Conditions: Liposarcoma, Dedifferentiated
Keywords: CDK4/6 inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
Study SPH4336-US-01 is an open-label (no placebo), multicenter clinical trial to evaluate the safety, blood levels (pharmacokinetics) and preliminary anti-tumor effects of SPH4336, a selective enzyme blocker, in patients with specific types of liposarcomas (tumors expressing the target of the study drug).

Detailed description:
Study SPH4336-US-01 is a multicenter, non-randomized, open-label Phase 2 study of SPH4336 with a safety lead-in in subjects with CDK4-positive liposarcomas (dedifferentiated or well-differentiated/dedifferentiated liposarcomas). SPH4336 is an orally administered, molecularly targeted chemotherapy drug called a cyclin-dependent kinase inhibitor (CDK4/6 inhibitor), which acts to block the ability of cancer cells to divide and thus prevents tumors from growing. SPH4336 (tablets) will be administered orally once each day in successive 28-day cycles until demonstration of progressive disease or the development of unacceptable toxicity.

The study will incorporate a safety lead-in for the initial 10 subjects. Safety will be evaluated after 10 subjects (minimum 1 cycle completed) by a Safety Review Committee (SRC). The study will be stopped if unacceptable toxicity is observed in more than 2 subjects.

Tumor assessments according to RECIST v1.1 will be performed at baseline and every 6 weeks (from Cycle 1, Day 1 (C1D1)) for 36 weeks, then every 12 weeks thereafter. Plasma samples for pharmacokinetics will be collected in all subjects. Baseline (pretreatment) tumor tissue (archival or fresh) will be collected from all subjects to confirm histologically a liposarcoma with a dedifferentiated component and CDK4 positivity. Tumor tissue biomarkers (e.g., phospho-Rb, Ki-67) will be analyzed in the first 10 study subjects in baseline (pretreatment) and C1D15 tumor tissue samples.

Arms:
arm 1: 400 mg (2 - 200 mg tablets) PO QD

Interventions: intervention 1: SPH4336
Intervention descriptions: intervention 1: 400 mg SPH4336 PO QD

Protocol document:
Prot_000.pdf: 
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A PHASE 2 MULTICENTER, OPEN-LABEL STUDY OF THE CDK4/6 
INHIBITOR SPH4336 IN SUBJECTS WITH LOCALLY ADVANCED OR 
METASTATIC LIPOSARCOMAS 
 
PROTOCOL NUMBER: 
SPH4336-US-01 
IND NUMBER: 
156878 
INVESTIGATIONAL PRODUCT: 
SPH4336 
SPONSOR: 
Shanghai Pharma Biotherapeutics USA Inc. 
3545 John Hopkins Court, Suite 160 
San Diego, CA 92121 
PROTOCOL VERSION: 
V2.0, Amendment 1.0 
DATE: 
26-July-2022 
 
VERSION HISTORY 
 
Version 
Version Date 
Notes 
1.0 
15-Dec-2021 
Original Protocol 
 
 


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STUDY CONTACT INFORMATION 
 
Sponsor Representative: 
Kenneth W. Locke, Ph.D. 
Chief Scientific Officer 
Shanghai Pharma Biotherapeutics USA Inc. 
kenneth@sphbio.com 
+1 (858) 775-5354 
Medical Monitor: 
Tariq Parvez, MD 
Senior Medical Director 
Precision for Medicine 
Tariq.Parvez@precisionformedicine.com 
+1 (804) 380-1675 
 
 
 
 
 
 


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CLINICAL PROTOCOL APPROVAL FORM 
 
Protocol Title: A Phase 2 Multicenter, Open-Label Study of the CDK4/6 Inhibitor SPH4336 in Subjects with 
Locally Advanced or Metastatic Liposarcomas 
Study No: SPH4336-US-01 
Protocol Version No: V2.0, Amendment 1.0 
Protocol Version Date: July 26, 2022 
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the Sponsor. The information contained in this protocol is 
consistent with: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies: 45 
CFR Part 46, 21 CFR Parts 11, 50, 54, 56, 312 
• International Conference on Harmonization (ICH) GCP 
• Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013) 
• Applicable local legal and regulatory requirements. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 
Name and Title 
Approval 
Signature 
Date 
Author: 
Kenneth W. Locke, Ph.D. - CSO 
Yes       No 
 
(circle one) 
 
7/25/22 
Clinical Operations: 
Li-Wei Jen- Sr Director, Clinical 
Operations 
Yes       No 
 
(circle one) 
 
 
7/25/22 
 
 
 


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SPH4336-US-01 v2.0, Amendment 1.0 
A Phase 2 Multicenter, Open-Label Study of the CDK4/6 Inhibitor SPH4336 
in Subjects with Locally Advanced or Metastatic Liposarcomas 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
 
The information contained in this protocol and all other information relevant to SPH4336 are the 
confidential and proprietary information of Shanghai Pharma Biotherapeutics USA Inc. 
(SPHBio), and except as may be required by federal, state or local laws or regulation, may not be 
disclosed to others without prior written permission of SPHBio. 
I have read the protocol, including all appendices, and I agree that it contains all the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Conference on Harmonization guidelines and will 
make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by SPHBio or specified designees. I will 
discuss the material with them to ensure that they are fully informed about SPH4336 and the 
study. 
 
 
 
 
 
     
                              
 
 
 
 
 
 
 
Principal Investigator Name (printed) 
Signature 
 
___________  
___________ 
Date 
 
 
Site Number 
 
 
 


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SPH4336-US-01 PROTOCOL SYNOPSIS 
 
Title 
A Phase 2 Multicenter, Open-Label Study of the CDK4/6 Inhibitor 
SPH4336 in Subjects with Locally Advanced or Metastatic 
Liposarcomas 
Protocol No. 
SPH4336-US-01 
Phase 
2 
Sponsor 
Shanghai Pharma Biotherapeutics USA Inc. 
Study location 
US 
Investigational 
Product 
SPH4336 
Study Population 
Subjects with locally advanced or metastatic CDK4-positive 
liposarcomas 
Primary Objectives 
[Endpoints] 
• Evaluate the efficacy of SPH4336 in subjects with CDK4-
positive liposarcomas [PFS at 12 weeks] 
Secondary 
Objectives 
[Endpoints] 
 
• Evaluate the safety and tolerability profile of SPH4336 [AEs] 
• Evaluate the pharmacokinetics of SPH4336 [Non-compartmental 
PK] 
• Median PFS, Best Overall Response, Duration of Response, 
Time to Response, Overall Survival and other efficacy 
assessments 
• Evaluate tumor tissue biomarkers for activity (e.g., phospho-Rb, 
Ki-67) in the first 10 patients 
Treatment 
Regimen 
The dose will be 400 mg QD. SPH4336 tablets will be administered 
orally each day on a continuous schedule. 


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Study Design 
The study is a multicenter, non-randomized, open-label Phase 2 study of 
SPH4336 with a safety lead-in in subjects with CDK4-positive 
liposarcomas. 
 
SPH4336 will be administered orally once each day in successive 28-
day cycles until demonstration of progressive disease or the 
development of unacceptable toxicity. 
 
The study will incorporate a safety lead-in for the initial 10 subjects. 
Safety will be evaluated after 10 subjects (minimum 1 cycle completed) 
by a Safety Review Committee (SRC). The study will be stopped if 
unacceptable toxicity is observed in more than 2 subjects. 
 
Tumor assessments according to RECIST v1.1 will be performed at 
baseline and every 6 weeks (from C1D1) for 36 weeks, then every 12 
weeks thereafter. PK samples will be collected in all subjects. Baseline 
(pretreatment) tumor tissue (archival or fresh) will be collected from all 
subjects to confirm histologically a liposarcoma with a dedifferentiated 
component and CDK4 positivity. Tumor tissue biomarkers (phospho-
Rb, Ki-67) will be analyzed in the first 10 study subjects in baseline 
(pretreatment) and C1D15 tumor tissue samples. 
 
A SRC will oversee study safety and will meet at a frequency 
commensurate with accrual during the study (e.g., 10 subjects (safety 
lead-in) and 20 subjects, and as needed). 
Pharmacokinetics 
Single dose pharmacokinetic samples will be collected during Cycle 1 at 
the following timepoints: 
• Day 1: pre-dose and 1 h, 2 h, 4 h, 6 h post-dose 
• Day 2: 24 h post-dose 
Multiple dose pharmacokinetic samples will be collected during Cycle 1 
at the following timepoints: 
• Day 15: pre-dose and 1 h, 2 h, 4 h, 6 h post-dose 
• Day 16: 24 h post-dose 
In addition, a single trough PK sample will be collected on the following 
days: 
• Cycle 2 Day 1 (pre-dose) 
Correlative science 
Baseline tumor biopsies (either fresh or archived) will be collected from 
all subjects to confirm histologically a liposarcoma with a 
dedifferentiated component and CDK4 positivity. Biomarkers (phospho-
Rb, Ki-67) will also be analyzed in baseline tumor tissue and in biopsies 
collected on C1D15 in the first 10 study subjects. 


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Safety Review 
Committee (SRC) 
The SRC will consist of the following individuals selected by the 
Sponsor: 
• At least one Investigator 
• The Sponsor Medical Officer or designee 
• The Medical Monitor 
Responsibilities of the SRC will include: 
• Review of all safety data 
• Evaluation of full safety data following the accrual of the initial 10 
subjects (minimum 1 cycle completed) 
• Adjustment of the frequency of administration of SPH4336 (e.g., 
addition of administration breaks, changes to the dosing frequency), 
if appropriate based on developing PK and safety data 
The Safety Review Committee will meet at appropriate intervals (e.g., 
after first 10 subjects (safety lead-in) and 20 subjects) and as needed 
during the study. 
Number of 
Subjects 
Total: approximately 33 (29 evaluable) 
Location 
US 
Number of Sites 
5-10 


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Inclusion Criteria 
• Informed consent 
• ≥ 18 years of age 
• ECOG performance status 0 or 11 
• Histologically confirmed, locally advanced or metastatic sarcoma 
o 
Dedifferentiated or well-differentiated/dedifferentiated 
liposarcomas  
• No more than 3 prior lines of therapy 
• Evidence of progression as evidenced by at least one of the 
following within the past 3 months: 
o 
An increase of at least 20% in measurable tumors 
o 
The appearance of new lesions 
o 
Unequivocal progression of non-measurable lesions 
• Measurable disease per RECIST v1.12 
• If residual treatment-related toxicity from prior therapy: 
o 
All treatment-related toxicity resolved to Grade 1 or baseline 
(alopecia excepted) 
• ANC ≥ 1,500/μL 
• Platelets ≥ 100,000/μL 
• Hgb ≥ 9.0 g/dL (in the absence of pRBC transfusion over the prior 4 
weeks) 
• Estimated glomerular filtration rate of ≥ 60 mL/min (based on the 
Cockcroft and Gault formula for individualized estimates of GFR3) 
• Total bilirubin ≤ 1.5 x the Upper Limit of Normal (ULN) or ≤ 3 x 
ULN if known Gilbert’s disease 
• AST and ALT ≤ 3 x ULN or ≤ 5 x ULN if malignant involvement 
of the liver 
• Sterile or willing to use effective contraception (approved hormonal 
contraceptive such as oral contraceptives, patches, implants, 
injections, rings or hormonally-impregnated intrauterine device 
(IUD), or an IUD in women of childbearing potential and a condom 
in men) during the study and for 3 months following the last dose of 
study drug 
• Availability of archived tumor tissue or willingness to undergo a 
baseline tumor biopsy, and in the first 10 study subjects, to 
determine baseline tumor biomarker levels and a willingness to 
undergo a second tumor biopsy at C1D15 to assess treatment-
induced changes in tumor biomarker levels 


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Exclusion Criteria 
• Prior treatment with a CDK4/6-targeted agent 
• Patient’s tumor known to be CDK4-negative 
• Anticancer therapy (e.g., chemotherapy, biologics, irradiation) 
within 14 days or 5 half-lives (whichever is greater) of screening 
• Major surgery within 28 days of screening 
• Requirement for systemic treatment with strong CYP3A4 inhibitors 
or inducers at study entry 
• Central nervous system metastases or leptomeningeal disease, 
unless appropriately treated and neurologically stable without 
steroids for ≥ 28 days 
• Other malignancy unless disease-free for ≥ 2 years and not expected 
to relapse or require treatment during study participation 
• Active systemic infection or severe localized infection 
• Known HIV-positive with CD4+ cell counts < 350 cells/uL or a 
history of an AIDS-defining opportunistic infection 
• Known hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection with viral load above the limit of quantification 
• Active COVID-19 infection 
• Major cardiac abnormalities (e.g., uncontrolled angina, unstable 
arrhythmias, myocardial infarction, NYHA Class ≥ 3 CHF) ≤ 6 
months of C1D1 
• Persistent (3 ECGs ≥ 5 mins apart) prolongation of the QTcF 
(Fridericia) > 470 msec4 
• [Females] Pregnant or nursing 
• Any other medical or psychiatric condition, or laboratory 
abnormality that would result in an unacceptable risk with study 
participation 
• Presence of active gastrointestinal disease or other condition 
expected to interfere significantly with absorption, distribution, 
metabolism or excretion of oral therapy (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, chronic diarrhea, malabsorption 
syndrome) 


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Dose Holds/ 
Modifications 
Subjects will have their dose of SPH4336 adjusted in response to 
SPH4336-related toxicity as follows: 
• Grade 1 or 2 
o 
No dose hold required 
• Grade 3 
o 
Hold dosing until toxicity has resolved to at least Grade 1 or 
baseline 
o 
Reduce dose for second occurrence by at least 100 mg 
o 
Permanently discontinue further SPH4336 administration for 
third occurrence 
• Grade 4 anemia or neutropenia 
o 
Restart dosing only if recovery to ≤ Grade 1 occurs in ≤ 14 
days, otherwise permanently discontinue 
o 
If resumed, reduce dose by at least 100 mg 
• Grade 4 lymphopenia 
o 
Hold dosing until toxicity has resolved to at least Grade 1 or 
baseline 
o 
If resumed, reduce dose by at least 100 mg 
• All other Grade 4 
o 
Permanently discontinue further SPH4336 administration 
Sample size 
The following assumptions were used to determine sample size:  
Based on historical data19, PFS at 12 weeks of > 60% is considered 
promising and a PFS of < 35% is considered not promising.19 A sample 
size of 29 subjects provides at least 90% power with type I error rate of 
0.1 to decide whether the PFS rate at 12 weeks is less than or equal to 
0.35 or greater than or equal to 0.60.23 If the number of subjects who are 
progression-free at 12 weeks is 14 or more, the hypothesis that the PFS 
rate at 12 weeks is less than or equal to 35% is rejected. If the number of 
subjects who are progression-free at 12 weeks is less than 14, the 
hypothesis that the PFS rate at 12 weeks is greater than or equal to 60% 
is rejected. Sample size was calculated using a single-stage Phase 2 
clinical trial design.23 A final sample size of 33 will be utilized to 
account for a non-evaluable rate of 15%. 


