FLX475 exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlating 
single-nucleotide polymorphisms with PK, safety, or pharmacodynamic data. 
Any data obtained will be used for research purposes to assist in developing safer and more 
effective treatments and will not be used to change the diagnosis of the subject or alter the 
therapy of the subject.  The DNA will not be used to determine or predict risks for diseases 
that an individual subject does not currently have.  Any sample or derivatives (DNA, RNA, 
and protein) may be stored for up to 15 years (if optional subject consent for sample banking 
is provided) to assist in any research scientific questions related to study treatment, cancer 
and/or for potential diagnostic development. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual. 
11.5 
Safety Assessments 
Safety assessments will consist of monitoring and recording of all AEs and SAEs using 
CTCAE v5.0 (Appendix 1), regular laboratory evaluation for hematology, blood chemistry, 
and urine values; regular performance of physical examinations and vital sign measurements; 
and periodic ECGs. 
11.5.1 
Adverse Events and Events of Clinical Interest 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  For this study, the study treatments are FLX475 and 
ipilimumab.  An AE does not necessarily have a causal relationship with the medicinal 
product.  Progression of the cancer under study is not considered an AE. 
Adverse events, SAEs, and other reportable safety events must be reported to the investigator 
by the subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally 
authorized representative). 
The criteria for identifying AEs in this study are: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE). 
• Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
• Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (e.g., ECG or radiograph) that results in symptoms, a change in treatment, or 
discontinuation of study treatment. 


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• Recurrence of an intermittent medical condition (e.g., headache) not present pretreatment 
(Baseline). 
• An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study treatment, or 
withholding of study treatment, whether prescribed in the protocol or not. 
 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE, as well as other reportable safety events (e.g., pregnancy).  Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. 
All AEs observed during the study will be reported on the appropriate eCRF. 
All AEs, SAEs, and other reportable safety events, regardless of relationship to study 
treatment or procedure, that occur after the consent form is signed but before treatment has 
started, must be reported by the investigator if the event caused the subject to be excluded 
from the study, or is the result of a protocol-specified intervention, including but not limited 
to, washout or discontinuation of usual therapy, diet, or a procedure.     
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event eCRF.   
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is ≥ 450 ms and 
there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such. 
All AEs or events of clinical interest (ECIs) that occur from the start of treatment through 
30 days following cessation of study treatment must be reported on the eCRF by the 
investigator.  See Section 11.5.2 for further discussion of SAEs and ECIs. 
All AEs present at time of cessation of study treatment must be followed for 90 days after the 
subject’s final dose (or 30 days after final dose if the subject initiates new anticancer 
therapy), or until resolution, whichever comes first.  All SAEs must be followed to resolution 
or, if resolution is unlikely, to stabilization. 


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Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v5.0 (Appendix 1).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).   
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• Temporal relationship of the onset of the event to the initiation of the study treatment 
• The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• The presence of non-study, treatment-related factors that are known to be associated with 
the occurrence of the event 
 
Classification of Causality 
The relationship of each AE to the study treatment will be recorded on the eCRF in response 
to the following question: 
Is there a reasonable possibility that the study treatment caused the AE? 
Not Related 
A causal relationship between the study treatment and the AE is not a 
reasonable possibility. 
Possibly Related 
Has a chronological relationship with the time of study drug 
administration and/or represents a known reaction to study drug but 
probably the result of another factor; not clearly the result of an external 
factor. 
Probably Related Has a chronological relationship with the time of study drug 
administration and/or represents a known reaction to study drug but 
possibly the result of another factor; not clearly the result of another 
factor, disappears or decreases after discontinuation of the study drug. 
Definitely Related Has a chronological relationship with the time of study drug 
administration and/or represents a known reaction to study drug, not the 


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result of another factor, disappears or decreases after discontinuation of 
the study drug, and recurs on re-challenge (if restarted). 
11.5.2 
Serious Adverse Events, Events of Clinical Interest, and Events Associated 
with Special Situations 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (i.e., the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect (in the child of a subject who was exposed to 
the study treatment) 
 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.   
Events of clinical interest (ECIs) in this study, whether serious or not, include: 
1. An overdose of FLX475 or ipilimumab, as defined in Section 11.5.3, Overdose, that is 
not associated with clinical symptoms or abnormal laboratory results. 
2. QTcF interval ≥ 450 ms with a > 60 ms increase from baseline (defined as average QTcF 
value from C1D1 pre-dose ECGs) 
 
In addition to the above ECIs, events associated with special situations include pregnancy or 
exposure to study treatment through breastfeeding; AEs associated with study treatment 
overdose, misuse, abuse, or medication error.  Events associated with special situations and 
ECIs are to be captured using the SAE procedures but are to be considered as SAEs only if 
they meet one of the above criteria.  All AEs associated with special situations are to be 
reported on the eCRF whether or not they meet the criteria for SAEs.  Any occurrences of 
pregnancies and exposure during breastfeeding must be reported by the investigator from the 
start of treatment through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the subject initiates new anticancer therapy, 
whichever is earlier. 


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Serious AEs must be reported for 90 days after the subject’s final dose of study treatment, or 
for 30 days after the final dose of study treatment if the subject initiates new anticancer 
therapy, whichever is earlier.  Additionally, any SAE brought to the attention of an 
investigator at any time outside the time periods specified above must be reported 
immediately to the Sponsor if the event is considered to be drug-related.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care 
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study treatment administration) 
• Hospitalization for administration of study treatment or insertion of access for 
administration of study treatment 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
 
If possible, blood sample(s) for the measurement of FLX475 plasma concentration should be 
drawn at the first report of an SAE or a severe unexpected AE and at its resolution. 
11.5.3 
Overdose 
For this study, an overdose of FLX475 will be defined as any dose ≥ 2 times the indicated 
dose.  An overdose of ipilimumab will be defined as any dose of ≥ 3 times the planned dose.  
No specific information is available on the treatment of an overdose of FLX475 or 
ipilimumab.  In the event of an overdose, the subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
11.5.4 
Pregnancy, Contraception, and Breastfeeding 
FLX475 and ipilimumab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if FLX475 or ipilimumab has transient adverse effects on the composition of sperm.   
Subjects should be informed that taking the study drug(s) may involve unknown risks to the 
unborn baby if pregnancy were to occur during the study.  In order to participate in the study, 
subjects of childbearing potential must adhere to the contraception requirement (from the 
start of study treatment [or 14 days prior to the initiation of study treatment for oral 
contraception] throughout the study period up to 120 days after the final dose of study 
treatment).  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study.   


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If a female subject inadvertently becomes pregnant while receiving treatment with FLX475, 
ipilimumab or both, she must immediately discontinue study treatment.  If a female partner 
of a male subject inadvertently becomes pregnant while the subject is receiving treatment 
with FLX475, ipilimumab, or both, the investigator must be informed immediately.  The 
investigator will contact the subject at least monthly and document the status of the mother 
and pregnancy until the pregnancy has been completed or terminated (spontaneously or 
through induced abortion).  See Section 11.7.2 for reporting requirement. 
It is unknown whether FLX475 or ipilimumab is excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions of 
drugs in the nursing infant, females who are breastfeeding are not eligible for enrollment in 
this study. 
11.5.5 
Laboratory Measurements 
Clinical laboratory tests to be performed are summarized in Table 5.  Subjects should be in a 
seated or supine position during blood collection.  The Schedule of Procedures/Assessments 
(Table 6) shows the visits and time points at which blood and urine samples for clinical 
laboratory testing will be collected in the study.   
All laboratory tests during the study will analyzed locally on the day of collection unless 
otherwise instructed. 


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Table 5 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, MCV, MCH, platelets, RBC count, 
ANC, and WBC count with differential 
Coagulation 
PT, PTT or aPTT 
INR 
Chemistry 
 
 
Electrolytes 
Bicarbonate, calcium, chloride, magnesium, phosphorous, 
potassium, sodium 
 
Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, total bilirubin 
 
Renal function tests 
Blood urea nitrogen, creatinine 
 
Thyroid function tests 
Triiodothyronine (T3) or free triiodothyronine (FT3), free 
thyroxine (FT4), thyroid-stimulating hormone (TSH) 
 
Other 
Albumin, glucosea, lactate dehydrogenase, total protein, 
amylase, lipase 
Pregnancy test (serum or urine β-hCG)b 
Urinalysis 
Glucose, blood, ketones, pH, protein, specific gravity, 
bilirubin (microscopic UA with WBC, RBC, epithelial cells, 
bacteria, casts and crystals, only if necessary) 
See Schedule of Procedures/Assessments (Table 6) for timing of all laboratory tests. 
ANC = absolute neutrophil count, aPTT = activated partial thromboplastin time, β-hCG = Beta-human 
chorionic gonadotropin, INR = international normalized ratio, PT = prothrombin time, PTT = partial 
prothrombin time, RBC = red blood cell, UA = urinalysis, ULN = upper limit of normal, WBC = white blood 
cell. 
a 
For subjects with blood glucose >ULN at screening or clinically significant elevations on study 
(e.g. potentially considered an AE), a fasting (> 6 h, water only) blood glucose sample should be obtained 
within 24 hours or as feasible 
b 
Females of childbearing potential.   
 
Results from all hematology, clinical chemistry (including serum pregnancy test, as 
applicable), or urinalysis samples (including urine pregnancy test, as applicable) obtained 
prior to study treatment administration should be reviewed prior to administration/dispensing 
of study treatment at the beginning of Cycle 1, at the investigator’s discretion, and upon 
request of the Sponsor (e.g. due to borderline or abnormal values at screening). 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 11.5.1 and the eCRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event 
eCRF. 
11.5.6 
Vital Signs and Weight Measurements 
Vital sign measurements (i.e., systolic and diastolic blood pressure [BP] [mmHg], heart rate 
[beats per minute], respiratory rate [per minute], body temperature [in centigrade]), and 
weight (kg) will be obtained at the visits designated in the Schedule of 


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Procedures/Assessments (Table 6) by a validated method.  Blood pressure and pulse will be 
measured with the subject in the sitting position, after resting for 5 minutes.  All BP 
measurements should be performed on the same arm, preferably by the same person. 
Only 1 BP measurement is needed for subjects with systolic BP < 140 mmHg and diastolic 
BP < 90 mmHg.  If the subject’s initial BP measurement is elevated (systolic BP 
≥ 140 mmHg or diastolic BP ≥ 90 mmHg), the BP measurement should be repeated at least 
5 minutes later.  The mean value of 2 measurements at least 5 minutes apart is defined as 
1 BP assessment.  If the BP assessment (i.e., the mean of the 2 BP measurements obtained at 
least 5 minutes apart) is elevated (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg), a 
confirmatory assessment should be obtained at least 30 minutes later by performing 
2 measurements (at least 5 minutes apart) to yield a mean value.   
11.5.7 
Physical Examinations 
Physical examinations (including a neurologic examination) will be performed as designated 
in the Schedule of Procedures/Assessments (Table 6).  Documentation of the physical 
examination will be included in the source documentation at the investigational site.  Only 
changes from screening physical examination findings that meet the definition of an AE will 
be recorded on the Adverse Events eCRF.  A symptom-directed physical examination will be 
performed as clinically indicated. 
11.5.8 
Electrocardiograms 
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 6).  Complete, standardized, 12-lead ECG recordings that 
permit all 12 leads to be displayed on a single page with an accompanying lead II rhythm 
strip below the customary 3 x 4 lead format are to be used.  In addition to a rhythm strip, a 
minimum of 3 full complexes should be recorded from each lead simultaneously.  Data 
should be collected using digital machines and electronically archived.  Subjects must remain 
undisturbed in the supine position for a period of ≥ 10 minutes prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in Section 11.5.1 of this 
protocol and the eCRF Completion Guidelines.  In these instances, the AE corresponding to 
the ECG abnormality will be recorded on the Adverse Events eCRF. 
11.6 
Schedule of Procedures/Assessments 
Table 6 presents the schedule of procedures/assessments for the study. 