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Table 1: Schedule of Assessments 
Cycle 
SCN 
C1 
C1 
C1 
C1 
C2 
C2 
C3+ 
C3+ 
ET 
SFU 
LTFU 
Day of cycle 
(+ 2 days) 
-28 to 0 
1 
2 
15 
16 
1 
15 
1 
15 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed exam 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG Performance status 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Adverse events 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
 
Hematology 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Chemistry 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Coagulation 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
COVID-19, HIV, TB, HBV, HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
[X] 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment 
X 
 
 
 
 
 
X 
[X] 
[X] 
[X] 
 
 
Tumor tissue collection 
[X] 
 
 
[X] 
 
 
 
 
 
 
 
 
PK samples 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
SPH4336 compliance 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Disease status 
 
 
 
 
 
 
 
 
 
 
 
X 
Study assessments (biopsy, laboratory and clinic visits) may be performed ± 2 days of the recommended date. Laboratory assessments may be 
performed in advance of clinic visits. 
Screening (SCN) is performed within 28 days of Cycle 1 Day 1 (C1D1). Screening evaluations may be repeated within 7 days of C1D1 if requested 
by the Medical Monitor (e.g., borderline eligibility or clinical instability) 


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End-of-Treatment (ET) visit is performed on day that decision is made to discontinue SPH4336 administration if the decision is made during a 
clinic visit. In subjects where the decision to discontinue SPH4336 administration is made outside of a clinic visit (e.g., based on scan results 
only available later), the ET visit may be combined with the SFU visit. 
Safety Follow-Up (SFU) visit is performed 28 days ± 14 days after last dose of SPH4336. 
ET and SFU visits may be combined if any of the following apply: 1) subject discontinued SPH4336 outside of a clinic visit, 2) subject had no 
Grade 2 or higher SPH4336-related toxicity at their last study visit or, 3) subject started a subsequent therapy. 
Long-Term Follow-Up (LTFU) – Performed at 3-month intervals (±1 month) following last study visit (i.e., ET or SFU) on all subjects achieving 
at least stable disease and do not develop progressive disease while on treatment. LTFU of disease status will be performed until progression 
of disease, start of a new treatment, death or 12 months after last study visit, whichever is sooner. May be conducted via review of the 
medical record without the need for a clinic visit. 
X - Required 
[X] – Optional, or not performed on every visit (see notes below for specific assessments). 
Informed consent – May be performed at any time prior to the start of screening procedures (i.e., outside of the 28-day screening window). 
Medical history – Includes all cancer-related history over a subject’s lifetime and non-cancer related history limited to the 2 years prior to C1D1. 
Symptom-directed exam – Limited physical exam performed in response to symptoms reported by the subject. 
Vital signs – Performed once on visit days. Vital signs to include heart rate (per minute), respiratory rate (per minute), blood pressure (mmHg), 
temperature (degrees Fahrenheit). 
Concomitant medications – Recorded from 28 days prior to C1D1 to the time of the ET or SFU visit, except for medications administered as 
cancer treatment, for which lifetime history will be recorded. 
12-lead ECG –ECGs performed as close as possible to each PK draw. ECGs should be performed in triplicate (at least 5 minutes apart) if the 
QTcF on the initial ECG is greater than 470 msecs. Additional ECGs may be collected if clinically indicated. On days without a PK draw, 
ECGs are performed once. 
Hematology – [Blood] Complete blood count with differential to include WBC, RBC, HGB, HCT, platelets, MCV, MCH and differential 
Chemistry – [Blood] Sodium, potassium, chloride, blood urea nitrogen, creatinine, glucose, calcium, AST, ALT, total, direct and indirect bilirubin, 
alkaline phosphatase, total protein, albumin 
Coagulation – [Blood] PT, activated PTT (aPTT) and INR 
Serum pregnancy test – [Blood] Only required for females of child-bearing potential 
Tumor assessment – Performed at baseline and every 6 weeks (from C1D1) for 36 weeks, then every 12 weeks thereafter. Disease assessments 
may be performed less frequently if appropriate (e.g., subjects with complete responses) and approved by the Medical Monitor. Disease 
assessment should be performed using CT with contrast or MRI (if medically necessary). 


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PK sample(s) – [Blood] Collected in Cycle 1 Day 1: pre-dose and 1 h, 2 h, 4 h, 6 h post-dose, Day 2: 24 h post-dose and Day 15: pre-dose and 1 
h, 2 h, 4 h, 6 h post-dose, Day 16: 24 h post-dose and in Cycle 2 (Day 1). 
Tumor Tissue – Availability of archived tumor tissue or performance of a tumor biopsy during screening for confirmation of histologically of a 
liposarcoma with a dedifferentiated component and of CDK4 positivity, if not already known, in all subjects and for baseline tumor 
biomarker (phospho-Rb, Ki-67) determination in the first 10 subjects. A fresh biopsy will be collected on Cycle 1 Day 15 in the first 10 
subjects to determine treatment-related changes in tumor biomarkers. Collection details are summarized in Section 5.4 and will be provided 
in the laboratory manual. 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CDK 
Cyclin-Dependent Kinase 
CFR 
Code of Federal Regulations 
CL/F 
Formation Clearance  
Cmax 
Maximum Drug Concentration in Body After Dosing 
CT 
Computerized Tomography 
CYP 
Cytochrome P450 
DLT 
Dose-Limiting Toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic Case Report Form 
EF2 
Elongation Factor 2 gene 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GLP 
Good Laboratory Practice 
HCT 
Hematocrit 
HED 
Human Equivalent Dose 
hERG 
Human Ether-À-Go-Go-Related Gene  
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-Severely Toxic Dose 
IC50 
Half-Maximal Inhibitory Concentration  
ICF 
Informed Consent Form 


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Abbreviation 
Term 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry  
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
Kd 
Kilodalton 
MCH 
Mean Cell Hemoglobin 
MCV 
Mean Cell Volume 
MDM2 
Mouse Double Minute 2 gene 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
No Observable Adverse Effect Level 
NYHA 
New York Heart Association 
PD 
Progressive Disease 
PET-CT 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
By Mouth 
PT 
Prothrombin 
PTT 
Partial Thromboplastin Time 
QD 
Once Daily 
QTc 
Corrected QT Interval 
QTcF 
QT Interval corrected using Fridericia’s formula 
RB1 
Retinoblastoma 1 gene 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SRC 
Safety Review Committee 
SOC 
Standard of Care 


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Abbreviation 
Term 
SPH3643 
Free base of SPH4336 
SRC 
Safety Review Committee 
t1/2 
Half-life 
Tmax 
Time to reach maximum (peak) plasma concentration 
ULN 
Upper Limit of Normal 
Vss/F 
Apparent volume of distribution at steady state 
WBC 
White Blood Cells 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................ 17 
LIST OF TABLES .................................................................................................................. 19 
LIST OF FIGURES ................................................................................................................ 19 
1 
BACKGROUND .............................................................................................................. 20 
1.1 
Liposarcoma ................................................................................................................ 20 
1.2 
Cyclin-Dependent Kinases 4 and 6 (CDK4/6)............................................................. 22 
1.3 
SPH4336 ....................................................................................................................... 22 
1.3.1 
Preclinical Safety Pharmacology and Toxicology ................................................. 23 
1.3.2 
Preclinical Efficacy ................................................................................................ 24 
1.4 
Prior Clinical Experience ............................................................................................ 24 
1.5 
Rationale for the Study................................................................................................ 24 
1.6 
Dose of SPH4336 .......................................................................................................... 24 
1.7 
Potential Risks and Benefits ........................................................................................ 25 
1.7.1 
Potential Risks ....................................................................................................... 25 
1.7.2 
Potential Benefits ................................................................................................... 26 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 26 
2.1 
Objectives ..................................................................................................................... 26 
2.1.1 
Primary Objectives ................................................................................................ 26 
2.1.2 
Secondary Objectives ............................................................................................. 26 
2.2 
Endpoints ..................................................................................................................... 26 
2.2.1 
Primary Endpoint .................................................................................................. 26 
2.2.2 
Secondary Endpoints ............................................................................................. 26 
3 
SUBJECT POPULATION ............................................................................................... 27 
3.1 
Inclusion Criteria......................................................................................................... 27 
3.2 
Exclusion Criteria ........................................................................................................ 27 
4 
STUDY DESIGN .............................................................................................................. 28 
4.1 
Safety Lead-In ............................................................................................................. 29 
4.2 
Unacceptable Toxicity ................................................................................................. 29 
4.3 
Concomitant Medications, Treatments, and Procedures ........................................... 29 
4.4 
Prophylactic Medications, Treatments, and Procedures ........................................... 30 
4.5 
Rescue Medications, Treatments, and Procedures ..................................................... 30 
4.6 
Prohibited Cancer Treatments.................................................................................... 30 
4.7 
Discontinuation of SPH4336 Administration ............................................................. 30 
4.8 
Replacement of Subjects.............................................................................................. 31 
4.9 
Removal of Subjects from Study Follow-up ............................................................... 31 
5 
STUDY ASSESSMENTS AND EVALUATIONS .......................................................... 31 
5.1 
Informed Consent ........................................................................................................ 31 
5.2 
Screen Failures ............................................................................................................ 31 
5.3 
Pharmacokinetic Assessments ..................................................................................... 31 
5.4 
Tumor Tissue Assessments .......................................................................................... 32 
5.5 
PFS and Response Evaluations ................................................................................... 32 
6 
INVESTIGATIONAL PRODUCT .................................................................................. 32 
6.1 
Dosage forms ................................................................................................................ 32 
6.2 
Storage ......................................................................................................................... 33 


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6.3 
Administration ............................................................................................................. 33 
6.3.1 
Missed doses ........................................................................................................... 33 
6.3.2 
Vomiting shortly after dosing ................................................................................ 33 
6.4 
Accountability .............................................................................................................. 33 
6.5 
Disposal ........................................................................................................................ 33 
6.6 
Dose Holds and Modifications ..................................................................................... 33 
6.6.1 
Maximum duration of dose hold ........................................................................... 34 
6.6.2 
Criteria for resumption of dosing ......................................................................... 34 
6.6.3 
Dose re-escalation .................................................................................................. 34 
6.7 
Overdose ...................................................................................................................... 35 
6.8 
Discontinuation ............................................................................................................ 35 
7 
SAFETY ........................................................................................................................... 35 
7.1 
Adverse Events ............................................................................................................ 35 
7.1.1 
Intensity and Causality of Adverse Events ........................................................... 37 
7.1.2 
Time Period for AE Reporting .............................................................................. 37 
7.1.3 
Reporting of Pregnancy ......................................................................................... 37 
7.2 
Serious Adverse Events (SAEs) ................................................................................... 38 
7.2.1 
Reporting of SAEs ................................................................................................. 38 
7.2.2 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)........ 39 
8 
EFFICACY ....................................................................................................................... 39 
9 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................... 39 
9.1 
Monitoring ................................................................................................................... 39 
9.2 
Audits and Inspections ................................................................................................ 39 
9.3 
Safety Review Committee (SRC) ................................................................................ 40 
10 STATISTICAL CONSIDERATIONS ............................................................................. 40 
10.1 
General Considerations ............................................................................................... 40 
10.2 
Statistical Design .......................................................................................................... 41 
10.3 
Statistical Methods ...................................................................................................... 41 
10.4 
Study Subjects ............................................................................................................. 41 
10.4.1 
Disposition of Subjects ........................................................................................... 41 
10.4.2 
Protocol Deviations ................................................................................................ 41 
10.4.3 
Analysis Populations .............................................................................................. 41 
10.5 
Demographics, Baseline Characteristics, and Concomitant Medications ................. 41 
10.6 
Treatment Compliance ................................................................................................ 42 
10.7 
Efficacy Analysis .......................................................................................................... 42 
10.8 
Safety Analyses ............................................................................................................ 43 
10.9 
Pharmacokinetic Analyses .......................................................................................... 43 
10.10 Interim Analyses .......................................................................................................... 43 
10.11 Determination of Sample Size ..................................................................................... 44 
10.12 Final Analysis Time Point ........................................................................................... 44 
11 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ...................... 44 
11.1 
Ethical Standard .......................................................................................................... 44 
11.2 
Institutional Review Board ......................................................................................... 44 
11.3 
Subject and Data Confidentiality ................................................................................ 45 
11.4 
Research Use of Stored Human Samples, Specimens or Data ................................... 45 
11.5 
Future Use of Stored Specimens ................................................................................. 45 


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11.6 
Investigator and Staff Information ............................................................................. 45 
11.7 
Financial Information ................................................................................................. 46 
12 DATA HANDLING AND RECORD KEEPING ............................................................ 46 
12.1 
Data Collection Responsibilities .................................................................................. 46 
12.2 
Amendments to the Protocol ....................................................................................... 46 
12.3 
Study Records Retention ............................................................................................. 46 
12.4 
Data Collection ............................................................................................................ 46 
12.5 
Disclosure and Publication Policy ............................................................................... 47 
12.6 
Data Handling for Subject Withdrawal or Termination ........................................... 47 
13 REFERENCES ................................................................................................................. 47 
14 APPENDICES .................................................................................................................. 50 
 
LIST OF TABLES 
Table 1: Schedule of Assessments ........................................................................................... 11 
Table 2: Clinical and Pathologic Features of the Four Principle Liposarcoma Subtypes* .. 21 
Table 3: Dose Hold Secondary to SPH4336-related Toxicity ................................................ 34 
Table 4: ECOG Performance Status Criteria ........................................................................ 50 
Table 5: New York Heart Association (NYHA) Classification .............................................. 51 
 
LIST OF FIGURES 
Figure 1: 
Chemical Structure of SPH4336 ...................................................................... 23 
 
 
 


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1 BACKGROUND 
1.1 
Liposarcoma 
Liposarcomas are rare tumors (~2000 new cases expected in 2021 in the US) derived from fat 
tissue. Liposarcomas are a subset of soft tissue sarcomas and make up about 20% of all soft 
tissue sarcomas.5 Liposarcomas can present in any location, but are more commonly found in the 
extremities and retroperitoneum. The incidence of liposarcomas appears to be increasing for 
high-risk subgroups (males) and in the retroperitoneal location.6 Risk factors for soft tissue 
sarcomas include prior radiation and certain familial cancer syndromes (e.g., neurofibromatosis, 
Li-Fraumeni syndrome). Oncogenes considered to be involved in liposarcoma include MDM2, 
CDK4 and HMGA2.7 Five-year survival for subjects with liposarcoma varies by subtype (95% 
for well-differentiated vs. 57% for dedifferentiated tumors) and location (90% for extremity vs. 
64% for retroperitoneal location).6 
Liposarcomas are classified into 3 main groups (Table 2): 
• Well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS) 
• Myxoid/round-cell liposarcoma (MLS) 
• Pleiomorphic liposarcoma (PLS) 
Well-differentiated/dedifferentiated liposarcomas (WDLS/DDLS) account for the majority of 
liposarcomas. WDLS/DDLS is considered a biphasic disease. The WD component is slow 
growing and complete resection often results in long-term survival and cure. The DD 
component, which often arises in the setting of a preexisting WDLS, can be rapidly growing, 
aggressive, and metastatic. Both WDLS and DDLS are relatively resistant to chemotherapy.5  
Genetic changes are common in liposarcoma and include amplification of 12q13-15 which 
harbors a number of cancer-related genes including MDM2, CDK4, HMG2A, TSPAN31. 
MDM2 amplification is a diagnostic marker of WDLS/DDLS, but is not pathognomonic for the 
disease as it is also seen in other sarcomas.7 Amplification of cyclin-dependent kinase 4 (CDK4) 
is present in >90% of WDLS/DDLS. The level of CDK4 amplification in WDLS/DDLS is about 
10x that seen in in normal fat tissue. Certain genes within the 12q13-15 amplicon have been 
associated with DDLS such as YEATS4, CPM and amplifications of 1p32 and 6p23.5 
MLSs are considered more sensitive to chemotherapy and irradiation compared to 
WDLS/DDLS. A number of poor prognostic signs have been identified in MLS including the 
presence of a round cell component, the tumor site, a high proliferative fraction (as noted with 
MIB-1 labeling), and TP53 missense mutations.5 The t(12;16)(q13;p11) translocation is 
considered pathognomonic for MLS.  
PLSs are rare and clinically aggressive with metastases observed in about 40% of subjects. PLSs 
are poorly responsive to chemotherapy and irradiation which is reflected in a disease-related 
mortality rate of about 50%. The genetic changes seen in PLS are complex and include deletion 
of 13q14.2-5 (containing Rb1), mutation or loss of TP53, and loss of NF1.5 


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Table 2: Clinical and Pathologic Features of the Four Principle Liposarcoma Subtypes* 
Subtype 
Well- 
differentiated 
Dedifferentiated 
Myxoid 
Pleomorphic 
Percent of 
liposarcoma 
40-50 
15-20 
20-30 
5-10 
Age (years) 
50-60 
50-60 
30-50 (also 
childhood/adolescence) 
>50 
Morphology 
Pleomorphic 
mature adipocytes, 
variable numbers 
of lipoblasts 
High-grade 
pleomorphic 
sarcoma on well-
differentiated 
background 
Round/oval mesenchymal 
cells plus signet ring 
lipoblasts within myxoid 
stroma 
Variable 
pleomorphic 
lipoblasts on 
background of high-
grade pleomorphic 
sarcoma 
Typical sites 
Extremities; 
retroperitoneum; 
paratesticular 
(rare); 
mediastinum (rare) 
Retroperitoneum; 
extremities; 
paratesticular; 
mediastinum; head 
and neck 
Thigh; other proximal 
extremities 
Limbs 
Recurrence 
Local recurrence 
(retroperitoneum > 
extremities); Rare 
metastatic potential 
Local recurrence in 
~ 40%; Metastasis 
(lung) ~ 20%-30% 
Local and/or metastatic 
(bone, soft tissue, serosa) 
~ 40% 
Local recurrence 
~ 30%-50%; 
Metastasis (lung) 
~ 30%-50% 
Response to 
therapy 
Poor 
Poor 
Generally sensitive to 
radiotherapy and 
chemotherapy 
Variable 
chemosensitivity 
Genomics 
12q13-15 
amplification 
12q13-15 
amplification plus 
other chromosomal 
abnormalities 
t(12;16) with FUS-DDIT3 
fusion 
Complex, with 
multiple 
chromosomal 
abnormalities and 
higher mutation rate 
*Adapted from Lee et al.5 
Initial treatment for liposarcoma depends on the type, size and location of the tumor. If feasible, 
surgery is often attempted, but the option of surgery may be limited by tumor location, invasion 
of critical structures (e.g., adjacent organs or major blood vessels) or evidence of metastases. 
Adjuvant chemotherapy may be considered in subjects with locally invasive tumors or for 
tumors with high metastatic potential (e.g., MLS, PLS).8 Nomograms have been developed that 
provide prognostic information to subjects undergoing surgery for liposarcoma.9  
A number of chemotherapy drugs are used for soft tissue sarcomas (e.g., gemcitabine, docetaxel, 
dacarbazine), but doxorubicin and ifosfamide remain the most effective agents.10,11 Systemic 
chemotherapy including an anthracycline has been reported to have only a modest response rate 
of 12% in soft tissue sarcomas with a median progression-free survival of 4.6 months and a 
median overall survival of 15.2 months.12  
Trabectedin (Yondelis), and alkylating agent, was approved in 2015 for unresectable or 
metastatic liposarcoma or leiomyosarcoma in subjects who had received a prior anthracycline-
containing regimen. Trabectedin was approved based on an improvement in progression-free 


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survival compared with dacarbazine (4.2 vs 1.5 months) despite no observed improvement in 
overall survival.11,13 
Eribulin (Halaven), a microtubule polymerization inhibitor, was approved in 2016 for 
unresectable or metastatic liposarcoma in subjects who had received a prior anthracycline. The 
approval was based on a 7-month improvement in survival (15.6 months with eribulin vs. 8.4 
months with dacarbazine). The improvement in OS was only statistically significant for 
advanced/metastatic DDLS and pleomorphic liposarcoma.14 
1.2 
Cyclin-Dependent Kinases 4 and 6 (CDK4/6) 
Cyclin-dependent kinases (CDKs), part of the serine/threonine protein kinase family, drive cell-
cycle progression, control transcriptional processes, and regulate cell proliferation. CDK4/6 
blocks the transition from the G1 to S phase of the cell cycle by blocking Rb phosphorylation 
and E2F release. Overexpression of the CDK4 protein leads to Rb (retinoblastoma) 
phosphorylation and progression in the cell cycle. Based on these effects, dysregulation of CDKs 
is considered to play a key role in tumorigenesis. CDK4/6 genes are widely expressed among 
various tumors, and high or moderate expression of CDK4/6 is commonly associated with poor 
survival. No CDK4/6 inhibitors are FDA-approved for the treatment of liposarcoma, however, 
several are approved for the treatment of post-menopausal hormone receptor-positive/human 
epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer including 
palbociclib (2015), ribociclib (2017) and abemaciclib (2018).15,16 
CDK4 is considered a potential target in WDLS/DDLS based on the amplification of CDK4 in 
>90% of these liposarcomas. Abemaciclib, a CDK 4/6 inhibitor, has been studied in a single-arm 
Phase 2 study in subjects with dedifferentiated liposarcomas where it demonstrated promising 
progression-free survival of 12 weeks in 76% of subjects. Median PFS was 30.4 weeks, and one 
subject had a partial response. Grade 3-4 toxicities included anemia (37%), neutropenia (20%), 
thrombocytopenia (17%) and diarrhea (7%).17 Similar results were reported in WDLS/DDLS 
patients with palbociclib treated on two different intermittent dosing regimen.18,19 
1.3 
SPH4336 
SPH4336 is a novel, highly selective CDK4/6 inhibitor currently being studied in a Phase 1 study 
in patients with solid tumors in China. The structure of SPH4336 is shown in Figure 1. 
 
 


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Figure 1: 
Chemical Structure of SPH4336 
 
1.3.1 
Preclinical Safety Pharmacology and Toxicology 
The selectivity of SPH3643 (free base of SPH4336) against 30 kinases was compared with 
abemaciclib and palbociclib. SPH3643 showed better selectivity for CDK4/6 relative to activity 
against CDK7/9/1/2. SPH3643 had an IC50 greater than 300 nmol/L against a number of other 
kinases, except PKCa (73 nmol/L), FLT3 (75 nmol/L), and GSK3b (88 nmol/L) and supports the 
observation that SPH3643 is a highly selective inhibitor of CDK4/6. 
After a single intravenous administration in rats, SPH3643 exhibited a moderate plasma t1/2 (~5.5 
h), high plasma clearance and apparent volume of distribution. After oral administration in rats, 
SPH3643 produced more than dose-proportional increases in exposure and t1/2 (~7-19 h). Oral 
bioavailability was ~20% at higher doses with no apparent difference in the fed or fasted state. 
Multiple oral dosing resulted in accumulation in rats. After a single intravenous administration in 
cynomolgus monkeys, SPH3643 exhibited a long plasma t1/2 (~11 h), high plasma clearance and 
apparent volume of distribution. Oral bioavailability was ~30% and no accumulation was 
observed with repeated oral dosing. 
Plasma protein binding of SPH3643 in several species, including humans, was high and ranged 
from 87 to 97%. SPH3643 was highly metabolized and eliminated mainly by phase I metabolic 
reactions (demethylation, dehydrogenation, and oxidation), predominately by CYP3A4. 
SPH3643 had minimal inhibitory activity on most CYP450 isoforms and moderate inhibitory 
activity on CYP2B6. There was no indication of any induction of human CYP1A2, CYP2B6 or 
CYP3A4. 
SPH3643 was generally well-tolerated in rats and monkeys with most drug-related findings 
being reversible. NOAELs of 30 and 10 mg/kg po were established for SPH3643 in the GLP 4-
week rat and monkey toxicology studies, respectively. No significant differences in toxicity 
profile were noted between SPH3643 (free base) and SPH4336 (maleate salt) at a dose of 100 
mg/kg po in a bridging GLP 4-week repeat-dose toxicity test in rats. Target organs were the 


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digestive (e.g., epithelial cell proliferation and macrophage infiltration in digestive tract), hepatic 
(e.g., liver enzyme elevations), hematologic (e.g., anemia) and immune systems (e.g., decreased 
bone marrow hematopoietic cells), consistent with the toxicities reported for other CDK4/6 
inhibitors. Safety margins of approximately 0.5-fold to 3.6-fold (based on body surface area 
scaling) over a projected daily human dose of 400 mg SPH4336 given orally were established in 
these nonclinical studies. 
1.3.2 
Preclinical Efficacy 
Studies of SPH3643 in a variety of xenograft models across a spectrum of CDK4-positive tumors 
(breast, colon, ovarian, lung, glioma, leukemia, liver, liposarcoma) demonstrated antitumor 
activity that was better or comparable with abemaciclib and palbociclib.20 
1.4 
Prior Clinical Experience 
SPH4336 is currently under investigation as monotherapy in a Phase 1 dose escalation trial in 
China (Study SPH4336-101) for subjects with advanced solid tumors. Interim safety reports 
from the initial dose cohorts (50, 100, 200, 300, 400, 600 mg) show SPH4336 to be generally 
well-tolerated with no DLTs and adverse events typical of CDK4/6 inhibitors (e.g., anemia, 
leukopenia, lymphopenia, neutropenia, transaminitis, diarrhea). 
1.5 
Rationale for the Study 
SPH4336 is considered appropriate for study in humans based on the following: 
• CDK4 is a validated target in human tumors with several CDK4/6 inhibitors approved for 
the treatment of various solid tumors; 
• CDK4 is considered a potential target in WDLS/DDLS based on the amplification of CDK4 
in > 90% of WDLS/DDLS tumors; 
• SPH4336 is a highly selective inhibitor of CDK4/6 with pharmacologic properties (e.g., 
increased exposure) that may result in an improved therapeutic index compared to currently 
available CDK4/6 inhibitors; 
• Preclinical studies have demonstrated a safety profile of SPH3643 and SPH4336 consistent 
with other CDK4/6 inhibitors; 
• Xenograft models have demonstrated antitumor activity of SPH3643 and SPH4336 at 
exposures that should be achievable in the clinic; and, 
• Interim PK and safety data from an ongoing Phase 1 trial of SPH4336 in China support a 
dose of 400 mg in liposarcoma patients. 
1.6 
Dose of SPH4336 
SPH4336 is under evaluation in China in an ongoing Phase 1, open-label, dose-escalation 
clinical study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of 
SPH4336 tablet monotherapy in patients with advanced solid tumors (Study SPH4336-101). 
Interim PK data from the first 6 dose cohorts (50, 100, 200, 300, 400, 600 mg) show that QD oral 
dosing of SPH4336 generally produced dose-related increases in exposure with increasing dose, 