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Study Period/Cycle 
Screening 
Treatment 
Early 
Discon./ 
End of Study 
Treatment 
(ED/EOST)s 
Long-
Term 
Follow-
Upt 
Cycle 1 
Cycle 2 
Cycle 3-4 
Cycle 5+ 
Cycle Day 
 
1 
8 
15 
1 
8 
1 
1 
Study Day 
-21 to 0 
1 
8 
15 
22 
29 
43, 64 
85+ 
Pregnancy Test l 
X 
X 
 
 
X 
 
X 
X 
X 
 
FLX475 PK Samples m 
 
X 
 
 
X 
 
X 
X 
X 
 
Immunophenotyping n 
 
X 
X 
 
X 
 
X 
X 
X 
 
Serum Biomarkers o 
 
X 
X 
 
X 
 
X 
X 
X 
 
Whole Blood Biomarkers p 
X 
 
 
 
 
 
 
 
 
 
Disease Assessments 
Disease Classification 
X 
 
 
 
 
 
 
 
 
 
Tumor Imaging/Staging (CT/MRI 
Scan) q 
X 
 
 
 
 
 
X 
X 
 
 
Tumor Biopsy r 
X 
 
 
 
 
X 
 
 
 
 
Post-Therapy Long-Term Follow-Up 
 
 
 
 
 
 
 
 
 
X 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST aspartate 
aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic case report form; INR = international normalized ratio; LDH = lactose dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCV = mean corpuscular volume; MRI = magnetic resonance imaging; PD = pharmacodynamic; PK = pharmacokinetic; 
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; UA = urinalysis; WBC = white blood cell. 
Cycle 1, Day 1 visit must occur as scheduled. Other study visits may occur within a window of ±3 days. 
a 
The dose of FLX475 will be administered in the clinic after the specified pre-dose visit assessments and procedures are performed.  In addition, the dose of 
FLX475 should be administered in the clinic on Day 1 of each cycle only after a new supply of drug has been dispensed for that cycle, for drug 
accountability purposes.  A diary card will be provided to each subject for recording of all dose administration information. 
Ipilimumab will be administered at the designated dose (e.g.3 mg/kg IV) over 30 or 90 minutes (per institutional protocol) on Day 1 of Cycles 1−4.  
Ipilimumab infusion should occur at least 1 hour after the dose of FLX475 is administered in the clinic and after all 1-hour post-FLX475 dose procedures 
have occurred. 
b 
Dispensing of 3-week supply of FLX475 to the subject with instructions for self-administration at home and drug diary card. 
c 
Relevant medical history including current disease and prior treatment, including last prior therapy, best response to last prior therapy (PR, CR, SD, or PD) 
and either time on last therapy or duration of response. 
d 
Clinical evaluation will include assessment of ECOG performance status, physical examination (at screening, response assessments, and as clinically 
indicated), and measurement of height (screening only) and weight. 


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e 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be collected with the subject in a sitting position.  Vital signs will be assessed at 
Screening Visit, pre-dose and at 0.5, 1, 2, and 4 hours post-dose on Cycle 1, Day 1; pre-dose and 2 hours post-dose on Cycle 1, Days 8 and 15; pre-dose and 
at 0.5, 1, 2, and 4 hours post-dose on Cycle 2, Day 1.  Vital signs will also be assessed pre-dose on Day 1 of all subsequent cycles and at Early 
Discontinuation / End of Study Treatment (ED/EOST).  Acceptable windows for collection are as follows: pre-dose samples must be within 6 hours prior to 
dosing; 0.5 hour post-dose ±5 minutes; 1 hour post-dose ±15 minutes; 2 and, 4 hour post-dose ±30 minutes. 
f 
Triplicate ECGs with tracings ≥ 30 seconds apart must be collected in digital format on designated calibrated ECG equipment after at least 10 minutes of 
quiet rest in supine position.  Meals should not be served shortly before ECGs.  Triplicate ECGs should be collected at Screening Visit; -0.75, -0.5, 
and -0.25 hours pre-dose and 2 and 4 hours post-dose on Cycle 1, Day 1; pre-dose and 2 hours post-dose on Cycle 1, Day 8; pre-dose and 2 hours post-dose 
on Day 1 of Cycles 2-6; and at Early Discontinuation / End of Study Treatment (ED/EOST).  Acceptable windows for collection are as follows: general 
pre-dose ECGs must be within 2 hours prior to dosing; -0.75, -0.5, -0.25 hour pre-dose ±5 minutes; 2 and 4 hour post-dose ±30 minutes. 
g 
Serum Chemistry:  including sodium, potassium, chloride, total protein, bicarbonate, albumin, calcium, magnesium, phosphorous, glucose, BUN, creatinine, 
total bilirubin, ALP, LDH, AST, ALT, amylase and lipase.  Serum Chemistry to be collected at Screening Visit, pre-dose (within 24 hours prior to dosing) 
on study visit days, and at Early Discontinuation / End of Study Treatment (ED/EOST). 
h 
Complete Blood Count and Differential:  WBC, RBC, ANC, hemoglobin, hematocrit, MCV, MCH, platelets, and WBC differential.  CBC with differential 
to be performed at Screening Visit, pre-dose (within 24 hours prior to dosing) on study visit days, and at Early Discontinuation / End of Study Treatment 
(ED/EOST). 
i 
Coagulation Tests should be obtained at Screening Visit and pre-dose (within 24 hours prior to dosing) for Day 1 visits of Cycles 1-2 and at Early 
Discontinuation / End of Study Treatment (ED/EOST): PT, PTT or aPTT, and INR. 
j 
Thyroid function tests should be obtained at Screening Visit, pre-dose (within 24 hours prior to dosing) Day 1 of Cycle 1 and every odd-numbered cycle 
during study treatment, and at Early Discontinuation / End of Study Treatment (ED/EOST).  Thyroid panel should include (1) Triiodothyronine (T3) or Free 
Triiodothyronine (FT3), (2) Free Thyroxine (FT4), and (3) Thyroid Stimulating Hormone (TSH). 
k 
Urinalysis should be obtained at Screening Visit, pre-dose (within 24 hours prior to dosing) on Day 1 of each cycle, and at Early Discontinuation / End of 
Study Treatment (ED/EOST). It will include specific gravity, pH, blood, protein, glucose, ketones and bilirubin (microscopic UA with WBC, RBC, 
epithelial cells, bacteria, casts and crystals, only if necessary). 
l 
Serum pregnancy test only in women of childbearing potential during screening; urine or serum pregnancy test at all other time points.  Pregnancy testing 
will be performed at Screening Visit and on Day 1 of Cycles 1, 2, and of every even-numbered cycle thereafter (e.g., Cycle 4, 6, etc.). 
m 
FLX475 PK samples will be collected at the following time points: pre-dose and 2 and 4 hours post-dose on Cycle 1, Day 1; pre-dose on Day 1 of Cycles 
2-6; and at Early Discontinuation / End of Study Treatment (ED/EOST).  Samples may also be drawn at investigator discretion, e.g., during a clinically 
significant adverse event potentially related to study treatment.  Acceptable windows for sampling include within 30 minutes prior to dose for pre-dose 
samples and ±30 minutes for other post-dose samples.  PK samples should be obtained as close as possible both to protocol stipulated times and to 
concurrently scheduled ECGs. 
n 
Immunophenotyping:  Samples will be obtained for T/B/NK and T cell panels pre-dose on Cycle 1, Days 1 and 8; pre-dose on Day 1 of Cycle 2, Cycle 4, 
and every 4 cycles thereafter; and at Early Discontinuation / End of Study Treatment (ED/EOST).  Acceptable window for pre-dose collection is within 2 
hours prior to dosing. 
o 
Serum Biomarkers:  Samples will be collected pre-dose on Cycle 1, Day 1; pre-dose on Cycle 1, Day 8; pre-dose on Day 1 of even-numbered Cycles 2 and 
beyond; and at Early Discontinuation / End of Study Treatment (ED/EOST).  Acceptable windows for collection are as follows: pre-dose within 2 hours 


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prior to dosing.  Samples may also be drawn at investigator discretion, e.g., during a clinically significant adverse event potentially related to study 
treatment. 
p 
Whole Blood Biomarkers: Sample will be collected at Screening Visit 
q 
Tumor Imaging/Staging (CT/MRI Scan):  After baseline scan, response assessments will be performed 9 weeks (±1 week) from Cycle 1, Day 1, then every 
9 weeks (±1 week) for the first year, followed by every 12 weeks (±1 week) thereafter, and at any time per investigator’s discretion.  Confirmatory scans 
should also be obtained at least 4-6 weeks following initial documentation of objective response. 
r 
Tumor Biopsy:  Subjects enrolled on the clinical trial must be willing and able to provide tissue from a newly obtained core (minimum of 3 cores) or 
excisional (or skin punch) biopsy of a tumor lesion.  Subjects will undergo a core biopsy (minimum of 3 cores) or excisional (or skin punch) biopsy of a 
lesion prior to starting treatment (during Screening) and at Cycle 2 Day 8 (±7 days).  There will be an option to also obtain additional biopsies at clinically 
significant time points (e.g., early disease response or upon progression of disease) with subject consent.   
s 
All Early Discontinuation / End of Study Treatment (ED/EOST) assessments must be performed within 90 days following the subject’s last administration of 
study treatment and prior to initiation of any other treatment, whichever comes first.  After the final dose of study treatment, subjects should be followed for 
any drug-related AEs and/or ongoing SAEs for 90 days or until those events have resolved or become stable, whichever occurs later (or through 30 days 
following cessation of study treatment if the subject initiates new anticancer therapy, if that occurs earlier). 
t 
Data regarding poststudy anti-tumor therapy and survival will be collected from all subjects who receive ≥ 1 dose of FLX475 or ipilimumab.  Such 
information will be collected at ~3 to 6-month intervals as described in Section 8.2.3 of the protocol.  This long-term follow-up information will be gathered 
during routine clinic visits, other study site contact with the subjects, or via telephone or e-mail with the subjects/caregivers or referring physician offices.  
These data will be collected in the source documents (e.g., subject medical record) and transcribed into a specific eCRF. 


 
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11.6.1 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of advanced 
solid tumors.  The safety assessments to be performed in this study, including hematology 
analyses, blood chemistry tests, urine dipstick testing, and assessment of AEs, are standard 
evaluations to ensure subject safety. 
11.6.2 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue treatment or withdraw from the study at any time for any 
reason.  All subjects who withdraw are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 6). 
The investigator will promptly explain to the subject involved that study treatment and 
procedures will be discontinued for that subject, and appropriate medical treatment and other 
necessary measures will be provided.  Subjects who consent to follow-up will be monitored 
for disease progression and/or survival.  A subject who has ceased to return for visits will be 
followed up by mail, phone, or other means to gather information such as the reason for 
failure to return, the status of treatment compliance, the presence or absence of AEs, and 
clinical courses of signs and symptoms.  If the subject cannot be successfully contacted 
(minimum of two documented attempts at contact), then the subject will be deemed lost to 
follow-up. 
Study disposition information will be collected on the appropriate eCRF.  Subjects who 
withdraw early from the study will be discontinued for 1 of these primary reasons: AE(s), 
lost to follow-up, subject choice, progression of disease, withdrawal of consent, pregnancy, 
study terminated by Sponsor, or other.   
11.7 
Reporting of Adverse Events 
11.7.1 
Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on the appropriate eCRF as soon as possible but no later than 24 
hours from when the investigator becomes aware of the event.   
Serious AEs regardless of causality assessment must be collected through the last visit and 
for 90 days after the subject’s final dose, or 30 days following the final dose if the subject 
initiates new anticancer therapy, whichever is earlier.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  Any 
SAE judged by the investigator to be related to the study treatment or any protocol-required 
procedure should be reported to the Sponsor regardless of the length of time that has passed 
since study completion. 


 
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The detailed contact information for reporting of SAEs is provided in the investigator’s 
Study File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the subject 
and contact the appropriate study team member listed in the Investigator Study File. 
 
It is very important that the eCRF or SAE report form be filled out as completely as possible 
at the time of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the eCRF or follow-up SAE form (if SAE occurred before first 
dose). 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the Sponsor. 
For sites in the US, the investigator must notify his/her IRB/IEC of the occurrence of the 
SAE in writing, if required by his/her institution.  A copy of this communication must be 
forwarded to the Sponsor’s designee for filing in the Sponsor’s Trial Master File. 
11.7.2 
Reporting of Pregnancy and Breastfeeding 
Any female subject who becomes pregnant must be withdrawn from the study.   
Any pregnancy, whether a female subject becomes pregnant or a female partner of a male 
subject becomes pregnant,  in which the estimated date of conception is either before the last 
visit or within 120 days of the final dose of study treatment or 30 days following the final 
dose of study treatment if the subject initiates new anticancer therapy, whichever is earlier, 
must be reported.  Also, any exposure of an infant to study treatment through breastfeeding 
during study treatment or within 120 days of the final dose of study treatment, or 30 days 
following the final dose of study treatment if the subject initiates a new anticancer therapy, 
whichever is earlier, must be reported. 
Regardless of study treatment agent, if an adverse outcome of a pregnancy is suspected to be 
related to study treatment exposure, this should be reported regardless of the length of time 
that has passed since the exposure to study treatment.  A congenital anomaly, death during 
perinatal period, an induced abortion, or a spontaneous abortion are considered to be an SAE 
and should be reported in the same time frame and in the same format as all other SAEs (see 
Section 11.7.1, Reporting of Serious Adverse Events,). 