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although plasma concentrations appear to plateau at the 400 mg dose. Accumulation was 
observed with repeated dosing, reaching steady-state within approximately 2 weeks of daily 
dosing. The ratio of Ctrough 400 mg QD (at steady-state)/IC50 CDK4 SPH3643, adjusted for PPB 
(Plasma Protein Binding) in vitro was approximately 6.6. A similar ratio was observed for 
abemaciclib (Verzenio®) at its approved dose of 200 mg BID. This suggests that significant 
inhibition of CDK4 is achieved at trough concentrations following multiple doses of ≥ 400 mg 
SPH4336. 
Safety data from the first 6 dose cohorts (50, 100, 200, 300, 400, 600 mg) as of a June 15, 2022 
data cutoff from the ongoing Phase 1 study showed that SPH4336 was well tolerated. The safety 
profile was generally consistent with the safety profile of other CDK4/6 inhibitors. Treatment 
Emergent Adverse Events (TEAEs) included gastrointestinal events (e.g., nausea, diarrhea), 
hepatic events (e.g., liver enzyme elevations), constitutional symptoms (e.g., fatigue) and 
decreased blood cell counts (e.g., leukopenia, lymphopenia, neutropenia, anemia). There appears 
to be no correlation between exposure (Cmax, AUC) and incidence or severity of adverse events. 
A total of 6 Grade 3 AEs (from 21 patients in the first 6 cohorts) were considered related to 
SPH4336, including anemia (50 mg cohort), lymphopenia (200 and 300 mg cohorts), leukopenia 
and neutropenia (400 mg cohort, 2 patients), and diarrhea (600 mg cohort). Both patients in the 
400 mg cohort entered the study with borderline blood cell counts. While experiencing 
leukopenia and neutropenia with no clinical symptoms, both patients underwent brief dose 
interruptions and dose reduction. One patient ultimately discontinued the study treatment despite 
recovery to Grade 2. There were two Serious Adverse Events (SAEs) reported; both were 
considered not related to the study drug by the Investigator. One patient in 200 mg cohort who 
experienced disease progression withdrew from the study and died 29 days after the last dose of 
SPH4336 (reported as a Grade 5 non-study drug-related SAE). The other patient in the 300 mg 
cohort experienced intestinal obstruction shortly after enrollment. This patient was hospitalized 
and treated with supportive care, and the patient later resumed trial participation and received 
SPH4336 treatment (reported as a Grade 3 non-study drug-related SAE). Although the data are 
limited, the safety profile of 400 mg SPH4336 is comparable to or better than that of the 3 FDA-
approved CDK4/6 inhibitors (abemaciclib (Verzenio®), palbociclib (Ibrance®) and ribociclib 
(Kisqali®)) at their approved dose. 
Taken together, the interim PK and clinical safety data from the ongoing Phase 1 study along 
with the nonclinical safety package, support a dose of 400 mg QD in this Phase 2 study in 
liposarcoma patients. Clinical benefit/efficacy is best addressed in this Phase 2 study in a patient 
population (dedifferentiated and well-differentiated/dedifferentiated liposarcomas) expressing 
the drug target (CDK4). 
1.7 
Potential Risks and Benefits 
1.7.1 
Potential Risks 
With limited human experience, the potential risks associated with SPH4336 are based on animal 
data and the safety profile of other CDK4/6 inhibitors. These risks include: 
• GI Toxicity (e.g., nausea, diarrhea) 
• Hepatic toxicity (e.g., transaminase elevations) 


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• Constitutional symptoms (e.g., fatigue) 
• Hematologic toxicity (e.g., called leukopenia, lymphopenia, neutropenia, anemia, 
thrombocytopenia) 
In addition, given the limited clinical experience with SPH4336, there may be risks that are not 
currently known. 
1.7.2 
Potential Benefits 
Information gained from the study may help other people with locally advanced or metastatic 
liposarcoma in the future. SPH4336 may benefit subjects by reducing tumor volume and/or 
slowing tumor growth. A significant extension of Progression-Free Survival (PFS), as seen with 
other drugs acting through the same mechanism, may be observed. In subjects with symptoms 
related to the presence of a tumor, SPH4336 may result in a reduction in symptoms. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objectives 
• To evaluate the efficacy of SPH4336 in subjects with CDK4-positive liposarcomas  
2.1.2 
Secondary Objectives 
• To evaluate the safety profile of SPH4336  
• To evaluate the pharmacokinetics of SPH4336  
• To evaluate other tumor responses  
• To evaluate various tumor tissue biomarkers for activity  
2.2 
Endpoints 
2.2.1 
Primary Endpoint 
• Progression-Free Survival (PFS) as assessed by the Investigator at 12 weeks 
2.2.2 
Secondary Endpoints 
• Type, incidence, severity (as graded by the National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] v5.0), seriousness and relationship to study 
medications of AEs and any laboratory abnormalities 
• Pharmacokinetics include plasma concentration-time profiles and Cmax, Tmax, AUClast, 
AUCinf, t1/2, CL/F, Vss/F, Accumulation Ratio for Cmax, AUC, as appropriate 
• Median PFS, Best Overall Response (BOR), Time to Response (TTR), Duration of 
Response (DOR), Overall Survival (OS), and other efficacy assessments 
• Tumor tissue biomarkers (e.g., phospho-Rb, Ki-67) in the first 10 patients  


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3 SUBJECT POPULATION 
3.1 
Inclusion Criteria 
• Informed consent 
• ≥ 18 years of age 
• ECOG performance status 0 or 11 
• Histologically confirmed, locally advanced or metastatic sarcoma 
o 
Dedifferentiated or well-differentiated/dedifferentiated liposarcomas  
• No more than 3 prior lines of treatment 
• Evidence of progression as evidenced by at least one of the following within the past 3 
months: 
o 
An increase of at least 20% in measurable tumors 
o 
The appearance of new lesions 
o 
Unequivocal progression of non-measurable lesions 
• Measurable disease per RECIST v1.12 
• If residual treatment-related toxicity from prior therapy: 
o 
All treatment-related toxicity resolved to Grade 1 or baseline (alopecia excepted) 
• ANC ≥ 1,500/μL 
• Platelets ≥ 100,000/μL 
• Hgb ≥ 9.0 g/dL (in the absence of pRBC transfusion over the prior 4 weeks) 
• Estimated glomerular filtration rate of ≥ 60 mL/min (based on the Cockcroft and Gault 
formula for individualized estimates of GFR3) 
• Total bilirubin ≤ 1.5 x the Upper Limit of Normal (ULN) or ≤ 3 x ULN if known Gilbert’s 
disease 
• AST and ALT ≤ 3 x ULN or ≤ 5 x ULN if malignant involvement of the liver 
• Sterile or willing to use effective contraception (approved hormonal contraceptive such as 
oral contraceptives, patches, implants, injections, rings or hormonally-impregnated 
intrauterine device (IUD), or an IUD in women of childbearing potential and a condom in 
men) during the study and for 3 months following the last dose of study drug 
• Availability of archived tumor tissue or willingness to undergo a baseline tumor biopsy, and 
in the first 10 study subjects, to determine baseline tumor biomarker levels and a willingness 
to undergo a second tumor biopsy at C1D15 to assess treatment-induced changes in tumor 
biomarker levels 
3.2 
Exclusion Criteria 
• Prior treatment with a CDK4/6-targeted agent 
• Patient’s tumor known to be CDK4 negative 
• Anticancer therapy (e.g., chemotherapy, biologics, irradiation) within 14 days or 5 half-lives 
(whichever is greater) of screening 


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• Major surgery within 28 days of screening 
• Requirement for systemic treatment with strong CYP3A4 inhibitors or inducers of CYP3A4 
at study entry 
• Central nervous system metastases or leptomeningeal disease, unless appropriately treated 
and neurologically stable without steroids for ≥ 28 days 
• Other malignancy unless disease-free for ≥ 2 years and not expected to relapse or require 
treatment during study participation 
• Active systemic infection or severe localized infection 
• Known HIV-positive with CD4+ cell counts < 350 cells/uL or a history of an AIDS-defining 
opportunistic infection 
• Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with viral load above 
the limit of quantification 
• Active COVID-19 infection 
• Major cardiac abnormalities (e.g., uncontrolled angina, unstable arrhythmias, myocardial 
infarction, NYHA Class ≥ 3 CHF) ≤ 6 months of C1D1 
• Persistent (3 ECGs ≥ 5 mins apart) prolongation of the QTcF (Fridericia) > 470 msec4 
• [Females] Pregnant or nursing 
• Any other medical or psychiatric condition, or laboratory abnormality that would result in an 
unacceptable risk with study participation 
• Presence of active gastrointestinal disease or other condition expected to interfere 
significantly with absorption, distribution, metabolism or excretion of oral therapy (e.g., 
ulcerative disease, uncontrolled nausea, vomiting, chronic diarrhea, malabsorption 
syndrome) 
4 STUDY DESIGN 
This is a multicenter, non-randomized, open-label Phase 2 study of SPH4336 in subjects with 
CDK4-positive liposarcomas. 
SPH4336 will be administered orally once each day in successive 28-day cycles until 
demonstration of progressive disease or the development of unacceptable toxicity. 
The study will incorporate a safety lead-in for the initial 10 subjects. Safety will be evaluated 
after 10 subjects (minimum 1 cycle completed) are accrued to allow a full assessment of safety 
by a Safety Review Committee (SRC). The study will be stopped if unacceptable toxicity is 
observed in more than 2 subjects based on SRC recommendation. 
Tumor assessments according to RECIST v1.1.22 will be performed at baseline and every 6 
weeks (from C1D1) for 36 weeks, then every 12 weeks thereafter. PK samples will be collected 
in all subjects. Baseline (pretreatment) tumor tissue will be collected from all subjects to confirm 
histologically a liposarcoma with a dedifferentiated component and CDK4 positivity, and in the 


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first 10 study subjects, tumor tissue biomarkers (phospho-Rb, Ki-67) will be analyzed in baseline 
(pretreatment) and C1D15 tumor tissue samples. 
A Safety Review Committee (SRC) will oversee study safety and will meet at a frequency 
commensurate with accrual during the study (e.g., after 10 subjects (safety lead-in) and 20 
subjects, and as needed). 
4.1 
Safety Lead-In 
The study will incorporate a safety lead-in for the initial 10 subjects. Safety will be evaluated 
after 10 subjects (minimum 1 cycle completed) are accrued to allow a full assessment of safety 
by a Safety Review Committee (SRC). The study will be stopped if unacceptable toxicity is 
observed in more than 2 subjects based on SRC recommendation. 
4.2 
Unacceptable Toxicity 
To be considered as unacceptable toxicity, an AE must meet each of the following 2 criteria: 
• Occur during the first 28 days of SPH4336 administration 
• Not be incontrovertibly related to underlying disease 
In addition, an AE must meet at least one of the following criteria: 
• Any Grade 4 AE 
• Any Grade 3 non-hematologic AE 
• Any AE that results in permanent treatment discontinuation 
The following are excluded from the definition of unacceptable toxicity: 
• Grade 4 anemia or neutropenia that resolves within 14 days and which is not expected to 
recur based on a treatment modification (e.g., use of erythrocyte or neutrophil growth 
factors) 
• Grade 4 lymphopenia 
• Grade 3 headache, nausea, vomiting, diarrhea, fatigue, or pain if controlled within 72 
hours 
• Grade 3 electrolyte abnormalities that are asymptomatic and resolve to at least Grade 2 
within 72 hours 
The SRC will have the option of declaring other toxicities not listed above as unacceptable, if 
necessary, to ensure subject safety. 
4.3 
Concomitant Medications, Treatments, and Procedures 
During their participation on this study, subjects may continue to use concomitant medications, 
treatments and procedures previously prescribed to treat non-cancer related conditions provided 
that, in the Investigator’s judgment, they will not interfere with the study outcomes. 