 
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Pregnancies or exposure of an infant to study treatment through breastfeeding must be 
reported by fax or email as soon as possible but no later than 24 hours from the time that the 
investigator becomes aware of the pregnancy.  The contact information for the reporting of 
pregnancies and exposure to study treatment through breastfeeding is provided in the 
investigator Study File.  The Pregnancy Report Form must be used for reporting.  All 
pregnancies must be followed to outcome.  The outcome of the pregnancy must be reported 
as soon as possible but no later than 24 hours from the time that the investigator becomes 
aware of the outcome, if the outcome is an SAE (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn). 
The investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. 
11.7.3 
Reporting of Events Associated with Special Situations 
11.7.3.1 
Reporting of Adverse Events Associated with Study Drug Overdose, 
Misuse, Abuse, or Medication Error 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of study treatment outside that specified by the protocol.   
Overdose, misuse, abuse, and medication error are defined as follows:  
• Overdose:  Accidental or intentional use of the study treatment in an amount higher than 
the protocol-defined dose 
• Misuse:  Intentional and inappropriate use of study treatment not in accordance with the 
protocol 
• Abuse:  Sporadic or persistent intentional excessive use of study treatment accompanied 
by harmful physical or psychological effects 
• Medication error:  Any unintentional event that causes or leads to inappropriate study 
treatment use or subject harm while the study treatment is in the control of site personnel 
or the subject.   
 
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Section 11.7.1 
(Reporting of Serious Adverse Events) even if the AEs do not meet serious criteria.  Abuse is 
always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF. 


 
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Note:  Overdose for ipilimumab is defined as a dose > 3 times assigned dose.  Overdose 
for FLX475 is defined as a dose > 2 times the assigned dose. 
11.7.4 
Expedited Reporting 
The Sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (i.e., within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above. 
11.7.5 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the Sponsor or designee to regulatory authorities in 
compliance with local and regional law and established guidance.  The format of these 
reports will be dictated by the local and regional requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
SUSARs will be reported, as required, to the competent authorities of all involved European 
member states. 
11.8 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
11.9 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines.  Site audits may be made periodically by the Sponsor’s or designee’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study. 
11.9.1 
Data Collection 
Data required by the protocol will be collected on eCRFs via a validated electronic data 
capture system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the Sponsor on each study subject. 


 
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Data collection on the eCRF must follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.  The investigator or designee as identified on FDA 
Form 1572 must sign the completed eCRF to attest to its accuracy, authenticity, and 
completeness. 
Completed eCRFs are the sole property of RAPT Therapeutics and should not be made 
available in any form to third parties without written permission from RAPT Therapeutics, 
except for authorized representatives of RAPT Therapeutics or appropriate regulatory 
authorities. 
11.9.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both eCRF and external data (e.g., laboratory data), will be entered into a clinical 
system. 


 
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12 
STATISTICAL METHODS 
12.1 
General Statistical Considerations 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS® software.  Descriptive statistics will be used to summarize data from 
this study, including mean, standard deviation, median, minimum, and maximum for 
continuous variables and frequency distributions and percentages for categorical variables.  
The specifics for these outputs will be described in detail within the Statistical Analysis Plan 
(SAP), which will be finalized before database lock.  
The last observation prior to the first dose of study medication will be used as the baseline 
value for calculating post-administration changes from baseline.  All data obtained on the 
eCRF will be presented in by-subject data listings.  
Confidence intervals will be at the 95% confidence level unless stated otherwise. 
Statistical analyses will be performed using SAS® software or other validated statistical 
software as required.  Details of the statistical analyses will be included in a separate 
statistical analysis plan (SAP), which will be finalized before the database lock. 
12.1.1 
Rationale for Sample Size  
The sample size of 20 subjects is considered adequate on clinical grounds to judge the safety 
of the combination therapy and obtain an initial estimate of its clinical efficacy. 
The primary efficacy endpoint will be the overall response rate (ORR). The ORR for the 
combination therapy is hypothesized to exceed the value observed with ipilimumab 
monotherapy (10−15%, Long et al., 2017). A decision to officially expand enrollment 
beyond the planned approximately 20 subjects will depend on the number of responders in 
the first 20 evaluable subjects and will require a protocol amendment. To be considered 
evaluable, subjects must meet criteria for the Efficacy Evaluable population, be evaluable for 
tumor response as per RECIST v1.1 at 9 weeks, and have no major protocol deviations. 
Evaluability for tumor response will be based on the following: 
• Subjects who remain on study until the first evaluation (at 9 weeks) and have a tumor 
assessment performed. 
• Subjects who withdraw from the study due to disease progression before the first 
evaluation (at 9 weeks) will be considered as subjects with early progression 
• Subjects who die from malignant disease before the first evaluation (at 9 weeks) will be 
considered as subjects with early death 


 
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• Subjects with measurable disease, for whom all baseline target lesions have been 
assessed at least once after 9 weeks, with the same method of measurement used at 
baseline. 
• Subjects with only non-measurable disease, for whom non-target lesions have been 
assessed at least once after 9 weeks. 
 
12.1.2 
Statistical and Analytical Plans 
The statistical analyses of the primary analysis of the study data are described in this section. 
Further details of the analytical plan will be provided in the SAP, which will be finalized 
before database lock. 
Based on the FAS, information regarding study treatment administration, study treatment 
compliance, safety variables, and poststudy therapies will be described and summarized. 
12.1.2.1 
Study Endpoints 
12.1.2.1.1 
Safety Endpoints 
The primary safety endpoint of the study is safety and tolerability by the determination of 
AEs, including DLTs.  The following safety parameters will be characterized and 
summarized:  
• Treatment-emergent adverse events (TEAEs) and SAEs together with all other safety 
parameters   
• Number (%) of subjects who discontinue treatment due to TEAEs 
• Time to treatment failure due to toxicity, defined as the time from the date of start of 
treatment to the date that a subject discontinues study treatment due to TEAEs  
• Dose-limiting toxicity (defined in Section 10.4) 
• Laboratory abnormalities 
• Vital sign abnormalities 
• Adverse ECG findings 
 
12.1.2.1.2 
Efficacy Endpoints 
The primary efficacy endpoint of the study is objective response rate (ORR), defined as the 
proportion of subjects who have best overall response of CR or PR as determined using 
RECIST 1.1 (Appendix 4). 


 
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Other efficacy endpoints are as follows: 
• Overall Survival (OS), defined as the time from the date of start of treatment to the date 
of death from any cause.  Subjects who are lost to follow-up and those who are alive at 
the date of data cutoff will be censored at the date the subject was last known alive, or 
date of data cutoff, whichever occurs first. 
• Clinical Benefit Rate (CBR), defined as the proportion of subjects who achieve a CR, a 
PR, or durable SD duration of at least 6 months from start of study treatment) 
• Time to Response, defined as the interval from start of study treatment to the first 
documentation of CR or PR 
• Duration of Response, defined as the interval from the first documentation of CR or PR 
to the earlier of the first documentation of PD or death from any cause  
• Progression-free Survival (PFS), defined as the interval from the start of study treatment 
to the earlier of the first documentation of PD or death from any cause 
 
12.1.2.2 
Pharmacokinetic and Pharmacodynamic Endpoints 
Plasma concentrations of FLX475 will be listed and summarized by time point. No PK 
parameters (e.g. Cmax and AUC) will be calculated. 
Pharmacodynamic endpoints are as follows: 
• Changes in immune parameters, e.g., lymphocyte subpopulations and plasma cytokines 
or chemokines in peripheral blood or in tumor 
 
Using data from the relevant evaluable data sets, study treatment plasma concentrations and 
PD markers will also be described and summarized.   
12.1.2.3 
Analysis Sets 
The allocation of subjects to analysis sets will be determined prior to database lock.  For the 
purpose of analysis, the following populations will be defined: 
Full Analysis Set:  All subjects enrolled in the study, also known as the “Intent-to-Treat” 
(ITT) population.  
Safety Analysis Set:  All subjects who receive at least one dose of the investigational 
product, FLX475 (even a partial dose).   
Efficacy Eligible Set:  All subjects who receive at least one dose of FLX475 in combination 
with ipilimumab, have measurable disease at baseline per RECIST v1.1, and have at least 


 
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one post-baseline scan or discontinue study treatment as a result of progressive disease, 
death, or a treatment-related adverse event before the first post-baseline scan. 
Efficacy Evaluable Set:  All subjects who complete at least one cycle of FLX475 and 
ipilimumab and have a baseline and at least one post baseline on-study assessment of tumor 
response.   
As warranted by the data, efficacy may also be assessed in a Per-Protocol Population 
comprising all Efficacy Evaluable subjects who have no major protocol violations, as defined 
by the Sponsor prior to database lock.   
Pharmacokinetic (PK) Analysis Set:  All subjects who receive at least 1 dose of FLX475 in 
combination with ipilimumab and have measurable plasma concentrations of FLX475. 
Pharmacodynamic (PD) Analysis Set:  All subjects who receive at least 1 dose of 
investigational product and have sufficient PD data to derive at least 1 PD measurement. 
12.1.3 
Subject Disposition   
The number and percentage of subjects who are enrolled, treated, complete the study, and 
discontinue from the study will be presented for the Full Analysis Set.  A summary of 
reasons for discontinuation will be provided.  The number of subjects included in the Safety 
Analysis and Efficacy Evaluable Sets will be summarized and the reasons for excluding 
subjects from the Efficacy Analysis Set will be listed. 
12.1.4 
Demographic and Other Baseline Characteristics 
Descriptive statistics will be used to summarize demographic and baseline characteristics of 
subjects in each analysis set.  Subject characteristics to be tabulated include:  age, sex, race, 
ethnicity, baseline performance status, primary diagnosis, disease stage at diagnosis and 
baseline, prior therapies (including systemic therapies, radiation, and surgeries), and best 
response to prior cancer therapies. 
12.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the eCRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for 
the FAS by treatment, Anatomical Therapeutic Chemical class, and WHO DD preferred 
term.  Prior medications will be defined as medications that were stopped before the first 
dose of study treatment.  Concomitant medications will be defined as medications that (1) 
started before the first dose of study treatment and were continuing at the time of the first 
dose of study treatment, or (2) started on or after the date of the first dose of study treatment 
up to 30 days after the subject’s final dose.  All medications will be presented in subject data 
listings. 


 
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12.1.6 
Efficacy Analyses 
The primary efficacy endpoint is ORR, and the secondary efficacy endpoints include PFS, 
TTR, DOR and OS.  Tumor-related endpoints will be analyzed for the FAS and Efficacy 
Evaluable Sets, as appropriate.  An additional sensitivity analysis of ORR will be performed 
for the Efficacy Eligible Set.  Efficacy will also be explored in subgroups of special interest, 
notably subjects who are anti-PD-(L)1 refractory (as defined in Appendix 8) and other 
prognostic subgroups pre-specified in the SAP. 
ORR will be defined as the proportion of subjects who are responders, i.e., CR and PR; the 
exact 95% confidence interval for ORR will be calculated using the Clopper-Pearson 
method.  The CBR (CR + PR + SD) will also be calculated; SD in the CBR determination is 
defined as SD that persists for ≥ 6 months.  The ORR and CBR analysis will be based on 
RECIST v1.1. 
Time-to-event endpoints, including PFS and OS, will be summarized descriptively and 
graphically using Kaplan-Meier (KM) methodology.  KM estimates for the median, first, and 
third quartiles will be determined along with 95% confidence intervals (CIs).  The 
Brookmeyer-Crowley method will be used for the CI calculations.  For the subset of subjects 
who have a CR or PR, DOR will be summarized similarly using the Kaplan-Meier method.  
TTR will be defined from the start of treatment to the first documented CR or PR and will be 
summarized descriptively as a continuous variable.  
PFS is defined as the time from the date of initiation of FLX475 to the date measurement 
criteria are first met for irPD/PD or death from any cause, whichever occurs first.  For 
subjects still alive at the time of analysis and without evidence of irPD/PD, PFS will be 
censored on the date of the most recent objective progression-free observation.  For subjects 
who receive subsequent anticancer therapy prior to irPD/PD or death, PFS will be censored 
on the date of the last objective progression-free observation prior to the date of subsequent 
therapy. 
DOR is defined as the time from first date measurement criteria are met for irPR/PR or 
irCR/CR (whichever status is recorded first) to the date measurement criteria are first met for 
irPD/PD or the date of death, whichever is sooner.  For subjects not known to have died as of 
the data cut-off date and who do not have irPD/PD, DOR will be censored at the last 
progression-free assessment date.  For responding subjects who receive subsequent 
anticancer therapy (after discontinuation from all study treatment) prior to disease 
progression, DOR will be censored at the date of last progression-free assessment prior to the 
initiation of a new anticancer therapy. 
OS is defined as the time from the date of initiation of FLX475 to the date of death from any 
cause.  For subjects who are still alive as of the data cut-off date, OS time will be censored 
on the date of the subject’s last contact (last contact for subjects post-treatment = last known 
alive date in mortality status). 


 
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12.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
12.1.7.1 
Pharmacokinetic Analyses 
Samples from all subjects receiving FLX475 plus ipilimumab will be analyzed.  Plasma 
concentrations of FLX475 will be quantified by liquid chromatography with tandem mass 
spectrometry (LC/MS/MS) methodology using previously validated assays.  Samples of 
plasma may be analyzed for metabolites of FLX475, and the results reported separately. 
12.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Soluble, tissue, genetic and/or imaging biomarkers (baseline and/or posttreatment) may be 
summarized using descriptive statistics and correlated with clinical outcomes-related 
endpoints for safety and/or efficacy (including OR, PFS and OS) as appropriate.  Changes 
from baseline in PD markers will be analyzed using appropriate methods if done.  Details 
may be included in a separate analysis plan. 
The effect of FLX475 in combination with ipilimumab on soluble, tissue, genetic and/or 
imaging biomarkers may be summarized using descriptive statistics based on the PK/PD 
analysis set.  Pharmacokinetic/pharmacodynamic relationships (i.e., exposure-efficacy, and 
exposure-safety and exposure-biomarker relationships) will be modeled, if possible, using a 
mechanistic approach for effects of study treatment.  Efficacy endpoints will include the 
primary endpoint of ORR and other efficacy-related metrics including but not limited to PFS 
(based on iRECIST) and OS.  Safety endpoints will be the most frequent AEs of special 
interest and dose reductions.  Exploratory/graphical analyses will be conducted for PK/PD 
evaluations, and, if possible, will be followed by model-based analyses.   
The PK (and PK/PD, if done) analyses will be detailed in a separate analysis plan that will be 
provided at a later date and the result will be provided in a standalone report.   
12.1.8 
Safety Analyses 
Safety analyses will be based on the Safety Analysis Set and summarized.  Adverse events 
and SAEs, laboratory test results, vital signs, and ECG results will be summarized.  Safety 
data will be summarized using descriptive statistics.  Categorical variables will be 
summarized by number and percentage.  Continuous variables will be summarized using n 
(number of subjects with available data), mean, standard deviation, median, first and third 
quartile, and range (minimum and maximum) unless otherwise specified.  The type, 
frequency, severity, timing of onset, duration, and relationship to study treatments of any 
TEAEs, DLTs, SAEs, or AEs leading to discontinuation or dose modification 
(reduction/interruption) of either study treatment (FLX475 or ipilimumab); laboratory 
abnormalities; vital sign abnormalities; and adverse ECG findings will be analyzed. 


 
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12.1.8.1 
Extent of Exposure 
The number of cycles/days on treatment, quantity of study treatments administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to AEs will be summarized.  A by-subject listing of FLX475 
administration data will be presented. 
12.1.8.2 
Adverse Events 
Adverse events will be graded using CTCAE v5.0.  The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology 
using the Medical Dictionary for Regulatory Activities (MedDRA).  Adverse events will be 
coded to the MedDRA lower level term closest to the verbatim term.  The linked MedDRA 
preferred term (PT) and primary system organ class (SOC) are also captured in the database. 
A TEAE is defined as an AE that starts or worsens in severity any time after the first dose of 
study treatment until 30 days after the last dose of study treatment.  Only those AEs that are 
treatment-emergent will be included in summary tables.  All AEs, treatment-emergent or 
otherwise, will be presented in subject data listings. 
The TEAEs will be summarized.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted only once 
within an SOC and PT, even if the subject experienced more than 1 TEAE within a specific 
SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized by 
maximum severity (highest CTCAE grade). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include TEAEs that were considered by the 
investigator to be possibly or probably related to study treatment or TEAEs with a missing 
causality.  The number (percentage) of subjects with treatment-related TEAEs will also be 
summarized by maximum severity (by highest CTCAE grade). 
The proportion of subjects who discontinue treatment due to toxicity will be summarized by 
frequency counts and percentages   
12.1.8.3 
Laboratory Values 
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 11.5.5, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit using descriptive statistics.  Laboratory 
parameters will be categorized according to CTCAE v5.0 grade, and shifts from baseline 
CTCAE grade to worst post-baseline grade will be summarized using shift tables.  
Percentages will be based on the number of subjects with baseline and at least 1 post-baseline 
assessment. 


 
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Common Terminology Criteria for Adverse Events v5.0 will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  A more detailed 
definition of TEMAV will be specified in the SAP.  A summary of TEMAVs will be 
presented by treatment arm. 
12.1.8.4 
Vital Signs 
Descriptive statistics for vital signs parameters (i.e., systolic and diastolic BP, resting heart 
rate, respiratory rate, temperature, and weight) and changes from baseline will be presented 
by visit.  Subjects will be included in the summary tables if they had both a baseline value 
and at least 1 post-baseline value for vital signs. 
12.1.8.5 
Electrocardiograms 
Change from baseline to worst post-baseline result in ECG findings (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) will be summarized 
using shift tables.  Descriptive statistics for ECG parameters and changes from baseline will 
be presented by visit. 
12.1.9 
Interim Analysis 
Safety monitoring will be conducted throughout the study.  A Safety Review Committee 
(SRC) will meet after the safety run-in phase and periodically to review accumulating safety 
information and make recommendations to continue or curtail enrollment.  The SRC will 
comprise appropriate Sponsor and CRO representatives, including the Sponsor’s medical 
monitor or designee(s), safety officer or designee, and clinical trial managers (CTMs). 
Additional members may be added as needed (e.g. PK scientist and/or biostatistician).     
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the Sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 


 
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13 
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Oncol.  1982;5:649-55. 
Pardoll DM.  The blockade of immune checkpoints in cancer immunotherapy.  Nat Rev 
Cancer.  2012;12(4):252. 
Powderly, J., Chmielowski, B., Brahmer, J., Piha-Paul, S., Bowyer, S., LoRusso, P., 
Catenacci, D., Wu, C., Barve, M., Chisamore, M., Nasrah, N., Johnson, D. and Ho, W., 2020. 
Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with 
pembrolizumab in advanced cancer. Journal of Clinical Oncology, 38(15_suppl), 
pp.TPS3163-TPS3163. 
Sansom, D., 2000. CD28, CTLA-4 and their ligands: who does what and to 
whom?. Immunology, 101(2), pp.169-177. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al.; RECIST 
working group.  iRECIST: Guidelines for response criteria for use in trials testing 
immunotherapeutics.  Lancet Oncol.  2017;18(3):e143-e152. 
Sharma P, Allison JP.  Immune checkpoint targeting in cancer therapy: toward combination 
strategies with curative potential.  Cell.  2015;161(2):205-14. 
Shin DS, Ribas A.  The evolution of checkpoint blockade as a cancer therapy: what's here, 
what's next?.  Curr Opin Immuno.  2015;33:23-35. 
van Marle S, van Hoogdalem EJ, Johnson D, Okal A., Kassner P., Wustrow DJ, et al. 
Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, 
and selective small-molecule antagonist of CCR4, in healthy volunteers. Society for 
Immunotherapy of Cancer Annual Meeting, 2018, P484.  


 
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Walunas, T., Lenschow, D., Bakker, C., Linsley, P., Freeman, G., Green, J., Thompson, C. 
and Bluestone, J., 1994. CTLA-4 can function as a negative regulator of T cell 
activation. Immunity, 1(5), pp.405-413. 
Yervoy® Package Insert  Packageinserts.bms.com. 2020. Yervoy® Package Insert. [online] 
Available at: <https://packageinserts.bms.com/pi/pi_yervoy.pdf> 


 
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14 
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
14.1 
Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
(e.g. via protocol clarification letter) that must be approved by the Sponsor before 
implementation.  Amendments specifically affecting the safety of subjects, the scope of the 
investigation, or the scientific quality of the study require submission to health or regulatory 
authorities as well as additional approval by the applicable IRBs/IECs.  These requirements 
should in no way prevent any immediate action from being taken by the investigator, or by 
the Sponsor, in the interest of preserving the safety of all subjects included in the study.  If 
the investigator determines that an immediate change to or deviation from the protocol is 
necessary for safety reasons to eliminate an immediate hazard to the subjects, the Sponsor’s 
medical monitor (or appropriate study team member) and the IRB/IEC for the site must be 
notified immediately.  The Sponsor must notify the health or regulatory authority as required 
per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
Sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, 
if regionally required, the head of the medical institution) detailing such changes. 
14.2 
Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
14.3 
Monitoring Procedures 
Monitoring visits to each site will be conducted by the assigned CRA as described in the 
monitoring plan.  The investigator (or if regionally required, the head of the medical 
institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to 
assure compliance with GCP and local regulatory requirements.  The eCRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the Sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB/IEC review.  The 
Sponsor’s/designee’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or electronic mail between study visits. 


 
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to: 
• Clinic, office, or hospital charts 
• Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
• Recorded data from automated instruments such as interactive web/voice response 
system, radiographs, and other imaging reports (e.g., sonograms, CT scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, electroencephalographs, 
polysomnographs, pulmonary function tests) regardless of how these images are stored, 
including microfiche and photographic negatives 
• Pain, quality of life, or medical history questionnaires completed by subjects 
• Records of telephone contacts 
• Diaries or evaluation checklists 
• Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• Laboratory results and other laboratory test outputs (e.g., urine pregnancy test result 
documentation and urine dip-sticks) 
• Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
• CRF components (e.g., questionnaires) that are completed directly by subjects and serve 
as their own source 
 
14.4 
Recording of Data 
A CRF (= eCRF) is required and must be completed for each subject by qualified and 
authorized personnel.  All data on the CRF must reflect the corresponding source document, 
except when a section of the CRF itself is used as the source document.  Any correction to 
entries made on the CRF must be documented in a valid audit trail where the correction is 
dated, the individual making the correct is identified, the reason for the change is stated, and 
the original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 


 
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14.5 
Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (e.g., Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the Sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the Sponsor, allowing the Sponsor the 
option of permanently retaining the study records. 
14.6 
Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the Sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the Sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the Sponsor or designee immediately. 
14.7 
Handling of Study Drug 
FLX475 will be supplied to the principal investigator (or a designated pharmacist) by the 
Sponsor. Ipilimumab will not be supplied by the Sponsor, but will come from local site 
pharmacies. Drug supplies must be kept in an appropriate secure area (e.g., locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist, or other equivalent designee allowed by local regulations) must 
maintain an accurate record of each receipt, all dispensing, and final disposition of the study 
treatment in a drug accountability ledger, a copy of which must be given to the Sponsor at the 
end of the study.  An accurate record of the date and amount of study treatment dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents, along with all other study conduct documents, at appropriate 
intervals once study treatment has been received by the site. 
All drug supplies provided by the Sponsor are to be used only for this study and not for any 
other purpose.  The investigator (or site personnel) must not destroy any drug labels or any 
partly used or unused drug supply before approval to do so by the Sponsor.  At the 
conclusion of the study and as appropriate during the study, the investigator (or a designated 
pharmacist, or other equivalent designee allowed by local regulations) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 


 
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to the Sponsor or designee or, when approval is given by the Sponsor, will destroy supplies 
and containers at the site. 
14.8 
Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the Sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the Sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the Sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the Sponsor or CRO, as appropriate. 
14.9 
Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others or used for any purpose other than 
reviewing or performing the study, without the written consent of the Sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the Sponsor.  These obligations of confidentiality and nonuse 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the Sponsor/CRO and the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and nonuse set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the Sponsor/CRO. 
14.10 
Termination of the Study 
The Sponsor reserves the right to terminate the study for medical reasons or any other reason 
at any time.  If a study is prematurely terminated or suspended, the Sponsor will promptly 
inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
Sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The investigator reserves the right to terminate participation in the study should his/her 
judgment so dictate.  If the investigator terminates or suspends a study without prior 
agreement of the Sponsor, the investigator should inform the institution where applicable, 
and the investigator/institution should promptly inform the Sponsor and the IRB/IEC and 


 
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provide the Sponsor and the IRB/IEC with a detailed written explanation of the termination 
or suspension.  Study records must be retained as noted above. 
14.11 
Subject Insurance and Indemnity 
The Sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 


 
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15 
APPENDICES 


 
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APPENDIX 1 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS (CTCAE) VERSION 5.0 
The Common Terminology Criteria for Adverse Events (CTCAE v5.0, published 
27 November 2017) provides descriptive terminology to be used for adverse event reporting 
in the clinical trials.  A brief definition is provided to clarify the meaning of each AE term.  
To increase the accuracy of AE reporting, all adverse event terms in CTCAE v5.0 have been 
correlated with single-concept MedDRA terms. 
The Common Terminology Criteria for Adverse Events v5.0 grading refers to the severity of 
the AE.  The Common Terminology Criteria for Adverse Events grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline: 
Grade 
CTCAE Status 
1 
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate:  minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADLb 
4 
Life-threatening consequences: urgent intervention indicated 
5 
Death related to adverse event 
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events. 
a 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b 
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v5.0 
 
For further details regarding MedDRA, refer to the MedDRA website at:  
http://www.meddra.org 


 
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APPENDIX 2 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS SCALE 
ECOG Performance Status Scale* 
Definitions Rating Criteria 
Score 
(Grade) 
Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair 
5 
Dead 
* As published in: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: 
Toxicity and response criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649-55. 
 


 
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APPENDIX 3 
NEW YORK HEART ASSOCIATION (NYHA) CARDIAC 
DISEASE CLASSIFICATION 
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for heart failure patients 
based on cardiac functional capacity.  Based on NYHA definitions, subjects are to be 
classified as follows: 
Class 
NYHA Status 
Class I: 
Patients with cardiac disease but without resulting limitation of physical 
activity; ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea or anginal pain. 
Class II: 
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: 
Patients with cardiac disease resulting in marked limitation of activity; they 
are comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
Class IV: 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or angina syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort 
is increased. 
NYHA = New York Heart Association. 
Source:  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; 1994:253-6. 
 