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Use of proton pump inhibitors are prohibited during the study. 
Although SPH4336 is mainly metabolized by CYP3A4, the impact of CYP3A4 inhibitors or 
inducers on SPH4336 PK has not been characterized in humans. Consequently, drugs, herbal 
medicines and substances that strongly inhibit or induce CYP3A4 will be prohibited during the 
study. Moderate inhibitors or inducers of CYP3A4 are to be used with caution. Examples of 
strong and moderate inhibitors and inducers of CYP3A4 include, but are not limited to: 
• Strong inhibitors - boceprevir, cobicistat, danoprevir, ritonavir, elvitegravir, grapefruit 
juice, itraconazole, ketoconazole, lopinavir, paritaprevir and (ombitasvir and/or 
dasabuvir), posaconazole, saquinavir, tipranavir, telithromycin, troleandomycin, 
voriconazole; 
• Moderate inhibitors - aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, 
diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, 
verapamil; 
• Strong inducers - apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort; and, 
• Moderate inducers - bosentan, efavirenz, etravirine, phenobarbital, primidone. 
4.4 
Prophylactic Medications, Treatments, and Procedures 
The use of prophylactic medications intended to reduce toxicity associated with SPH4336 will 
not be allowed initially. 
The SRC may elect to institute the use of prophylactic medications (e.g., for prevention of 
nausea and vomiting secondary to study medication) during the study. The specific medications 
used will be in keeping with generally accepted standards of care and the institutional guidelines 
of the participating sites. 
4.5 
Rescue Medications, Treatments, and Procedures 
The Investigator will determine the appropriateness and use of any medications, treatments or 
procedures required to treat study-related toxicities or complications (e.g., treatment of drug-
induced nausea or vomiting, treatment of drug-induced myelosuppression or anemia). Any 
rescue medication, treatments or procedures will be consistent with accepted medical practice 
and institutional guidelines. 
4.6 
Prohibited Cancer Treatments 
Other medications/therapies intended to treat the subjects’ underlying cancer are prohibited 
during the study (investigational or approved). 
4.7 
Discontinuation of SPH4336 Administration 
SPH4336 may no longer be administered to a subject in the event of any of the following: 
• Clinically and/or radiologically significant progressive disease; 


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• Unacceptable adverse event(s) considered secondary to SPH4336 despite appropriate 
therapy; 
• Withdrawal of consent for SPH4336 administration by the subject (subject may agree to 
continued follow-up for safety and long-term outcome endpoints); 
• Noncompliance by the subject as determined by the Investigator with agreement from the 
Medical Monitor; or,  
• Termination of study by the Sponsor. 
4.8 
Replacement of Subjects 
Non-evaluable subjects who are unable to complete at least two tumor assessments to evaluate 
efficacy (PFS at 12 weeks) may be replaced to ensure the appropriate number of subjects are 
fully evaluable for efficacy. 
4.9 
Removal of Subjects from Study Follow-up 
No additional follow-up of a subject will occur in the event of any of the following: 
• Withdrawal of consent for follow-up by the subject; 
• Subject is lost to follow-up; or, 
• Termination of study by Sponsor. 
 
5 STUDY ASSESSMENTS AND EVALUATIONS 
5.1 
Informed Consent 
Written informed consent will be obtained prior to the performance of any study-related 
procedures. 
5.2 
Screen Failures 
Subjects who have provided informed consent, but were subsequently found to be ineligible for 
study participation will be considered screen failures. 
5.3 
Pharmacokinetic Assessments 
Single dose pharmacokinetic samples will be collected during Cycle 1 at the following 
timepoints: 
• Day 1: pre-dose and 1 h, 2 h, 4 h, 6 h post-dose 
• Day 2: 24 h post-dose 
Multiple dose pharmacokinetic samples will be collected during Cycle 1 at the following 
timepoints: 
• Day 15: pre-dose and 1 h, 2 h, 4 h, 6 h post-dose 


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• Day 16: 24 h post-dose 
In addition, a single trough PK sample will be collected on the following days: 
• Cycle 2 Day 1 
The window for collection of PK samples with be ± 25% of the scheduled time. 
PK analysis will be conducted as outlined in Section 10.9. 
5.4 
Tumor Tissue Assessments 
Archived tumor tissue or tissue obtained from a tumor biopsy at baseline will be examined 
histologically to confirm a diagnosis of a dedifferentiated or well-differentiated/dedifferentiated 
liposarcoma. CDK4 positivity (at least 1+ per IHC or evidence of amplification on FISH18) will 
also be confirmed in baseline tumor tissue, if not already known. Baseline tumor biomarker 
(phospho-Rb, Ki-67) determinations will be performed in the first 10 study subjects. A fresh 
biopsy will be collected on Cycle 1 Day 15 in the first 10 subjects to determine treatment-related 
changes in those tumor biomarkers. Collection and processing of tumor tissue will be detailed in 
a laboratory manual. Briefly, tumor cores are obtained by needle (e.g., 2 mm) biopsy (5 cores or 
as specified by institutional policy). Tissue is fixed in formalin and embedded in paraffin for 
preparation of 4 μm thickness unstained slides. Slides will be distributed to the appropriate 
laboratories for analysis using validated assays.  
5.5 
PFS and Response Evaluations 
Tumor assessments according to RECIST v1.122 will be performed at baseline and every 6 weeks 
(from C1D1) for 36 weeks, then every 12 weeks thereafter.  
6 INVESTIGATIONAL PRODUCT 
6.1 
Dosage forms 
SPH4336 will be provided as film-coated tablets containing 100 or 200 mg SPH4336 free base 
(30 tablets per soda-lime glass bottle with a high-density polyethylene cap and a sealing gasket 
for a medicinal glass bottle). 
Excipients in the formulation include the following: 
• povidone K30 
• cellactose® 80 
• croscarmellose sodium 
• magnesium stearate 
• a film coating premix (gastric soluble, Opadry®, model 85G630034-CN, orange) 


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6.2 
Storage 
SPH4336 tablets are stored in a secure location at ambient temperatures 20-25 °C (68-77 °F) 
with excursions permitted between 15-30°C (59-86°F). 
6.3 
Administration 
SPH4336 tablets should be swallowed whole, without chewing or crushing the tablets. SPH4336 
will be administered at least 1 hour before eating or 2 hours after eating. SPH4336 should be 
taken at a consistent time each day. 
On scheduled PK collection days, patients will be instructed to only take SPH4336 when 
instructed in the clinic. 
6.3.1 
Missed doses 
If a patient misses a dose of SPH4336, the patient should take the dose as soon as possible, but 
not less than 8 hours before the next dose is due. If the next dose is due in less than 8 hours, the 
patient should skip the missed dose and take the next scheduled dose. 
6.3.2 
Vomiting shortly after dosing 
If a patient vomits shortly after taking SPH4336, the patient should not retake the dose, but 
should resume dosing with the next scheduled dose. If vomiting persists, the patient should 
contact the Investigator. 
6.4 
Accountability 
SPH4336 compliance will be assessed at each visit where SPH4336 is dispensed. The study 
pharmacist or coordinator and clinical Investigator will maintain accurate records of receipt of all 
study drug, including dates of receipt. Study personnel will maintain accurate records regarding 
when and how much study drug is dispensed to and used by each subject in the study. Reasons 
for departure from the expected dispensing regimen must also be recorded. At completion of the 
study, to satisfy regulatory requirements regarding study drug accountability, all study drug will 
be reconciled and retained or destroyed according to applicable state and federal regulations and 
International Conference on Harmonisation (ICH) guidelines. 
6.5 
Disposal 
SPH4336 tablets must not be destroyed unless prior approval has been granted by the Sponsor or 
its representative. Disposal will be performed using institutional guidelines. 
6.6 
Dose Holds and Modifications 
Subjects experiencing SPH4336-related toxicity may have SPH4336 held or reduced as outlined 
in Table 3. 
 


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Table 3: Dose Hold Secondary to SPH4336-related Toxicity 
Toxicity 
(CTCAE Grading) 
Dose Hold 
Dose modification on resumption 
1 or 2 
No dose hold required 
None 
3 
Hold dosing until toxicity has 
resolved to at least Grade 1 or 
baseline 
First occurrence (of same AE): No 
dose reduction 
Second occurrence: Reduce dose by at 
least 100 mg 
Third occurrence: Permanently 
discontinue 
4 anemia or neutropenia 
Restart dosing only if recovery 
to ≤ Grade 1 occurs in ≤ 14 
days, otherwise permanently 
discontinue 
First occurrence (of same AE): 
Reduce by at least 100 mg 
Second occurrence: Permanently 
discontinue 
4 lymphopenia 
Hold dosing until toxicity has 
resolved to at least Grade 1 or 
baseline 
First occurrence (of same AE): 
Reduce by at least 100 mg 
Second occurrence: Permanently 
discontinue 
4 (non-hematologic) 
N/A, permanently discontinue 
N/A, permanently discontinue 
6.6.1 
Maximum duration of dose hold 
Subjects are allowed to remain on study following a delay of up to 21 days due to SPH4336-
related toxicity. Subjects who experience a delay of > 21 days due to SPH4336-related toxicity 
may be permanently discontinued from further SPH4336 administration. 
6.6.2 
Criteria for resumption of dosing 
If a dose hold is implemented for SPH4336-related toxicity, in addition to the criteria listed in 
Table 3, subjects may restart study drugs only if the following conditions are met: 
• No more than 21 days has passed since the last dose of SPH4336; 
• The AE is not expected to recur (per the Investigator and Medical Monitor) at the same 
grade with resumption of SPH4336 based on an intervention such as the addition of a 
prophylactic treatment (e.g., prophylactic anti-emetics), or a reduction in the dose of 
SPH4336; and, 
• Continued administration of SPH4336 is considered to be in the subject’s best interest (per 
the Investigator). 
6.6.3 
Dose re-escalation 
In subjects who undergo dose reduction, re-escalation may be considered if the following criteria 
are met: 
• The toxicity responsible for the prior dose reduction is considered unlikely with return to the 
prior higher dose based on a change in subject status or treatment (e.g., successful medical 
management of underlying condition, uncertain relationship of prior toxicity to SPH4336); 
and, 


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• Approval of the Medical Monitor. 
After dose reescalation, if the toxicity recurs and requires another dose reduction, the subject is 
not allowed to return to the higher dose level. 
6.7 
Overdose 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it involved 
SPH4336) must be communicated to Shanghai Pharma Biotherapeutics USA Inc. or a specified 
designee. Details of any signs or symptoms and their management should be recorded including 
details of any antidote(s) administered. 
6.8 
Discontinuation 
SPH4336 may be discontinued in the event of any of the following: 
• Clinically and or radiologically significant progressive disease; 
• Unacceptable adverse event(s) considered secondary to SPH4336 despite appropriate 
therapy; 
• Withdrawal of consent for SPH4336 administration by the subject (subject may agree to 
continue to be followed for safety and long-term outcome endpoints); 
• Noncompliance by the subject as determined by the Investigator with agreement from the 
Medical Monitor and the Sponsor Medical Officer or designee; or, 
• Termination of study by the Sponsor. 
7 SAFETY 
Safety assessments will consist of monitoring and recording AEs and Serious AEs (SAEs), 
measurement of protocol-specified hematology, chemistry, urinalysis, vital signs, and other 
protocol-specified tests that are deemed critical to the safety evaluation of the SPH4336. 
The Principal Investigator is responsible for recognizing and reporting AEs to the Sponsor or 
designee. It is the Sponsor’s responsibility to ensure the reporting of relevant SAEs to the 
applicable local, national, or international regulatory bodies. In addition, Investigators must 
report SAEs and follow-up information to their responsible Institutional Review Board 
(IRB)/Ethics Committee (EC) according to the policies of that IRB/EC. 
The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the safety reporting requirements. 
7.1 
Adverse Events 
An AE is any untoward medical event that occurs to a subject following signing of the study 
Informed Consent Form (ICF), whether or not the event is considered SPH4336-related. 
 


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Abnormal Laboratory Values  
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be 
reported as an adverse event if it meets any of the following criteria:  
• Is accompanied by clinical symptoms;  
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation);  
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy;  
• Is clinically significant in the Investigator's judgment. 
(Note: For oncology trials, certain abnormal values may not qualify as adverse events).  
It is the Investigator's responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an adverse event.  
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5xULN associated with cholestasis), only the diagnosis (i.e., 
cholestasis) should be recorded on the Adverse Event eCRF. If a clinically significant laboratory 
abnormality is not a sign of a disease or syndrome, the abnormality itself should be recorded on 
the Adverse Event eCRF, along with a descriptor indicating whether the test result is above or 
below the normal range (e.g., "elevated potassium," as opposed to "abnormal potassium"). If the 
laboratory abnormality can be characterized by a precise clinical term per standard definitions, 
the clinical term should be recorded as the adverse event. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
Pre-existing conditions are not considered an AE unless the condition worsens by at least one 
grade following the start of SPH4336 administration. 
Adverse events will be captured starting at the time of informed consent. AEs occurring between 
the time of informed consent and the first dose of SPH4336 will only be captured if related to a 
study mandated procedure. AEs will continue to be captured until the sooner of 28 days after the 
last dose of SPH4336 or until a new anti-cancer treatment is started. 
 
 


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7.1.1 
Intensity and Causality of Adverse Events 
The event’s relationship to the study drug or treatment procedure should be indicated 
according to the following definitions: 
Related 
The adverse event is related to the treatment or procedure. An adverse event (AE) is 
considered related if there is “a reasonable possibility” that the AE may have been 
caused by the study drug (i.e., there are facts, evidence, or arguments to suggest 
possible causation). 
Not Related 
The adverse event is clearly not related to the treatment or procedure. 
The frequency of the event should be indicated according to the following definitions: 
Single episode  
This is the first and only experience/episode of the event in the trial.  
Recurrent  
The event has occurred before in the trial.  
Continuous  
The event is continuing.  
 
The intensity grade of the event should be indicated according to the following definitions: 
All intensity of AEs will be assessed by the Investigator using NCI CTCAE v5.0. 
The outcome should be indicated according to the following definitions: 
Recovered without 
sequelae 
Patient recovered completely from the AE. 
Recovered with sequelae 
Patient has recovered from the AE but displays other symptoms. 
Ongoing 
Patient continues to exhibit symptoms of the AE. The patient will be 
followed until the AE is resolved. 
Death 
Patient died (the date of death should be entered as the SAE resolution 
date). 
Unknown 
Outcome is unknown due to loss to follow-up. 
 
7.1.2 
Time Period for AE Reporting 
AEs will be recorded as those that occur following signing the ICF through the sooner of 28 days 
after the last dose of SPH4336 or until the start of additional anticancer therapy. Treatment-
emergent AEs will be recorded from the first administration of SPH4336 up to the sooner of 28 
days after the last dose of SPH4336 or until the start of additional anticancer therapy. 
7.1.3 
Reporting of Pregnancy 
Pregnancy is neither an AE nor an SAE. However, all pregnancies occurring in subjects, or their 
partner, will be followed to assess for pregnancy-associated AEs or SAEs such as congenital 
anomaly. If, at any time between the first study drug dispensing and 7 days after the last dose of 
study drug, a pregnancy is suspected, the patient/partner will be instructed/requested to return to 


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the study center within 48 hours and undergo a serum pregnancy test, as confirmation of 
pregnancy. All confirmed pregnancies must be immediately reported using the appropriate form. 
Upon confirmation of a subject pregnancy, no further investigational treatment will be 
administered. All pregnancies with study drug exposure will be followed until resolution (i.e., 
termination [voluntary or spontaneous] or birth). 
7.2 
Serious Adverse Events (SAEs) 
An SAE is any AE that results in any of the following outcomes: 
• Death 
• A life-threatening experience 
• An inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• An event that is not listed above, but that requires intervention to prevent one of the 
outcomes listed above also is considered a SAE 
The following will be excluded from the definition of an SAE: 
• Elective hospitalizations that are not in response to an AE 
• Hospitalizations that are of less than 24 hours duration 
• Hospitalization related to disease progression 
7.2.1 
Reporting of SAEs 
The recording of SAEs (regardless of their relationship to study drug) will begin with the 
Screening visit (signing of ICF) until the Final Visit or Early Termination Visit. Any SAE, 
including death due to any cause, which occurs during the conduct of this study, regardless of 
relationship to study drug, must be reported within 24 hours of the Investigator’s (or designee’s) 
first awareness of the event. 
An initial Serious Adverse Event Form (SAE form) should be completed and submitted per the 
SAE form instructions. 
The Investigators should attempt to group signs and symptoms into a single term that constitutes 
a single unifying diagnosis and indicate the serious criteria that are applicable to the SAE (the list 
of serious criteria is also provided in the above section). The Investigator’s opinion of the 
relationship of the SAE to study drug, the duration, intensity, frequency, actions taken with study 
drug, and the outcome of the SAE will be documented using the definitions/criteria in Section 
7.2. 
All serious adverse events are to be reported to the Institutional Review Board (IRB) by the 
Investigator. 


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7.2.2 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SAEs that meet the criteria for a suspected unexpected serious adverse reactions (SUSARs) will 
be reported as an IND Safety Report to the appropriate regulatory authorities and participating 
investigators, in accordance with International Conference on Harmonization (ICH) guidelines 
and FDA regulations. A SUSAR that meets the seriousness criteria of life-threatening and/or 
results in death will be reported within seven (7) calendar days. A SUSAR that is not life-
threatening or does not result in death will be submitted to the regulatory authorities within 
fifteen (15) calendar days. 
Unexpected adverse reactions are adverse reactions, the nature, severity, consequences, or 
frequency of which are not consistent with the anticipated risks described in current relevant 
information (e.g., Investigator's Brochure) for the investigational product. The Investigator's 
Brochure serves as a primary document to provide safety reference information to determine 
whether an adverse reaction is expected or unexpected. Prior to submitting the appropriate IND 
safety report, the Sponsor will ensure that the event meets all three of the definitions for 
“suspected adverse reaction,” “serious,” and “unexpected.” 
8 EFFICACY 
Tumor assessments according to RECIST v1.1.22 will be performed at baseline and every 6 
weeks (from C1D1) for 36 weeks, then every 12 weeks thereafter. 
The Sponsor will have the option of collecting de-identified copies of all scans. The Sponsor 
may elect to conduct a central assessment of response prior to the completion of the study. 
Other secondary efficacy endpoints (e.g., Median PFS, Best Overall Response, Time to 
Response, Duration of Response, Overall Survival) and tumor tissue biomarkers (in the first 10 
patients) will also be assessed. 
9 QUALITY ASSURANCE AND QUALITY CONTROL 
9.1 
Monitoring 
Site monitoring shall be conducted to ensure that subject protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, Good Clinical Practice (GCP)/ICH and, when appropriate, regulatory 
guidelines. 
9.2 
Audits and Inspections 
The Investigator will permit study-related quality audits and inspections by the Sponsor or its 
representative(s), government regulatory authorities, and the IRB/EC of all study-related 
documents (e.g., source documents, regulatory documents, data collection instruments, case 
report forms). The Investigator will ensure the capability for review of applicable study-related 
facilities. The Investigator will ensure that the auditor or inspector or any other compliance or 


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quality assurance reviewer is given access to all study-related documents and study-related 
facilities. 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB/EC, and the Sponsor or its representative(s). 
9.3 
Safety Review Committee (SRC) 
A Safety Review Committee will govern the conduct of the study. The SRC will consist of the 
following individuals selected by the Sponsor: 
• At least one Investigator 
• The Sponsor Medical Officer or designee 
• The Medical Monitor 
Responsibilities of the SRC will include: 
• Review of all safety data at the completion at appropriate intervals; 
• Evaluation of safety data following the accrual of the initial 10 subjects (minimum 1 
cycle completed); and, 
• Adjusting the dose and/or schedule used in the study as appropriate based on 
accumulating safety data from the study. 
Additional responsibilities may be asked of the SRC as appropriate to ensure subject safety. 
The Safety Review Committee will meet as needed based on the rate of subject accrual (e.g., 
after 10 subjects (safety lead-in) and 20 subjects). SRC meetings may be conducted by 
teleconference or through email communications. Decisions made during the SRC meeting will 
be recorded in meeting minutes and will be part of the study documentation. 
10 STATISTICAL CONSIDERATIONS 
10.1 
General Considerations 
Data collected in this study will be presented using summary tables and subject data listings. 
Continuous variables will be summarized using descriptive statistics, specifically the mean, 
median, standard deviation, minimum, and maximum. 
Categorical variables will be summarized by frequencies and percentages. 
An assessment of protocol violations, SPH4336 accountability, and other data that may impact 
the general conduct of the study will be presented. 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the SAP. In the event of differences between the protocol and the SAP, the SAP will 


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prevail. The SAP will be finalized prior to database lock. Any changes to the methods described 
in the final SAP will be described and justified in the clinical study report. 
10.2 
Statistical Design 
This is a multicenter, open-label, Phase 2 study of SPH4336 in subjects with advanced or 
metastatic liposarcoma. 
10.3 
Statistical Methods 
A separate Statistical Analysis Plan (SAP) will be prepared, providing detailed methods for the 
analyses. 
Any deviations from the planned analyses will be described and justified in the final integrated 
study report. 
10.4 
Study Subjects 
10.4.1 
Disposition of Subjects 
The number and percentage of subjects screened and entered on study will be presented. Reasons 
for withdrawal will also be summarized. 
10.4.2 
Protocol Deviations 
A summary of the number and percentage of subjects with protocol deviations by type of 
deviation will be provided. 
10.4.3 
Analysis Populations 
The Safety Population will include all subjects who receive at least one dose of SPH4336. 
The PK-Evaluable Population will include all subjects who have had at least one pre- and post-
dose PK assessment performed. 
The Efficacy-Evaluable Population will include all subjects who receive at least 1 dose of 
SPH4336 and meet at least one of the following 2 criteria: 
• Have at least 2 post-baseline disease assessments (for PFS at 12 weeks); or, 
• Experience clinical progression.  
10.5 
Demographics, Baseline Characteristics, and Concomitant Medications 
Demographic data, medical history, concomitant disease, and concomitant medications will be 
summarized. 


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Baseline characteristics will be summarized for the safety population. Subjects who died or 
withdrew before treatment started or do not complete the required safety observations will be 
described and evaluated separately. 
10.6 
Treatment Compliance 
Treatment administration will be summarized including dose administration, dose modifications 
or delays, cumulative dose, average dose, number of doses, and the duration of therapy. 
10.7 
Efficacy Analysis 
Details of efficacy analyses will be outlined in the Statistical Analysis Plan (SAP).  The 
progression-free survival (PFS) rate and overall response rate (ORR) will be summarized with 
frequencies and percentages, as appropriate. The duration of response for complete and partial 
response subjects will be summarized with descriptive statistics (N, mean, standard deviation, 
median, minimum, and maximum) as well as categorically. PFS, Median PFS, Time to 
Response, Duration of Response and Overall Response Rate will be determined using RECIST 
v1.1.22 Kaplan-Meier methodology will be used to summarize time to events. 
Subjects will be classified according to their best overall tumor response (complete response, 
partial response, stable disease, or progressive disease). Frequencies, proportions, and exact 95% 
CI of subjects, when appropriate, stratified by their best overall tumor response will be 
calculated. Subjects with a best overall tumor response of complete or partial with a confirmed 
duration of at least 4 weeks (28 days) will be further classified as having an objective tumor 
response. A listing of subjects with an objective tumor response will be presented. 
Duration of response will be calculated as the number of days from the first documentation of 
response (complete or partial) to the first documentation of disease progression or death, 
whichever comes first. 
Time to response will be calculated as the number of days from the first dose of SPH4336 to the 
first documentation of response. 
Subjects who are alive and progression-free at the time of data analysis will be censored at the 
time of their last tumor assessment. 
Duration of stable disease will be calculated from Cycle 1 Day 1. 
Based on historical data19, PFS at 12 weeks of > 60% is considered promising and a PFS of < 
35% is considered not promising.19 A sample size of 29 subjects provides at least 90% power 
with type I error rate of 0.1 to decide whether the PFS rate at 12 weeks is less than or equal to 
0.35 or greater than or equal to 0.60.23 If the number of subjects who are progression-free at 12 
weeks is 14 or more, the hypothesis that the PFS rate at 12 weeks is less than or equal to 35% is 
rejected. If the number of subjects who are progression-free at 12 weeks is less than 14, the 
hypothesis that the PFS rate at 12 weeks is greater than or equal to 60% is rejected. 


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Tumor tissue biomarkers (phospho-Rb, Ki-67) will be analyzed by immunohistochemistry in 
pretreatment and C1D15 tumor tissue samples; individual and mean change from baseline in the 
markers and % of subjects with biomarker reductions will be determined. 
The methods for all efficacy statistical analyses will be defined in the SAP. 
10.8 
Safety Analyses 
Data from all subjects that receive at least 1 dose of SPH4336 will be included in the safety 
analyses. AEs, clinical laboratory information, vital signs, ECOG performance status, body 
weight, ECGs, and concomitant medications and procedures will be tabulated and summarized. 
AEs will be summarized overall and with separate summaries for serious AEs, AEs leading to 
discontinuation, AEs leading to death, and CTCAE v5.0 Grade 3 or higher AEs. AEs will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA) and summarized using 
system organ class and preferred term for all subjects in the Safety Population. 
Body weight and vital signs will be summarized descriptively (N, mean, standard deviation, 
median, minimum, and maximum). ECOG will be summarized categorically and descriptively. 
Shift tables displaying subject counts and percentages classified by baseline grade and maximum 
grade on treatment will be provided for all laboratory data. A marked laboratory change is 
defined as a shift from a baseline Grade 0 to Grade 3 (non-hematologic) or Grade 4 or greater 
(hematologic) on treatment, or a shift from a baseline Grade 1 to Grade 4 or greater on treatment. 
The number and percentage of subjects with marked laboratory changes will be tabulated. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO Drug) and they will be listed and summarized by dose level. 
10.9 
Pharmacokinetic Analyses 
Individual and mean (± standard deviation) plasma SPH4336 concentration-time data (and 
SPH4336, metabolites if appropriate) will be tabulated and plotted. SPH4336 PK parameters will 
be estimated from the plasma SPH4336 concentration-time data using a non-compartmental 
analysis method. Alternative methods may be considered. Estimated individual and mean (±SD) 
PK parameters will be tabulated and summarized. Other descriptive statistics may be reported for 
plasma SPH4336 concentration-time data and estimated PK parameters. Dose proportionality, 
SPH4336 accumulation, and attainment of steady state will be evaluated as data allow. 
PK parameters evaluated will include plasma concentration-time profiles and Cmax, Tmax, AUClast, 
AUCinf, t1/2, CL/F, Vss/F, Accumulation Ratio for Cmax, AUC, as appropriate. These parameters 
will be listed by individual subject and summarized by descriptive statistics (means, medians, 
ranges, standard deviations and coefficient of variation, as appropriate). 
10.10 Interim Analyses 
No formal interim analysis is planned. 


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10.11 Determination of Sample Size 
Based on historical data19, PFS at 12 weeks of > 60% is considered promising and a PFS of < 
35% is considered not promising.19 A sample size of 29 subjects provides at least 90% power 
with type I error rate of 0.1 to decide whether the PFS rate at 12 weeks is less than or equal to 
0.35 or greater than or equal to 0.60.23 If the number of subjects who are progression-free at 12 
weeks is 14 or more, the hypothesis that the PFS rate at 12 weeks is less than or equal to 35% is 
rejected. If the number of subjects who are progression-free at 12 weeks is less than 14, the 
hypothesis that the PFS rate at 12 weeks is greater than or equal to 60% is rejected. Sample size 
was calculated using a single-stage Phase 2 clinical trial.23 A final sample size of 33 will be 
utilized to account for a non-evaluable rate of 15%. 
10.12 Final Analysis Time Point 
The final analysis of the study will occur when the first of either of the following occurs: 
• Accrual has ceased and no subjects remain on study 
• Accrual has ceased and no subject has been on study for less than 12 months 
11 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
11.1 
Ethical Standard 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Subjects of Research codified in: 
• United States Code of Federal Regulations (CFR) applicable to clinical studies: 45 CFR 
Part 46, 21 CFR Parts 11, 50, 54, 56, 312 
• ICH E6 
• Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013) 
• Applicable local legal and regulatory requirements 
11.2 
Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment material by an appropriate IRB 
registered with the OHRP. 
Protocol amendments require review and approval by the applicable IRB prior to 
implementation. 
Changes to the informed consent form will be submitted to the appropriate IRB for review. 
At the time of any protocol amendment or change to the informed consent document, an 
assessment will be made regarding the need for re-consenting existing subjects. 