 
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APPENDIX 4 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) 
Tumor response assessments in this clinical trial will use modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) based on the 2009 article by Eisenhauer, et al., entitled 
New Response Evaluation Criteria in Solid Tumors: revised RECIST guideline (version 1.1). 
Modifications to RECIST 1.1 will be implemented in this study.  One is that chest x-rays 
may not be used to follow disease; only CT scans may be used to follow chest disease.  
Second, as required by RECIST 1.1, the protocol states that the minimum duration of SD is 
7 weeks.  Third, although RECIST allows the site to select up to 5 target lesions at baseline, 
2 per organ, if clinically relevant via CT/MRI scans or by electronic calipers for skin lesions, 
this protocol will follow up to 10 target lesions with up to5 per organ to maintain consistency 
in target lesion selection across tumor types. 
The Eisenhauer article published in the European Journal of Cancer, is available online at: 
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733. 


 
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APPENDIX 5 
DESCRIPTION OF THE MODIFIED RESPONSE 
EVALUATION CRITERIA IN SOLID TUMORS 1.1 FOR 
IMMUNE-BASED THERAPEUTICS (IRECIST) PROCESS FOR 
ASSESSMENT OF DISEASE PROGRESSION 
Tumor progression in this clinical trial may be evaluated by the investigator using modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics (iRECIST) 
based on the 2017 article by Seymour, et al., entitled iRECIST: Guidelines for response 
criteria for use in trials testing immunotherapeutics.  The Seymour article, published in the 
Lancet Oncology, is available online at: 
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30074-8/supplemental. 
These guidelines are an adaptation of RECIST 1.1.  Although RECIST allows the site to 
select up to 5 target lesions at baseline, 2 per organ, if clinically relevant via CT/MRI scans 
or by electronic calipers for skin lesions, this protocol will follow up to 10 target lesions with 
up to5 per organ to maintain consistency in target lesion selection across tumor types. 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic PD based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For subjects who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to allow a subject to continue to receive 
study treatment until repeat imaging is obtained (using iRECIST for subject management 
(see Table 7).  This decision by the investigator should be based on the subject’s overall 
clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care 
 
Any subject deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST. 
If the investigator decides to continue treatment, the subject may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. 


 
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Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
◦ 
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
• Unequivocal progression of nontarget lesion(s) identified at baseline 
• Development of new lesion(s) 
 
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the subject will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (immune-based stable 
disease/immune-based partial response/immune-based complete response [iSD/iPR/iCR]). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
- 
For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point 


 
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- 
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1 
- 
For new lesions, worsening is any of these: 
◦ 
An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point  
◦ 
Visible growth of new nontarget lesions  
◦ 
The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.   
 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.”  This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned. 


 
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Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
subject continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, subjects will be discontinued from study treatment. 
NOTE:  If a subject has confirmed radiographic progression (iCPD) as defined above, but 
the subject is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor.  In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 11.3.1. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• Target lesions 
◦ 
Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression.  
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 
• Non-target lesions 
◦ 
If nontarget lesions have never shown unequivocal progression, their doing so for 
the first-time results in iUPD. 
◦ 
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole. 
• New lesions 
◦ 
New lesions appear for the first time 
◦ 
Additional new lesions appear 
◦ 
Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
◦ 
Previously identified nontarget lesions show any significant growth 
 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 


 
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imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥ 5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR.  It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details are provided in the iRECIST publication (Seymour, et al., 2017). 


 
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Table 7 
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease in Subjects Receiving FLX475 and Ipilimumab 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging at 4 to 
8 weeks to confirm 
PD. 
May continue study 
treatment at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only. 
Discontinue 
treatment 
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment 
No additional imaging 
required. 
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per investigator 
assessment 
Repeat imaging at 4 to 
8 weeks to confirm 
PD.  May occur at next 
regularly scheduled 
imaging visit. 
Continue study 
treatment at the 
investigator’s 
discretion. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only. 
Discontinue 
treatment 
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment. 
Continue regularly 
scheduled imaging 
assessments. 
Continue study 
treatment at the 
investigator’s 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion.  Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule. 
iCPD = iRECIST-confirmed progressive disease, iCR = iRECIST complete response, iRECIST = modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics, iSD = iRECIST stable 
disease, iUPD = iRECIST unconfirmed progressive disease, PD = progressive disease, RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors 1.1 


 
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APPENDIX 6 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND 
OTHER BIOMARKER RESEARCH 
Subjects enrolled in this clinical study will have biologic samples collected for PD, PG, and 
other biomarker analysis.  Optional subject consent must be obtained for banking of samples 
for future research.  These samples may be used for discovery and validation to identify 
biomarkers that may be used for exploratory evaluation of response and/or safety-related 
outcomes as well as for use in diagnostic development. 
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study treatment, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or noncoding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the PK or 
therapeutic response of the study treatment. 
Collection of the pharmacodynamic, PG, and other biomarker samples will be bound by the 
sample principles and processes outlined in the main study protocol.  Sample collection for 
pharmacodynamic, PG, and other biomarker analysis is required as per the study protocol 
unless the collection and use of the samples is prohibited by specific country laws. 
Sample Collection and Handling 
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff. 
Security of the Samples, Use of the Samples, Retention of the Samples 
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the Sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy. 
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the Sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The Sponsor will not sell the samples to a third party. 
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed. 


 
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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.   
Right to Withdraw 
If, during the time the samples are stored, a subject would like to withdraw his/her consent 
for participation in this research, RAPT Therapeutics will destroy the samples.  Information 
from any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project. 
Subject Privacy and Return of Data 
No subject-identifying information (e.g., initials, date of birth, government identifying 
number) will be associated with the sample.  All pharmacodynamic and other biomarker 
samples will be single coded.  Genomic DNA samples used to explore the effects on PK, 
treatment response, and safety will be single coded.  Genomic DNA samples that will be 
stored for long-term use (defined as 15 years after the completion of the study) will be double 
coded.  Double coding involves removing the initial code (subject ID) and replacing with 
another code such that the subject can be re-identified by use of 2 code keys.  The code keys 
are usually held by different parties.  The key linking the sample ID to the subject number 
will be maintained separately from the sample.  At this point, the samples will be 
double-coded, the first code being the subject number.  Laboratory personnel performing 
genetic analysis will not have access to the “key.”  Clinical data collected as part of the 
clinical trial will be cleaned of subject identifying information and linked by use of the 
sample ID “key.” 
The Sponsor will take steps to ensure that data are protected accordingly, and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The Sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include: 
• Clinical research organizations retained by the Sponsor  
• Independent ethics committees or institutional review boards that have responsibility for 
this research study  
• National regulatory authorities or equivalent government agencies 
 


 
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At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (e.g., in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed. 
Given the research nature of the pharmacodynamic, PG, and other biomarker analysis, it will 
not be possible to return individual data to subjects.  The results that may be generated are 
not currently anticipated to have clinical relevance to the subjects or their family members.  
Therefore, these results will not be disclosed to the subjects or their physicians. 
If at any time, pharmacodynamic, PG, and/or other biomarker results are obtained that may 
have clinical relevance, IRB review and approval will be sought to determine the most 
appropriate manner of disclosure and to determine whether or not validation in a Clinical 
Laboratory Improvement Amendments (CLIA)-certified setting will be required.  Sharing of 
research data with individual subjects should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 


 
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APPENDIX 7 
PROHIBITED MEDICATIONS AND THERAPIES 
The following is a list of all medications, therapies (including procedures) that are prohibited 
while the subject is enrolled in this study.  Subjects receiving any of these medications at 
study entry should discontinue the treatment or be switched to a different medication with 
similar pharmacology prior to starting study treatment.  Subjects who receive any of these 
medications during the Treatment Phase must discontinue study treatment. 
Medications that potentially prolong the QT interval  
A list of medications known to cause QTc interval prolongation is provided in the table 
below and is also available at the following link: 
https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.  This list is not all-inclusive. 
Compounds 
Compound Half-Life 
Possible Washout 
Period – Hours 
Possible 
Washout Period 
- Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10–25) 
 
4 
Amiodarone 
(cordaron) 
58 days (15–142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hours (26-64) 
 
10 
Chloral hydrate Readily converted to Trichloroethanol (active 
metabolite T1/2 = 7–10 hours) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
 
Clarithromycin 
Non-linear PK3-4 hr (250mg Q12) 
5–7 hr (500 mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient variability 
 
 
Disopryramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hours 
48 
 
Dolesetron 
8.1 hours 
 
 
Domperidone 
7−8 hours 
48 
 
Doxepin* 
> 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
*Each salt form has different Half-Life* 
 
 
Felbamate 
20–23 hours 
 
5 
Flecainide 
20 hours (12–27) 
 
5 
Foscarnet 
87.5 +/-41.8 hours 
*distribution and release from bone* 
 
20 


 
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Compounds 
Compound Half-Life 
Possible Washout 
Period – Hours 
Possible 
Washout Period 
- Days 
Fosphenytoin 
12–29 hours 
 
6 
Gatifloxacin 
7–14 hours 
48 
 
Gemiflozacin 
7 hours 
48 
 
Grepafloxacin 
16 hours 
 
3 
Halofantrine 
6–10 days (variable among individual) 
 
45 
Haloperidol 
18 +/-5 hours 
 
5 
Ibutilide 
6 hours (2–12) *variable among subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isardipine 
8 hours (multiple metabolites) 
48 
 
Levofloxacin 
6–8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active 
metabolite 
2.6 days for LAAM, 2 day for nor-LAAM, 
4 day for dinor-LAAM 
 
20 
Lithium 
24 hours (10–50) 
 
7 
Mesoridazine 
24–48 hours (animal study) 
 
10 
Methadone 
15–30 hours 
 
7 
Moexipril/HCTZ 
2–9 hour (include active metabolite) for 
moexipril; 
5.6–14.8 hours for HCTZ 
48 
 
Moxifloxacin 
12 +/-1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2-hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4 +/- 1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3–4 hours for PA and NAPA (active 
metabolite) 
24 
 
Protriptyline* 
> 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3–4 hours in children 
36 
 
Quinine 
4–5 hours 
 
 
Risperidone 
3–20 hours (extensive to poor metabolizer) 
 
4 




 
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APPENDIX 8 
ANTI-PD-(L)1 REFRACTORY DEFINITION 
Subjects must have progressed on treatment with an anti-PD-(L)1 monoclonal antibody 
(mAb) administered either as monotherapy, or in combination with other checkpoint 
inhibitors or other therapies as defined below.  Anti-PD-(L)1 treatment progression is defined 
by meeting all of the following criteria: 
a. Has received at least 2 doses of an approved anti-PD-(L)1 mAb.  
b.  Has demonstrated disease progression after anti-PD-(L)1 as defined by RECIST 
v1.1.  The initial evidence of disease progression (PD) is to be confirmed by a second 
assessment no less than four weeks from the date of the first documented PD, in the 
absence of rapid clinical progression. 1,2 
c. Progressive disease has been documented within 12 weeks from the last dose of 
anti-PD-(L)1 mAb.  
 
 
 
 
 
1 Seymour et al; iRECIST:  Guidelines for response criteria for use in trials testing immunotherapeutics.  Lancet 
Oncol 18: e143-52 
 
2 This determination is made by the investigator.  Once PD is confirmed, the initial date of PD documentation 
will be considered the date of disease progression. 