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11.3 
Subject and Data Confidentiality 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
The study subject’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and Institutional regulations. 
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored by the Sponsor. This will not include the subject’s contact or 
identifying information. Rather, individual subjects and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by the Sponsor will be secured and password protected. At the end of the study, 
all study databases will be de-identified and archived by the Sponsor. 
11.4 
Research Use of Stored Human Samples, Specimens or Data 
The Sponsor will be responsible for all stored samples generated during this study. Some 
samples will be stored with specific vendors as appropriate (e.g., pharmacokinetic samples). 
Samples and data will be stored using codes assigned by the clinical data system. Data will be 
kept in password-protected computers. 
11.5 
Future Use of Stored Specimens 
Data collected for this study will be analyzed and stored by the Sponsor. After the study is 
completed, the de-identified, archived data will be maintained by the Sponsor and may be made 
available for use by other researchers including those outside of the study. 
With the subject’s approval and as approved by local IRBs, de-identified biological samples will 
be stored by the Sponsor with the same goal as the sharing of data with other researchers, some 
of whom may be outside of this study. 
During the conduct of the study, an individual subject can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage will not be possible after the study is completed. 
11.6 
Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the clinical database 
and shall be treated in compliance with all applicable laws and regulations. When archiving or 
processing personal data pertaining to the Investigator or sub investigator, all appropriate 
measures will be taken to safeguard and prevent access to this data by any unauthorized party. 


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11.7 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between the 
Sponsor and applicable parties. 
12 DATA HANDLING AND RECORD KEEPING 
12.1 
Data Collection Responsibilities 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported by his or her site to the Sponsor. 
This study will utilize a 21 CFR Part 11-compliant data capture system provided by the Sponsor 
or its representative for the purposes of data collection. Specific instructions on the system used 
for data collection will be provided to the study sites. Clinical data will be entered directly from 
the source documents. 
12.2 
Amendments to the Protocol 
If an amendment to the protocol is required, the amendment will originate from and be 
documented by the Sponsor or its representative. 
The amendment will be submitted to the FDA or other regulatory authorities by the Sponsor as 
applicable. IRB/EC approval will be obtained as applicable. 
If an amendment to the protocol substantially alters the risk or benefit to the subjects, subject 
consent to continue participation in the study may be required. 
12.3 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications in 
an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of SPH4336. These documents may be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the 
Sponsor. It is the responsibility of the Sponsor to inform the Investigator when these documents 
no longer need to be retained. 
12.4 
Data Collection 
The study electronic CRF is the primary data collection instrument for the study. Case report 
forms will be completed in English. 
In order to maintain confidentiality only study number, subject number and date of birth will 
identify the subject in the eCRF system. If the subject’s name appears on any other document 
(e.g., laboratory report), it must be redacted on the copy of the document to be supplied to the 
Sponsor and replaced instead with the subject number. The Investigator will maintain a personal 


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subject identification list (subject numbers with corresponding subject identifiers) for subjects 
enrolled at his or her site to enable records to be identified and verified as authentic. Subject 
data/information will be kept confidential, and will be managed according to applicable local, 
state, and federal regulations. 
All data requested by the eCRF system must be supported by and be consistent with the subject’s 
source documentation. All missing data must be explained. For any entry errors made, the 
error(s) must be corrected, and a note explaining the reason for change should be provided. 
The Investigator will electronically sign and date the subject eCRF indicating that the data in the 
eCRF is accurate. Each completed eCRF will be signed and dated by the Investigator once all 
data for that subject is final. 
12.5 
Disclosure and Publication Policy 
The Sponsor reserves the right to release literature publications based on the results of the study. 
Results from the study will be published/presented as per the Sponsor’s publication process. In 
general, authorship will be determined by the number of eligible subjects enrolled in the study by 
any given Investigator site and/or by the extent to which an individual Investigator may have 
contributed to the scientific design of the protocol. The Sponsor will have final say in 
determining authorship on any publication. 
12.6 
Data Handling for Subject Withdrawal or Termination 
Data generated from subjects prior to withdrawal of consent or withdrawal from the study will be 
maintained and utilized in the final study analysis. 
No data generated from subjects after their withdrawal from the study will be collected. 
13 REFERENCES 
1.  European Society of Medical Oncology. Performance Scales: Karnofsky & ECOG Scores. 
Oncology//Pro. 2018. https://oncologypro.esmo.org/oncology-in-practice/practice-
tools/performance-scales 
2.  Schwartz LH, Litière S, Vries E de, et al. RECIST 1.1 – Update and Clarification: From the 
RECIST Committee. Eur J Cancer. 2016;62:132-137. 
3.  https://www.kidney.org/professionals/kdoqi/gfr_calculatorCoc 
4.  Fridericia LS. The duration of systole in an electrocardiogram in normal humans and in 
patients with heart disease. Ann Noninvasive Electrocardiol. 2003;8(4):343-351. 
5.  Jones RL, Lee ATJ, Thway K, Huang PH. Clinical and molecular spectrum of liposarcoma. 
J Clin Oncol. 2018;36(2):151-159. 


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6.  Bock S, Hoffmann DG, Jiang Y, Chen H, Il’yasova D. Increasing incidence of liposarcoma: 
A population-based study of national surveillance databases, 2001–2016. Int J Environ Res 
Public Health. 2020;17(8). 
7.  Assi T, Kattan J, Rassy E, et al. Targeting CDK4 (cyclin-dependent kinase) amplification in 
liposarcoma: A comprehensive review. Crit Rev Oncol Hematol. 2020;153(June):103029. 
8.  Crago AM, Dickson MA. Liposarcoma: multimodality management and future targeted 
therapies. Surg Oncol Clin N Am. 2016;25(4):761–773. 
9.  Dalal KM, Kattan MW, Antonescu CR, Brennan MF, Singer S. Subtype specific prognostic 
nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or 
trunk. Ann Surg. 2006;244(3):381-389. 
10.  Ratan R, Patel SR. Chemotherapy for soft tissue sarcoma. Cancer. 2016;122(19):786-789. 
11.  Chamberlain F, Benson C, Thway K, Huang P, Jones RL, Gennatas S. Pharmacotherapy for 
liposarcoma: Current and emerging synthetic treatments. Futur Oncol. 2021;17(20):2659-
2670. 
12.  Italiano A, Toulmonde M, Cioffi A, et al. Advanced well-differentiated/dedifferentiated 
liposarcomas: Role of chemotherapy and survival. Ann Oncol. 2012;23(6):1601-1607. 
13.  Demetri GD, Von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or 
dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional 
chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol. 
2016;34(8):786-793. 
14.  Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated 
patients with advanced liposarcoma or leiomyosarcoma: A randomised, open-label, 
multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-1637. 
15.  Sheppard KE, Mcarthur GA. The Cell-Cycle Regulator CDK4: An Emerging Therapeutic 
Target in Melanoma. Clin Cancer Res. 19. www.aacrjournals.org. 
16.  Du Q, Guo X, Wang M, Li Y, Sun X, Li Q. The application and prospect of CDK4/6 
inhibitors in malignant solid tumors. J Hematol Oncol. 2020;13(1):1-12. 
17.  Dickson MA, Koff A, D’Angelo SP, et al. Phase 2 study of the CDK4 inhibitor abemaciclib 
in dedifferentiated liposarcoma. J Clin Oncol. 2019;37(15_suppl):11004. 
18.  Dickson MA, Tap WD, Keohan ML, D'Angelo SP, Gounder MM, Antonescu CR, Landa J, 
Qin LX, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK. Phase 
II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-
differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024-2028. 


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19.  Dickson MA, Schwartz GK, Keohan ML, D'Angelo SP, Gounder MM, Chi P, Antonescu 
CR, Landa J, Qin LX, Crago AM, Singer S, Koff A, Tap WD. Progression-Free Survival 
Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With 
CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. JAMA Oncol. 2016; 2(7):937-40. 
20.  Liao XM, Hong Y, Mao Y, et al. SPH3643: A novel cyclin-dependent kinase 4/6 inhibitor 
with good anticancer efficacy and strong blood-brain barrier permeability. Cancer Sci. 
2020;111(5):1761-1773. 
21.  Thway K, Wang J, Swansbury J, Min T, Fisher C. Fluorescence in situ hybridization for 
MDM2 amplification as a routine ancillary diagnostic tool for suspected well-differentiated 
and dedifferentiated liposarcomas: Experience at a tertiary center. Sarcoma. 2015;2015. 
22.  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
23.  Pass 2020 Power Analysis & Sample Size software. 
https://www.ncss.com/download/pass/updates/pass-2020/ 
 
 


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14 APPENDICES 
Table 4: ECOG Performance Status Criteria 
Grade Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time. 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 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead 
Source: European Society of Medical Oncology. Performance Scales: Karnofsky & ECOG Scores. 
Oncology//Pro. 2018. 
 
 
 


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Table 5: New York Heart Association (NYHA) Classification 
Class Functional Capacity 
Objective Assessment 
I 
Subjects with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Subjects 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. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Subjects with cardiac disease resulting in marked limitation 
of physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Subjects with cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present even 
at rest. If any physical activity is undertaken, discomfort is 
increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 
1994:253-256. 
 

SAP_001.pdf: 
Shanghai Pharma Biotherapeutics USA Inc. 
SPH4336-US-01 
Statistical Analysis Plan 
Version 1.0 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: 
 
A PHASE 2 MULTICENTER, OPEN-LABEL STUDY OF 
THE CDK4/6 INHIBITOR SPH4336 IN SUBJECTS WITH 
LOCALLY ADVANCED OR METASTATIC 
LIPOSARCOMAS 
 
 
Phase: 
2 
 
 
Protocol No.: 
SPH4336-US-01 
 
 
Protocol Date(s): 
V2.0 Amendment 1.0 Final Draft 26 July 2022 
 
 
 
 
 
 
Analysis Plan Version and 
Date: 
Version 1.0: 28 October 2024 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION


Shanghai Pharma Biotherapeutics USA Inc. 
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STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL 
 
This Statistical Analysis Plan has been prepared in accordance with team reviewers’ specifications.   
 
Reviewed and Approved By:  
 
 
 
 
 
 
 
28Oct2024 
Kenneth W. Locke, Ph.D. 
Chief Scientific Officer 
Shanghai Pharma Biotherapeutics USA Inc. 
 
Date 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ............................................ 2 
1. 
INTRODUCTION ............................................................................................................... 5 
1.1. 
STUDY OVERVIEW ..................................................................................................... 5 
1.2. 
SCHEDULE OF ASSESSMENTS ................................................................................. 6 
1.3. 
GLOSSARY OF ABBREVIATIONS ............................................................................. 9 
2. 
OBJECTIVES.................................................................................................................... 11 
3. 
GENERAL STATISTICAL CONSIDERATIONS .......................................................... 11 
3.1. 
SAMPLE SIZE AND POWER ..................................................................................... 11 
3.2. 
RANDOMIZATION AND MASKING ........................................................................ 11 
3.3. 
HANDLING OF DATA ................................................................................................ 11 
3.3.1. 
Strata and Covariates ........................................................................................... 11 
3.3.2. 
Examination of Subject Subsets ........................................................................... 12 
3.3.3. 
Multiple Testing and Comparisons ...................................................................... 12 
3.3.4. 
Missing Data and Outliers .................................................................................... 12 
3.3.5. 
Imputation of Incomplete Dates ........................................................................... 12 
3.3.5.1. 
Imputation of Adverse Events and Prior/Concomitant Medications and Procedures
 
12 
3.3.5.2. 
Imputation of Missing Date of Initial Cancer Diagnosis ...................................... 13 
3.3.5.3. 
Imputation of Missing Date of Death .................................................................. 13 
3.3.6. 
Imputation of Missing Severity or Relationship for Adverse Events .................. 13 
3.3.7. 
Data Handling Rules for Efficacy Data ................................................................ 14 
3.3.8. 
Presentations by Study Visit................................................................................. 14 
3.3.9. 
Definitions and Terminology ................................................................................ 14 
3.4. 
TIMING OF ANALYSES ............................................................................................. 16 
4. 
ANALYSIS POPULATIONS ............................................................................................ 16 
4.1. 
SAFETY ANALYSIS POPULATION ......................................................................... 17 
4.2. 
EFFICACY-EVALUABLE POPULATION ................................................................ 17 
5. 
STATISTICAL METHODS.............................................................................................. 18 


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5.1. 
SUBJECT DISPOSITION ............................................................................................ 18 
5.2. 
DEMOGRAPHIC CHARACTERISTICS ................................................................... 18 
5.3. 
BASELINE CHARACTERISTICS AND CANCER HISTORY................................. 18 
5.4. 
MEDICAL HISTORY .................................................................................................. 18 
5.5. 
PRIOR THERAPIES AND SURGERY ....................................................................... 19 
5.6. 
EXPOSURE AND COMPLIANCE.............................................................................. 19 
5.7. 
EFFICACY ANALYSIS ............................................................................................... 19 
5.7.1. 
Primary Efficacy Endpoint .................................................................................. 19 
5.7.2. 
Primary Efficacy Analysis .................................................................................... 19 
5.7.3. 
Secondary Efficacy Endpoints ............................................................................. 20 
5.8. 
SAFETY ........................................................................................................................ 21 
5.8.1. 
Adverse Events ..................................................................................................... 21 
5.8.2. 
Clinical Laboratory Assessments ......................................................................... 21 
5.8.3. 
Prior and Concomitant Medications .................................................................... 22 
5.8.1. 
Concomitant Procedures ...................................................................................... 22 
5.8.1. 
Electrocardiogram (ECG) .................................................................................... 23 
5.8.2. 
Vital Signs ............................................................................................................. 23 
5.8.1. 
ECOG ................................................................................................................... 23 
6. 
PROTOCOL DEVIATIONS ............................................................................................. 23 
7. 
CHANGES IN THE PLANNED ANALYSES .................................................................. 23 
8. 
REFERENCES .................................................................................................................. 23 
9. 
PROPOSED TABLES, LISTINGS, AND FIGURES ....................................................... 24 
 


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1. 
INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the planned 
data summary and analysis of data from Protocol SPH4336-US-01. Background information is 
provided for the overall study design and objectives.  The reader is referred to the study protocol 
and case report forms (CRFs) for details of study conduct and data collection. 
1.1. 
STUDY OVERVIEW 
This is a multicenter, non-randomized, open-label Phase 2 study of SPH4336 in subjects with well-
differentiated/dedifferentiated or dedifferentiated liposarcomas. 
SPH4336 was administered orally once each day in successive 28-day cycles until demonstration 
of progressive disease or the development of unacceptable toxicity. 
The study incorporated a safety lead-in for the initial 10 subjects. Safety data was evaluated by the 
Safety Review Committee (SRC) after 10 subjects (minimum 1 cycle completed) were accrued and 
the SRC recommended that the study could continue. 
Tumor assessments according to RECIST v1.1 were performed at baseline and every 6 weeks 
(from C1D1) for 36 weeks, then every 12 weeks thereafter.  
 