 
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APPENDIX 9 
SUMMARY OF CHANGES 
 
Amendment 1 (Section numbers refer to updated version): 
• Section 11.6, Table 6 updated to include Whole Blood Biomarker sample that had 
been omitted, and frequency of Immunophenotyping samples decreased 
 
 




 
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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
FLX475-03 
Study Protocol Title: 
Phase 2 Study of FLX475 in Combination with Ipilimumab in 
Advanced Melanoma 
Amendment Number: 
1 (19 October 2020) 
Investigational Product 
Name: 
FLX475 (F003475) 
IND Number: 
138286 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
Medical Institution 
 
 
  
  
Investigator 
 Signature 
 Date 
 
As regionally required 
 
  
  
Head 
Medicine Development 
Center 
 Signature 
 Date 
 

SAP_001.pdf: 


RAPT Therapeutics, Inc. 
Statistical Analysis Plan
FLX475-03 
 
Version 1.0; 02 November 2022
 
Confidential                                    Precision for Medicine                                                          Page 2 of 26 
1 STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
RAPT Therapeutics, Inc. 
Clinical Protocol Number: FLX475-03 
Protocol Title: 
Phase 2 Study of FLX475 in Combination with 
Ipilimumab in Advanced Melanoma 
Document File Name: 
Rapt_FLX475-03_SAP_V1.0_02NOV2022 
Document Version and 
Effective Date: 
Version 1.0; 02 November 2022 
Approved By: 
 


RAPT Therapeutics, Inc. 
Statistical Analysis Plan
FLX475-03 
 
Version 1.0; 02 November 2022
 
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2 TABLE OF CONTENTS 
 
1 
Statistical Analysis Plan Approval ............................................................................2 
2 
Table of Contents ........................................................................................................3 
3 
List of Abbreviations ..................................................................................................6 
4 
Introduction.................................................................................................................7 
5 
Study Objectives .........................................................................................................7 
• 
5.1 Primary Study Objective(s) ..................................................................................7 
• 
5.2 Secondary Study Objective(s) ...............................................................................7 
6 
Investigational Plan ....................................................................................................8 
• 
6.1 Overall Study Design .............................................................................................8 
• 
6.2 Schedule of Assessments ........................................................................................9 
• 
6.3 Treatments ............................................................................................................10 
• 
6.3.1 Treatments Administered .............................................................................10 
• 
6.3.2 Method of Assigning Subjects to Treatment Groups .................................11 
• 
6.4 Efficacy and Safety Variables .............................................................................11 
• 
6.4.1 Efficacy Variable(s) .......................................................................................11 
• 
6.4.2 Description of Safety Variables ....................................................................12 
• 
6.4.3 Description of Pharmacokinetic Variables ..................................................18 
• 
6.4.4 Description of Pharmacodynamic Variables ...............................................19 
• 
6.5 Data Quality Assurance .......................................................................................19 
7 
Statistical Methods ....................................................................................................19 
• 
7.1 General Methodology ..........................................................................................19 
• 
7.1.1 Reporting Conventions ..................................................................................19 
• 
7.1.2 Summarization by Visit .................................................................................20 
• 
7.1.3 Data Handling Rules ......................................................................................20 
• 
7.1.4 Standard Calculations ...................................................................................21 
• 
7.2 Analysis Populations ............................................................................................21 
• 
7.3 Study Subjects ......................................................................................................22 
• 
7.3.1 Disposition of Subjects ...................................................................................22 
• 
7.3.2 Protocol Deviations ........................................................................................22 
• 
7.3.3 Demographic and Other Baseline Characteristics ......................................22 
• 
7.4 Efficacy Evaluation ..............................................................................................23 
• 
7.4.1 Primary and Secondary Efficacy Endpoints ...............................................23 
• 
7.4.2 Pharmacokinetic Analysis .............................................................................23 
• 
7.4.3 Pharmacodynamic Analysis ..........................................................................23 
• 
7.5 Safety Evaluation .................................................................................................23 
• 
7.5.1 Extent of Exposure .........................................................................................23 
• 
7.5.2 Adverse Events ...............................................................................................23 
• 
7.5.3 Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...............................................................................................25 
• 
7.5.4 Clinical Laboratory Evaluation ....................................................................25 
• 
7.5.5 Vital Signs, Physical Findings, and Other Observations Related to 
Safety ...............................................................................................................25 
• 
7.6 Determination of Sample Size .............................................................................26 


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• 
7.7 Changes in the Conduct of the Study or Planned Analyses .............................26 
8 
Reference List ............................................................................................................26 
 
 


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TABLE OF TABLES 
Table 1 
List of Abbreviations .................................................................................6 
Table 2 
Study Treatments .....................................................................................10 
 
 


 
 
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3 LIST OF ABBREVIATIONS  
Table 1 
List of Abbreviations  
Abbreviation 
Definition  
AE 
Adverse event 
AUC 
Area under the plasma time-concentration curve 
BMI 
Body mass index 
BP 
Blood pressure 
Cmax 
Maximum concentration 
CSR 
Clinical study report 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report Form 
FAS 
Full Analysis Set 
ICH 
International Council for Harmonisation 
iRECIST 
Modified RECIST for immunotherapies 
ITT 
Intent-to-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Pharmacodynamics, protocol deviation 
PO 
By mouth 
PK 
Pharmacokinetics 
PS 
Performance status 
PT 
Preferred term 
Q3W 
Every 3 weeks 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 


 
 
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Abbreviation 
Definition  
TEAE 
Treatment-emergent adverse event 
WHODD 
World Health Organization Drug Dictionary 
4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for 
RAPT Therapeutics, Inc. Protocol FLX475-03 (Phase 2 Study of FLX475 in 
Combination with Ipilimumab in Advanced Melanoma). Descriptions of planned 
analyses are provided in order to avoid post hoc decisions that may affect the 
interpretation of the statistical analysis. The statistical methods applied in the design and 
planned analyses of this study are consistent with the International Council for 
Harmonisation (ICH) guideline Statistical Principles for Clinical Trials (E9) (1998).  
This SAP will be finalized prior to data analysis and before database lock to provide full 
details to be presented in the clinical study report (CSR). Any changes between the 
statistical methods provided in the clinical study protocol and this SAP will be explained 
herein; any changes or deviations from this SAP relative to the final analysis will be fully 
documented in the CSR. Minor changes or deviations from the templates for tables, 
figures, and listings need not be documented in the CSR. 
5 STUDY OBJECTIVES 
5.1 
Primary Study Objective(s) 
The primary objectives of this study are: 
• To evaluate the objective response rate (ORR), defined as confirmed complete or 
partial response per RECIST 1.1, of FLX475 in combination with ipilimumab in 
subjects with advanced melanoma previously treated with an anti-PD-1 or anti-
PD-L1 agent 
• To evaluate the safety and tolerability of FLX475 in combination with 
ipilimumab in subjects with advanced melanoma previously treated with an 
anti-PD-1 or anti-PD-L1 agent 
5.2 
Secondary Study Objective(s) 
The secondary objectives of this study are to evaluate: 
• To evaluate the progression-free survival (PFS) of subjects with advanced 
melanoma treated with FLX475 in combination with ipilimumab who have been 


 
 
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previously treated with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the overall survival (OS) of subjects with advanced melanoma treated 
with FLX475 in combination with ipilimumab who have been previously treated 
with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the objective response rate (ORR), defined as confirmed complete or 
partial response per modified RECIST for immunotherapies (iRECIST), of 
FLX475 in combination with ipilimumab in subjects with advanced melanoma 
previously treated with an anti-PD-1 or anti-PD-L1 agent 
• To evaluate the plasma concentrations of FLX475 when it is given in 
combination with ipilimumab 
• To assess the effects of FLX475 in combination with ipilimumab on 
pharmacodynamic (PD) markers relating to drug mechanism of action 
• To characterize the onset, magnitude, and duration of tumor control in subjects 
receiving FLX475 in combination with ipilimumab 
6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
This clinical trial is a Phase 2, open-label study at approximately 3−5 investigational sites 
in the US to determine the anti-tumor activity of FLX475 in combination with 
ipilimumab in subjects with advanced melanoma previously treated with an anti-PD-1 or 
anti-PD-L1 agent. 
The study will be conducted starting with a safety run-in portion in which 6 eligible 
subjects will be enrolled and treated for at least one 3-week cycle to determine if the 
safety profile of FLX475+ ipilimumab is acceptable to complete enrollment of the 
approximately 20-subject study. Should the safety profile be deemed not acceptable for 
the 100 mg FLX475 PO QD and 3 mg/kg ipilimumab intravenous (IV) Q3W 
combination regimen, an alternative (lower) dose regimen of either or both drug(s) may 
be selected and tested in an additional 6-subject safety run-in phase. Ultimately at least 
20 subjects should be treated and evaluated with a single chosen combination dose 
regimen. 
Accrual to the study may be discontinued prior to completing enrollment, for reasons 
including, but not limited to, unacceptable safety, slow/insufficient enrollment, or 
changes in standard clinical practice. For each subject, the study consists of the 
following: screening period, treatment phase, and long-term follow-up: 


 
 
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• Screening visit within 21 days of enrollment into the Treatment Phase 
• Treatment Phase comprising up to a maximum of 4 cycles (4 doses) of 
ipilimumab and up to 35 treatment cycles (2 years) of FLX475, unless another 
intervening reason for discontinuation occurs. Each treatment cycle is 3 weeks in 
duration. Treatment beyond 35 cycles may be considered only if it is felt to be in 
the best interests of the subject by the investigator and upon Sponsor agreement 
(if feasible) 
• End-of-treatment visit within 90 days after the final dose of study treatment 
• Posttreatment survival follow-up phase 
The definition of the end of the study is the date of the data cutoff for the final analysis or 
last subject/last visit, including discontinuation from the study for any reason, whichever 
occurs later. 
The study will start with a safety run-in phase. The first six subjects enrolled and treated 
at the recommended Phase 2 dose of FLX475 (100 mg/dose QD) plus ipilimumab (3 
mg/kg IV q3W, up to 4 doses) will be followed for at least one 3-week cycle (21 days) to 
monitor for any unacceptable (or dose-limiting) toxicities prior to enrolling additional 
subjects. 
After the first six subjects enrolled have completed the 3-week safety observation period, 
a Safety Review Committee (SRC) will be convened. The SRC members will comprise 
appropriate Sponsor and contract research organization (CRO) representatives, including 
the Sponsor’s medical monitor or designee(s), safety officer or designee, and clinical trial 
managers (CTMs). Additional members may be added as needed (e.g. Pharmacokinetics 
(PK) scientist and/or biostatistician). The SRC will carefully consider all available safety, 
laboratory, and PK information in consultation with the study investigators. After review 
of all available data, the SRC may recommend continued enrollment of the entire study 
(e.g. if no unacceptable toxicities are observed); dose reduction of either FLX475 and/or 
ipilimumab; or discontinuation of the study. Beyond the safety run-in phase, the SRC will 
continue to meet at least quarterly during the study to review accumulating safety data 
and may also recommend an amendment to the protocol to evaluate alternate study drug 
administration schedules or other changes in study design as may be appropriate based on 
emerging clinical data. 
6.2 
Schedule of Assessments 
For the complete schedule of assessments, refer to Section 11.6 of the protocol. 


 
 
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6.3 
Treatments 
6.3.1 
Treatments Administered 
Subjects will take FLX475 orally once daily (QD) starting on Day 1 of Cycle 1. See 
Section 6.3.1.1.1 for details of the planned dose administration schema. 
Subjects will also receive ipilimumab. Ipilimumab 3 mg/kg will be administered IV Q3W 
for up to four doses. 
The treatments to be used in this study are outlined in Table 2. 
Table 2 
Study Treatments 
Study 
Treatment 
Formulation 
Dose Levels 
Route of 
Administration 
Sourcing 
FLX475 
Tablets 
100 mg (with 
possible dose 
reduction to 75, 
50, or 
25 mg) QD 
Oral 
Provided 
centrally by the 
Sponsor 
Ipilimumab 
Solution for 
infusion 
3 mg/kg Q3W 
IV infusion 
Provided by the 
site 
IV = intravenous, Q3W = once every 3 weeks, QD = once daily. 
6.3.1.1 
FLX475 Administration 
All subjects will take FLX475 orally once daily on a continual basis. On days when 
ipilimumab is also administered (i.e., Day 1 of Cycles 1−4), FLX475 should be taken 
approximately 1 hour before the ipilimumab infusion. 
The dose administration schema for FLX475 is provided below, along with instructions 
for dose modification. 
6.3.1.1.1 
Dosing Plan 
As noted in Section 6.1.4 of the protocol, the recommended Phase 2 dose of FLX475 of 
100 mg PO QD has been selected both for monotherapy and for combination therapy 
with pembrolizumab in study FLX475-02. Therefore, this same dose will be used in this 
study in combination with ipilimumab. Should the safety run-in safety data suggest that 
the 100 mg of FLX475 dose is not acceptable in combination with ipilimumab, a lower 
dose (e.g. 75 or 50 mg PO QD) may be chosen to be used after evaluation in a new safety 
run-in cohort of six subjects. In the event of a change in FLX475 dose, additional 
subjects may be enrolled to ensure that a minimum of 20 subjects are treated at the 
chosen combination dose regimen. 


 
 
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After all subjects in the safety run-in phase have completed the 3-week safety observation 
period, a Safety Review Committee (SRC) will be convened. The SRC members will be 
composed of appropriate Sponsor and CRO representatives, including the Sponsor’s 
medical monitor or designee(s), safety officer or designee, and clinical trial managers 
(CTMs). Additional members may be added as needed (e.g., PK scientist, and/or 
biostatistician). The SRC will carefully consider all available safety, laboratory, and PK 
information in consultation with the study investigators. After review of all available 
data, and if the safety profile of the combination therapy is deemed acceptable, the SRC 
will recommend continuation of the study and enrollment of the remainder of the 
subjects. If the safety profile of the combination regimen is not deemed to be acceptable 
(e.g. dose-limiting toxicity (DLT) observed in > 1 of 6 subjects), the SRC may 
recommend de-escalation of FLX475 to a lower dose (e.g. 75 or 50 mg PO QD); de-
escalation of ipilimumab to a lower approved dose (e.g. 1 mg/kg); delay, or termination 
of dosing. Beyond the safety run-in, the SRC will continue to meet at least quarterly 
during the study to review accumulating safety data and may also recommend an 
amendment to the protocol to evaluate alternate study drug administration schedules or 
other changes in study design as may be appropriate based on emerging clinical data. 
6.3.1.2 
Ipilimumab Administration 
Ipilimumab 3 mg/kg will be administered as an IV infusion over 30 or 90 minutes (per 
institutional protocol) on Day 1 of the first four 3-week treatment cycles (i.e., 21 days [± 
3 days]) after all procedures and assessments have been completed, including any 1 hour 
post-FLX475 dose procedures, approximately 1 hour after the Day 1 dose of FLX475. 
The investigational staff should make every effort to ensure that the infusion duration be 
as close to 30 or 90 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window between -5 minutes and + 10 minutes is permitted. 
Ipilimumab should be prepared and administered per standard institutional protocol and 
the approved label instructions. 
6.3.2 
Method of Assigning Subjects to Treatment Groups 
All subjects in the study will be assigned to the treatment described in Section 6.3.1 
6.4 
Efficacy and Safety Variables 
6.4.1 
Efficacy Variable(s) 
6.4.1.1 
Primary Efficacy Variable 
Primary and secondary efficacy analyses will not be summarized due to early 
discontinuation of the study and a limited amount of available efficacy data. 


 
 
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6.4.2 
Description of Safety Variables 
Safety assessments will consist of monitoring and recording of all AEs and serious 
adverse events (SAEs) using Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 (Appendix 1 of the protocol), regular laboratory evaluation for 
hematology, blood chemistry, and urine values; regular performance of physical 
examinations and vital sign measurements; and periodic electrocardiograms (ECGs). 
6.4.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product. For this study, the study treatments are FLX475 
and ipilimumab. An AE does not necessarily have a causal relationship with the 
medicinal product. Progression of the cancer under study is not considered an AE. 
Adverse events, SAEs, and other reportable safety events must be reported to the 
investigator by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The criteria for identifying AEs in this study are: 
• Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the 
investigational product (Note: Every sign or symptom should not be listed as a 
separate AE if the applicable disease [diagnosis] is being reported as an AE). 
• Any new disease or exacerbation of an existing disease. However, worsening 
of the primary disease should be captured under efficacy assessments as 
disease progression rather than as an AE. 
• Any deterioration in non-protocol-required measurements of a laboratory value or 
other clinical test (e.g., ECG or radiograph) that results in symptoms, a change in 
treatment, or discontinuation of study treatment. 
• Recurrence of an intermittent medical condition (e.g., headache) not present 
pretreatment (Baseline). 
• An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, withdrawal of study 
treatment, or withholding of study treatment, whether prescribed in the protocol or 
not. 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE 
or SAE, as well as other reportable safety events (e.g., pregnancy). Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. 


 
 
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All AEs observed during the study will be reported on the appropriate electronic Case 
Report Form (eCRF). 
All AEs, SAEs, and other reportable safety events, regardless of relationship to study 
treatment or procedure, that occur after the consent form is signed but before treatment 
has started, must be reported by the investigator if the event caused the subject to be 
excluded from the study, or is the result of a protocol-specified intervention, including 
but not limited to, washout or discontinuation of usual therapy, diet, or a procedure. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to 
be part of the clinical syndrome that is being reported as an AE. It is the responsibility of 
the investigator to review all laboratory findings in all subjects and determine if they 
constitute an AE. Medical and scientific judgment should be exercised in deciding 
whether an isolated laboratory abnormality should be classified as an AE. Any laboratory 
abnormality considered to constitute an AE should be reported on the Adverse Event 
eCRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that 
is being reported as an AE, should be considered an AE if the QTcF interval is ≥ 450 ms 
and there is an increase of more than 60 ms from baseline. Any ECG abnormality that the 
investigator considers as an AE should be reported as such. 
All AEs or events of clinical interest (ECIs) that occur from the start of treatment through 
30 days following cessation of study treatment must be reported on the eCRF by the 
investigator. See Section 6.4.2.2 for further discussion of SAEs and ECIs. 
All AEs present at time of cessation of study treatment must be followed for 90 days after 
the subject’s final dose (or 30 days after final dose if the subject initiates new anticancer 
therapy), or until resolution, whichever comes first. All SAEs must be followed to 
resolution or, if resolution is unlikely, to stabilization. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v5.0 (Appendix 1 
of the protocol). Investigators will report CTCAE grades for all AEs (for both increasing 
and decreasing severity). 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment 
are: 


 
 
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• Temporal relationship of the onset of the event to the initiation of the study 
treatment 
• The course of the event, especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or 
with other similar treatments 
• The presence of risk factors in the study subject known to increase the 
occurrence of the event 
• The presence of non-study, treatment-related factors that are known to be 
associated with the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study treatment will be recorded on the eCRF in 
response to the following question: 
Is there a reasonable possibility that the study treatment caused the AE? 
Not Related 
A causal relationship between the study treatment and the AE 
is not a reasonable possibility. 
Possibly Related 
Has a chronological relationship with the time of study drug 
administration and/or represents a known reaction to study drug 
but probably the result of another factor; not clearly the result of 
an external factor. 
Probably Related 
Has a chronological relationship with the time of study drug 
administration and/or represents a known reaction to study 
drug but possibly the result of another factor; not clearly the 
result of another factor, disappears or decreases after 
discontinuation of the study drug. 
Definitely Related Has a chronological relationship with the time of study drug 
administration and/or represents a known reaction to study drug, 
not the result of another factor, disappears or decreases after 
discontinuation of the study drug, and recurs on re-challenge (if 
restarted). 
6.4.2.2 
Serious Adverse Events, Events of Clinical Interest, and Events Associated 
with Special Situations 
An SAE is defined as any untoward medical occurrence that at any dose: 


 
 
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• Results in death 
• Is life-threatening (i.e., the subject was at immediate risk of death from the 
adverse event as it occurred; this does not include an event that, had it 
occurred in a more severe form or was allowed to continue, might have caused 
death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect (in the child of a subject who was 
exposed to the study treatment) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may 
jeopardize the subject or may require intervention to prevent one of the outcomes in the 
definition of SAE listed above should also be considered SAEs. Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
such situations. 
Events of clinical interest (ECIs) in this study, whether serious or not, include: 
1. An overdose of FLX475 or ipilimumab, as defined in Section 6.4.2.3, Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results. 
2. QTcF interval ≥ 450 ms with a > 60 ms increase from baseline (defined as 
average QTcF value from C1D1 pre-dose ECGs) 
In addition to the above ECIs, events associated with special situations include pregnancy 
or exposure to study treatment through breastfeeding; AEs associated with study 
treatment overdose, misuse, abuse, or medication error. Events associated with special 
situations and ECIs are to be captured using the SAE procedures but are to be considered 
as SAEs only if they meet one of the above criteria. All AEs associated with special 
situations are to be reported on the eCRF whether or not they meet the criteria for SAEs. 
Any occurrences of pregnancies and exposure during breastfeeding must be reported by 
the investigator from the start of treatment through 120 days following cessation of study 
treatment, or 30 days following cessation of study treatment if the subject initiates new 
anticancer therapy, whichever is earlier. 
Serious AEs must be reported for 90 days after the subject’s final dose of study treatment, 
or for 30 days after the final dose of study treatment if the subject initiates new anticancer 
therapy, whichever is earlier. Additionally, any SAE brought to the attention of an 
investigator at any time outside the time periods specified above must be reported 


 
 
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immediately to the Sponsor if the event is considered to be drug related. All SAEs must 
be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
• Hospitalizations for respite care 
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed after study treatment 
administration) 
• Hospitalization for administration of study treatment or insertion of access for 
administration of study treatment 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) 
that was in place before study entry 
If possible, blood sample(s) for the measurement of FLX475 plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution. 
6.4.2.3 
Overdose 
For this study, an overdose of FLX475 will be defined as any dose ≥ 2 times the indicated 
dose. An overdose of ipilimumab will be defined as any dose of ≥ 3 times the planned 
dose. No specific information is available on the treatment of an overdose of FLX475 or 
ipilimumab. In the event of an overdose, the subject should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
6.4.2.4 
Pregnancy, Contraception, and Breastfeeding 
FLX475 and ipilimumab may have adverse effects on a fetus in utero. Furthermore, it is 
not known if FLX475 or ipilimumab has transient adverse effects on the composition of 
sperm. 
Subjects should be informed that taking the study drug(s) may involve unknown risks to 
the unborn baby if pregnancy were to occur during the study. In order to participate in the 
study, subjects of childbearing potential must adhere to the contraception requirement 
(from the start of study treatment [or 14 days prior to the initiation of study treatment for 
oral contraception] throughout the study period up to 120 days after the final dose of 
study treatment). If there is any question that a subject of childbearing potential will not 


 
 
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reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
If a female subject inadvertently becomes pregnant while receiving treatment with 
FLX475, ipilimumab or both, she must immediately discontinue study treatment. If a 
female partner of a male subject inadvertently becomes pregnant while the subject is 
receiving treatment with FLX475, ipilimumab, or both, the investigator must be informed 
immediately. The investigator will contact the subject at least monthly and document the 
status of the mother and pregnancy until the pregnancy has been completed or terminated 
(spontaneously or through induced abortion). See Section 11.7.2 of the protocol for 
reporting requirement. 
It is unknown whether FLX475 or ipilimumab is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse 
reactions of drugs in the nursing infant, females who are breastfeeding are not eligible for 
enrollment in this study. 
6.4.2.5 
Laboratory Measurements 
Clinical laboratory tests to be performed are summarized in Table 5 of the protocol. 
Subjects should be in a seated or supine position during blood collection. The Schedule 
of Procedures/Assessments (Table 6 of the protocol) shows the visits and time points at 
which blood and urine samples for clinical laboratory testing will be collected in the 
study. 
All laboratory tests during the study will analyzed locally on the day of collection unless 
otherwise instructed. 
Results from all hematology, clinical chemistry (including serum pregnancy test, as 
applicable), or urinalysis samples (including urine pregnancy test, as applicable) obtained 
prior to study treatment administration should be reviewed prior to 
administration/dispensing of study treatment at the beginning of Cycle 1, at the 
investigator’s discretion, and upon request of the Sponsor (e.g. due to borderline or 
abnormal values at screening). 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 6.4.2.1 and the eCRF Completion Guidelines. In these instances, 
the AE corresponding to the laboratory abnormality will be recorded on the Adverse 
Event eCRF. 
6.4.2.6 
Vital Signs and Weight Measurements 
Vital sign measurements (i.e., systolic and diastolic blood pressure (BP) [mmHg], heart 
rate [beats per minute], respiratory rate [per minute], body temperature [in centigrade]), 
and weight (kg) will be obtained at the visits designated in the Schedule of 


 
 
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Procedures/Assessments (Table 6 of the protocol) by a validated method. Blood pressure 
and pulse will be measured with the subject in the sitting position, after resting for 5 
minutes. All BP measurements should be performed on the same arm, preferably by the 
same person. 
Only 1 BP measurement is needed for subjects with systolic BP < 140 mmHg and 
diastolic BP < 90 mmHg. If the subject’s initial BP measurement is elevated (systolic BP 
≥ 140 mmHg or diastolic BP ≥ 90 mmHg), the BP measurement should be repeated at 
least 5 minutes later. The mean value of 2 measurements at least 5 minutes apart is 
defined as BP assessment. If the BP assessment (i.e., the mean of the 2 BP measurements 
obtained at least 5 minutes apart) is elevated (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 
90 mm Hg), a confirmatory assessment should be obtained at least 30 minutes later by 
performing 2 measurements (at least 5 minutes apart) to yield a mean value. 
6.4.2.7 
Physical Examinations 
Physical examinations (including a neurologic examination) will be performed as 
designated in the Schedule of Procedures/Assessments (Table 6 of the protocol). 
Documentation of the physical examination will be included in the source documentation 
at the investigational site. Only changes from screening physical examination findings 
that meet the definition of an AE will be recorded on the Adverse Events eCRF. A 
symptom-directed physical examination will be performed as clinically indicated. 
6.4.2.8 
Electrocardiograms 
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 6 of the protocol). Complete, standardized, 12-lead ECG 
recordings that permit all 12 leads to be displayed on a single page with an accompanying 
lead II rhythm strip below the customary 3 x 4 lead format are to be used. In addition to a 
rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously. Data should be collected using digital machines and electronically 
archived. Subjects must remain undisturbed in the supine position for a period of ≥ 10 
minutes prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in Section 6.4.2.1 and 
the eCRF Completion Guidelines. In these instances, the AE corresponding to the ECG 
abnormality will be recorded on the Adverse Events eCRF. 
6.4.3 
Description of Pharmacokinetic Variables 
Plasma concentrations of FLX475 will be determined with a validated bioanalytical 
method, and listed and summarized by time point. No PK parameters (e.g., maximum 
concentration (Cmax) and area under the plasma time-concentration curve (AUC)) will be 
calculated. Pharmacokinetic analysis may be summarized in a separate report and is 
outside the scope of this SAP. 


 
 
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6.4.4 
Description of Pharmacodynamic Variables 
Pharmacodynamic endpoints are as follows: 
• Changes in immune parameters, e.g., lymphocyte subpopulations and plasma 
cytokines or chemokines in peripheral blood or in tumor 
Pharmacodynamic analysis may be summarized in a separate report and is outside the 
scope of this SAP. 
6.5 
Data Quality Assurance 
Report summaries will be generated using validated Base SAS software, version 9.4 or 
higher, on a PC or server-based platform. Additional validated software may be used to 
generate analyses, as needed. 
All SAS programs that create outputs or supporting analysis datasets will be validated by 
a second statistical programmer or biostatistician. At a minimum, validation of programs 
will consist of a review of the program log, review of output or dataset format and 
structure, and independent confirmatory programming to verify output results or dataset 
content. Additionally, all outputs will undergo a review by a senior level team member 
before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, 
and extreme outliers through defensive programming applications, analysis-based edit 
checks, and other programmatic testing procedures. All findings will be forwarded to the 
project data manager for appropriate action and resolution. 
7 STATISTICAL METHODS 
7.1 
General Methodology 
Data will be analyzed by Precision for Medicine biostatistics personnel. Statistical 
analyses will be reported with tables, figures, and listings, presented in rich text format, 
and using recommended ICH numbering. Output specifications for all tables, figures, and 
listings will be in conformance with guidelines specified by the ICH in Appendix 7 of the 
Electronic Common Technical Document Specification (Apr 2003). 
7.1.1 
Reporting Conventions 
Tables and figures will be summarized by treatment group. Tables summarizing 
demographics and other baseline characteristics will also include a column for all 
subjects combined. In general, all data collected and any derived data will be presented in 
subject data listings, for all screened subjects. Listings will be ordered by treatment 


 
 
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group, site, subject number, and assessment or event date. The treatment group presented 
in listings will be based on the planned assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population 
sample size (N), number of subjects with available data (n), mean, SD, median, 25th (Q1) 
and 75th (Q3) quartiles, minimum, and maximum values. Categorical variables will be 
summarized by the population size (N), number of subjects with available data (n), 
number of subjects in each category, and the percentage of subjects in each category. 
Unless otherwise noted, the denominator to determine the percentage of subjects in each 
category will be based on the number of subjects with available data. Select ordinal data 
may be summarized using both descriptive statistics and counts and percentages of 
subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (i.e., on the eCRF or as provided 
within an external file) and are outlined as follows: 
• The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization; 
• Measures of variability (e.g., SD, SE) will be rounded to two more decimal places 
than the precision of the variable of summarization; and 
• Minimum and maximum values will be presented using the same precision as the 
variable of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above, 
or assessed for the most appropriate presentation based on the underlying data. 
7.1.2 
Summarization by Visit 
Data summarized by study visit will be based on the nominal, scheduled visit label as 
reported on the eCRF. 
Data collected at unscheduled visits will not be included in by-visit summaries, but will 
be considered when endpoint derivations potentially include multiple visits (e.g., 
determination of baseline value, determination of worst post-baseline value, etc.). All 
data will be included in subject listings. 
7.1.3 
Data Handling Rules 
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (e.g., “< 1.0”) will be summarized with the sign suppressed in summary tables and 


 
 
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figures, using the numeric value reported. Data will display on subject listings to include 
the sign. 
7.1.4 
Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be 
presented with the assessment or event date on subject data listings, where study day will 
be determined as: 
• The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
• The assessment/event date minus the date of first dose of study drug, plus one, if 
the assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
• Days: A duration between two dates expressed in days will be calculated using 
the following conventions: 
o Later date – earlier date + 1, if the earlier date is on or after the date of 
first dose of study drug; or 
o Later date – earlier date, if the earlier date is prior to the date of first dose 
of study drug. 
• Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12); 
• Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25; 
• Change from Baseline: Change from baseline will be calculated as the 
post-baseline value minus the baseline value; 
• Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100. 
7.2 
Analysis Populations 
The analysis populations are defined as follows:  
• Full Analysis Set: All subjects enrolled in the study, also known as the “Intent-to-
Treat” (ITT) population. 


 
 
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• Safety Analysis Set: All subjects who receive at least one dose of the 
investigational product, FLX475 (even a partial dose). 
7.3 
Study Subjects 
7.3.1 
Disposition of Subjects 
Subject disposition will be summarized for all enrolled subjects by treatment group . 
Summaries will include the number and percentage of subjects in each analysis 
population, completing the treatment, discontinuing from treatment (by reason), 
completing the study, and discontinued from study (by reason). 
7.3.2 
Protocol Deviations 
Protocol deviations (PDs) will be identified, logged, and reviewed during the course of 
the study. A determination of major versus minor PDs will be made according to the 
criteria outlined in the study protocol deviation review plan. A listing of all PDs will be 
provided. For purposes of CSR reporting, all important/major protocol deviations will be 
identified based on the following minimum criteria: 
• Subjects who entered the study even though they did not satisfy the entry criteria. 
• Subjects who developed withdrawal criteria during the study but were not 
withdrawn. 
• Subjects who received the wrong treatment or incorrect dose. 
• Subjects who received an excluded concomitant treatment. 
7.3.3 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the Safety 
Analysis Set by treatment group. Gender, race, ethnicity, and baseline Eastern 
Cooperative Oncology Group (ECOG) performance status (PS) will be summarized with 
number and percentage presented for each category. Age, height, weight, and body mass 
index (BMI) at baseline will be described with summary statistics (n, mean, Std Dev, 
median, Q1, Q3, minimum, and maximum). BMI will be calculated as: weight (kg) / 
[height (cm) / 100]2. In addition, primary cancer history will be summarized 
descriptively.  
All demographic and baseline characteristics will be presented in a data listing. 


 
 
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7.4 
Efficacy Evaluation 
7.4.1 
Primary and Secondary Efficacy Endpoints  
Primary and secondary efficacy analyses will not be summarized due to early 
discontinuation of the study and a limited amount of available efficacy data. 
7.4.2 
Pharmacokinetic Analysis 
Pharmacokinetic analysis may be summarized in a separate report and is outside the 
scope of this SAP. 
7.4.3 
Pharmacodynamic Analysis 
Pharmacodynamic analysis may be summarized in a separate report and is outside the 
scope of this SAP. 
7.5 
Safety Evaluation 
Safety analysis will be carried out for the Safety Analysis Set, to include all subjects who 
receive at least one dose of study drug. Subjects who do not complete the study, for 
whatever reason, will have all available data up until the time of termination included in 
the analysis. For safety analysis presented by study visit, the baseline value will be 
defined as the last value reported prior to the first FLX475 dose. 
7.5.1 
Extent of Exposure 
Extent of exposure to study treatment FLX475 will be summarized for by treatment 
group for the Safety Analysis Set. The duration of exposure will be presented in days and 
calculated as the date of last dose of study drug minus the date of first dose of study drug, 
plus one. The total dose received will be determined using the drug dosing log CRF. For 
ipilimumab, number of infusions will be presented. A by-subject listing of FLX475 and 
ipilimumab administration data will be presented. 
7.5.2 
Adverse Events 
All subjects will be assessed regularly for the potential occurrence of adverse events 
(AEs) from the date of informed consent to 90 days after the last dose of study treatment. 
The incidence of treatment-emergent adverse events (TEAEs) will be summarized and 
tabulated using Medical Dictionary for Regulatory Activities (MedDRA), by System 
Organ Class (SOC) and Preferred Term (PT). A TEAE is defined as an AE that first 
occurs or worsens in severity on or after the first dose of FLX475. All adverse events 
recorded in the eCRF will be presented in data listings. 
The National Cancer Institute (NCI)/CTCAE v5.0 will be used to grade both clinical and 
laboratory AEs. A subject with several occurrences of the same AE will be counted once 


 
 
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and classified by the most severe occurrence. AEs with missing severity ratings will be 
classified as having unknown severity, but will be assigned Grade 3 severity for analysis 
and summarization. 
The relationship of each AE to the study treatment will be classified as related or 
unrelated; an AE that is possibly, probably or definitely related to study treatment will be 
considered related. Any AE with an eCRF description of related will be considered 
related. A subject with several occurrences of the same AE will be counted once and 
classified as related if at least one of them is classified as related. An AE with a missing 
relationship to study treatment will be assumed to be related to study treatment for the 
purpose of analysis and summarization. Relationship of AEs to FLX475 and ipilimumab 
will be separately recorded and analyzed. 
An overview of adverse events for the Safety Analysis Set will be provided, summarizing 
the incidence of the following: 
• Any DLT; 
• Any TEAEs; FLX475-related TEAEs; ipilimumab-related TEAEs; 
• Any NCI/CTCAE Grade ≥3 TEAEs; FLX475-related NCI/CTCAE Grade ≥3 
TEAEs; ipilimumab-related NCI/CTCAE Grade ≥3 TEAEs; 
• Any serious TEAEs; FLX475-related serious TEAEs; ipilimumab-related serious 
TEAEs; 
• Any discontinuation of study treatment due to TEAEs; discontinuation of FLX475 
due to FLX475-related TEAEs; discontinuation of ipilimumab due to ipilimumab-
related TEAEs; 
• Any NCI/CTCAE Grade 5 TEAEs; FLX475-related NCI/CTCAE Grade 5 
TEAEs; ipilimumab-related NCI/CTCAE Grade 5 TEAEs. 
TEAE summaries by SOC and PT will be provided for the following: 
• TEAEs (overall and FLX475 or ipilimumab related); 
• Grade ≥3 TEAEs (overall and FLX475 or ipilimumab related); 
• TEAEs leading to discontinuation of study treatment (overall and FLX475 or 
ipilimumab related); 
• Serious TEAEs (overall and any serious FLX475 or ipilimumab related); 


 
 
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In addition, a summary will be provided for the number and percentage of subjects with 
TEAEs by the highest NCI CTCAE grade. For this summary, subjects with multiple 
adverse events will be counted only once by the highest NCI CTCAE grade within an 
SOC and preferred term. 
7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 
All deaths during the study, including the post treatment follow-up period, will be listed 
by subject, to include the primary cause of death. Serious AEs, AEs of clinical interest, 
and AEs associated with DLT will be provided in separate subject data listings.  
7.5.4 
Clinical Laboratory Evaluation 
Hematology and chemistry parameters will be summarized by visit for the Safety 
Analysis Set. Only scheduled visit values will be included in this summary.  
All clinical laboratory data will be listed by subject. Values outside the normal ranges 
will be flagged and toxicity grades will be displayed for relevant parameters. Hematology 
and chemistry measurements identified as abnormal (i.e., outside the normal range) will 
also be listed separately by subject, laboratory test, and unit. 
7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
7.5.5.1 
Vital Signs 
Vital signs measurements include heart rate, respiratory rate, temperature, systolic blood 
pressure, and diastolic blood pressure. Vital signs will be listed by subject. 
7.5.5.2 
12-Lead Electrocardiogram 
ECG measurements include heart rate, PR interval, RR interval, QRS interval, QT 
interval, QTc intervals. The number and percentage of subjects with elevated QTcF 
values (≥ 450 msec, > 480 msec, and > 500 msec) at baseline and any time post baseline 
will be presented. In addition, the number and percentage of subjects with QTcF values 
that increase by > 30 msec and > 60 msec from baseline to any time post baseline will be 
presented. ECG data will also be listed by subject. 
7.5.5.3 
Physical Examination 
Results of the physical examination will be presented in subject data listings. 
7.5.5.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHODD). Prior medications include medications that were stopped 


 
 
RAPT Therapeutics, Inc. 
Statistical Analysis Plan 
FLX475-03 
 
Version 1.0; 02 November 2022 
 
Confidential                                         Precision for Medicine                                                     Page 26 of 26 
 
before the first dose of FLX475. Concomitant medications include medications that (1) 
started before the first dose of FLX475 and are continuing at the time of the first dose of 
FLX475, or (2) started on or after the date of the first dose of FLX475 up to 30 days after 
the subject’s final dose. All medications will be presented in subject data listings. 
7.6 
Determination of Sample Size 
The sample size of 20 subjects is considered adequate on clinical grounds to judge the 
safety of the combination therapy and obtain an initial estimate of its clinical efficacy. 
The sample size of 6 subjects for the safety run-in portion is considered adequate to make 
an initial assessment of the safety of the combination therapy prior to enrolling a full 20-
subject cohort. 
7.7 
Changes in the Conduct of the Study or Planned Analyses 
The analyses outlined in this SAP include deviations from the protocol as outlined below. 
• Efficacy analyses will not be summarized due to early discontinuation of the 
study and a limited amount of available efficacy data. 
8 REFERENCE LIST 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 1982;38:29-41. 
Hollander M, Wolfe DA. Nonparametric statistical methods. John Wiley & Sons, Inc. 
1973. 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. John Wiley & 
Sons, Inc. 1980. 
Long, G., Mortier, L., Schachter, J., Middleton, M., Neyns, B., Sznol, M., Zhou, H., 
Ebbinghaus, S., Ibrahim, N., Arance, A., Ribas, A., Blank, C. and Robert, C., 2017. 
Society for Melanoma Research 2016 Congress. Pigment Cell & Melanoma Research, 
30(1), pp.76- 156