 
 
 
 
 
 


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1.2. 
SCHEDULE OF ASSESSMENTS 
Table 1: Schedule of Assessments 
Cycle 
SCN 
C1 
C1 
C1 
C1 
C2 
C2 
C3+ 
C3+ 
ET 
SFU 
LTFU 
Day of cycle 
(+ 2 days) 
-28 to 0 
1 
2 
15 
16 
1 
15 
1 
15 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed exam 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG Performance status 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Adverse events 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
 
Hematology 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Chemistry 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Coagulation 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
COVID-19, HIV, TB, HBV, HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
[X] 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment 
X 
 
 
 
 
 
X 
[X] 
[X] 
[X] 
 
 
Tumor tissue collection 
[X] 
 
 
[X] 
 
 
 
 
 
 
 
 
PK samples 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
SPH4336 compliance 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Disease status 
 
 
 
 
 
 
 
 
 
 
 
X 


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Study assessments (biopsy, laboratory and clinic visits) may be performed ± 2 days of the recommended date. Laboratory assessments may be performed in 
advance of clinic visits. 
Screening (SCN) is performed within 28 days of Cycle 1 Day 1 (C1D1). Screening evaluations may be repeated within 7 days of C1D1 if requested by the 
Medical Monitor (e.g., borderline eligibility or clinical instability) 
End-of-Treatment (ET) visit is performed on day that decision is made to discontinue SPH4336 administration if the decision is made during a clinic visit. In 
subjects where the decision to discontinue SPH4336 administration is made outside of a clinic visit (e.g., based on scan results only available later), 
the ET visit may be combined with the SFU visit. 
Safety Follow-Up (SFU) visit is performed 28 days ± 14 days after last dose of SPH4336. 
ET and SFU visits may be combined if any of the following apply: 1) subject discontinued SPH4336 outside of a clinic visit, 2) subject had no Grade 2 or 
higher SPH4336-related toxicity at their last study visit or, 3) subject started a subsequent therapy. 
Long-Term Follow-Up (LTFU) – Performed at 3-month intervals (±1 month) following last study visit (i.e., ET or SFU) on all subjects achieving at least 
stable disease and do not develop progressive disease while on treatment. LTFU of disease status will be performed until progression of disease, start 
of a new treatment, death or 12 months after last study visit, whichever is sooner. May be conducted via review of the medical record without the need 
for a clinic visit. 
X - Required 
[X] – Optional, or not performed on every visit (see notes below for specific assessments). 
Informed consent – May be performed at any time prior to the start of screening procedures (i.e., outside of the 28-day screening window). 
Medical history – Includes all cancer-related history over a subject’s lifetime and non-cancer related history limited to the 2 years prior to C1D1. 
Symptom-directed exam – Limited physical exam performed in response to symptoms reported by the subject. 
Vital signs – Performed once on visit days. Vital signs include heart rate (per minute), respiratory rate (per minute), blood pressure (mmHg), temperature 
(degrees Fahrenheit). 
Concomitant medications – Recorded from 28 days prior to C1D1 to the time of the ET or SFU visit, except for medications administered as cancer 
treatment, for which lifetime history will be recorded. 
12-lead ECG –ECGs performed as close as possible to each PK draw. ECGs should be performed in triplicate (at least 5 minutes apart) if the QTcF on the 
initial ECG is greater than 470 msecs. Additional ECGs may be collected if clinically indicated. On days without a PK draw, ECGs are performed 
once. 
Hematology – [Blood] Complete blood count with differential to include WBC, RBC, HGB, HCT, platelets, MCV, MCH and differential 
Chemistry – [Blood] Sodium, potassium, chloride, blood urea nitrogen, creatinine, glucose, calcium, AST, ALT, total, direct and indirect bilirubin, alkaline 
phosphatase, total protein, albumin 


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Coagulation – [Blood] PT, activated PTT (aPTT) and INR 
Serum pregnancy test – [Blood] Only required for females of child-bearing potential 
Tumor assessment – Performed at baseline and every 6 weeks (from C1D1) for 36 weeks, then every 12 weeks thereafter. Disease assessments may be 
performed less frequently if appropriate (e.g., subjects with complete responses) and approved by the Medical Monitor. Disease assessment should be 
performed using CT with contrast or MRI (if medically necessary). 
PK sample(s) – [Blood] Collected in Cycle 1 Day 1: pre-dose and 1 h, 2 h, 4 h, 6 h post-dose, Day 2: 24 h post-dose and Day 15: pre-dose and 1 h, 2 h, 4 h, 
6 h post-dose, Day 16: 24 h post-dose and in Cycle 2 (Day 1). 
Tumor Tissue – Availability of archived tumor tissue or performance of a tumor biopsy during screening for confirmation of histologically of a liposarcoma 
with a dedifferentiated component and of CDK4 positivity, if not already known, in all subjects and for baseline tumor biomarker (phospho-Rb, Ki-67) 
determination in the first 10 subjects. A fresh biopsy will be collected on Cycle 1 Day 15 in the first 10 subjects to determine treatment-related changes 
in tumor biomarkers. Collection details are summarized in Protocol Section 5.4 and will be provided in the laboratory manual. 


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1.3. 
GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BLQ 
Below the Limit of Quantification 
BOR 
Best Overall Response 
CDK 
Cyclin-Dependent Kinase 
CI 
Confidence Interval  
COVID 
Coronavirus Disease 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
ET 
End-of-Treatment 
HBV 
Hepatitis B Virus 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HGB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
INR 
International Normalized Ratio 
KM 
Kaplan-Meier 
LLOQ 
Lower limit of quantification 
LTFU 
Long-Term Follow-Up 
MCH 
Mean Cell Hemoglobin 
MCV 
Mean Cell Volume 
MedDRA Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NE 
Not Evaluable 
ORR 
Overall Response Rate 
OS 
Overall Survival 
OTR 
Objective Tumor Response 


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PD 
Progressive Disease 
PD 
Pharmacodynamic 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin Time 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
QTcF 
QT Interval corrected using Fridericia’s formula 
RBC 
Red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCN 
Screening 
SD 
Standard Deviation 
SD 
Stable Disease 
SFU 
Safety Follow-Up 
SOC 
System Organ Classification 
SRC 
Safety Review Committee 
TB 
Tuberculosis  
TEAE 
Treatment Emergent Adverse Events 
TTR 
Time to Response  
WBC 
White blood cells 
WHO 
World Health Organization  
WHODD 
WHO Drug Dictionary 
 


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2. 
OBJECTIVES 
Primary Objective: 
 
The objective of this study was to evaluate the efficacy (PFS at Week 12) of SPH4336 in subjects 
with well-differentiated/dedifferentiated (WDLS/DDLS) or dedifferentiated (DDLS) liposarcomas. 
 
Secondary Objectives: 
 
The secondary objectives were as follows:  
• To evaluate the safety and tolerability profile of SPH433 (AEs)  
• To evaluate the pharmacokinetics of SPH4336 (non-compartmental PK)  
• Median PFS, Best Overall Response, Duration of Response, Time to Response, Overall 
Survival and other efficacy assessments 
• To evaluate various tumor tissue biomarkers (phospho-Rb, Ki-67) for activity in the first 10 
patients enrolled  
 
3. 
GENERAL STATISTICAL CONSIDERATIONS 
3.1. 
SAMPLE SIZE AND POWER 
Based on historical data, Progression Free Survival (PFS) at 12 weeks of > 60% is considered 
promising and a PFS of < 35% is considered not promising. A sample size of 29 subjects provides at 
least 90% power with type I error rate of 0.1 to decide whether the PFS rate at 12 weeks is less than 
or equal to 0.35 or greater than or equal to 0.60. If the number of subjects who are progression-free 
at 12 weeks is 14 or more, the hypothesis that the PFS rate at 12 weeks is less than or equal to 35% 
is rejected. If the number of subjects who are progression-free at 12 weeks is less than 14, the 
hypothesis that the PFS rate at 12 weeks is greater than or equal to 60% is rejected. Sample size was 
calculated using a single-stage Phase 2 clinical trial design. A final sample size of 33 was intended 
to be utilized to account for a non-evaluable rate of 15%. 
 
3.2. 
RANDOMIZATION AND MASKING 
 
This is a non-randomized, open-label study. 
3.3. 
HANDLING OF DATA 
3.3.1. 
Strata and Covariates 
No stratifications among subjects or the use of covariates is planned. 


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3.3.2. 
Examination of Subject Subsets 
No subgroup analyses are planned.  
3.3.3. 
Multiple Testing and Comparisons  
No adjustments for multiplicity are planned. 
3.3.4. 
Missing Data and Outliers 
Every effort was made to obtain required data at each scheduled evaluation from all subjects. In 
situations where it was not possible to obtain all data, imputations of missing data may be 
necessary. These situations are described below. Unless otherwise specified, no imputation for 
missing data will be performed. 
 
3.3.5. 
Imputation of Incomplete Dates 
3.3.5.1. 
Imputation of Adverse Events and Prior/Concomitant Medications and 
Procedures 
An incomplete date occurs when the exact date an event started or ended cannot be obtained from a 
subject. The database contains data fields for month, day, and year. A date is incomplete if at least 
one of these three fields is not known.  
For many of the planned analyses, a complete date is necessary to determine if the event should be 
included in the analysis (i.e., if the event is treatment-emergent) or to establish the duration of an 
event. In such cases, incomplete dates will be imputed. 
For the purposes of handling partially reported start and stop dates for an event the following 
algorithm will be applied: 
• Missing start day, but month and year present: 
If the event occurs in the same month and year as the dosing of study drug, then the start day of the 
event will be assigned to the day of first dose of study drug. 
Otherwise, the start day will be set to the first day of the month. 
• Missing start day and month, but year present: 
If an event occurs in the same year as study drug dosing, then the start date of the event will be 
assigned to Day 1. 
Otherwise, the start day and month will be set to 01 January. 


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• Missing all components of a start date:  
Assign the date of Day 1. 
• Missing end day, but month and year present: 
The day will be set to the last day of the month. 
• Missing end day and month, but year present: 
The end day and month will be set to the date of study completion/discontinuation.  However, if the 
study completion/discontinuation year is greater than the year of the event, then the day and month 
will be set to 31 December. 
• In the event of a completely missing end date (year not present and ongoing not checked), the end 
date will be imputed as the last day of dosing. If the imputed date is later than the date of study 
completion/discontinuation, then the date of study completion/discontinuation will be imputed for 
the date. 
If any imputed date causes the end date to occur prior to the start date of the event, the start date of 
the event will be used for the imputation of the end date. If any imputed date causes the start date 
of the event to occur after the end date of the event, the end date of the event will be used for the 
imputation of the start date. In subject data listings, start and stop date of events will be displayed 
as reported on the eCRF (i.e., imputed values will not be listed). 
3.3.5.2. 
Imputation of Missing Date of Initial Cancer Diagnosis 
For any partial initial diagnosis dates, the following imputation rules will be applied: 
• Missing day will be set to 01.  
• If both month and day are missing, the date will be set to 01 January. 
 
3.3.5.3. 
Imputation of Missing Date of Death 
Partial death dates are not expected. However, for any partial death dates, the following imputation 
rules will be applied: 
• Missing day will be set to 01.  
• If both month and day are missing, the date will be set to 01 January. 
 
3.3.6. 
Imputation of Missing Severity or Relationship for Adverse Events 
Adverse events (AEs) with missing severity or relationship to study drug will not be imputed. 
Actual values will be presented in the data listings.  
 


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3.3.7. 
Data Handling Rules for Efficacy Data 
Subjects were assigned to one of the following best overall response categories: Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), or Not 
Evaluable (NE) by the investigator. 
Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, a subject response was 
classified as NE for a timepoint if no measurement is performed. If only a subset of lesion 
measurements are made at an assessment, the case will be considered NE unless the contribution of 
the individual missing lesion(s) is considered to not change the assigned time point response.  
A subject will be considered to have a response if all the criteria for response have been met per 
RECIST v1.1. 
3.3.8. 
Presentations by Study Visit 
Visits will be presented according to the nominal visit obtained from the CRF or laboratory data. 
Unscheduled assessments will be included in the listings. 
3.3.9. 
Definitions and Terminology 
Age 
The age of a subject is defined as the number of whole years between the subject’s birth date and 
the date of informed consent. 
 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value obtained prior 
to administration of SPH4336. If the last non-missing collection of ECGs is collected in triplicate, 
the average will be used for the baseline value.   
 
Day 1 (Baseline)  
Day 1 is the earliest day that study drug is initiated. 
 
Study Day  
Study Day is defined relative to the day of first dose administration on Cycle 1, Day 1. Thus, the 
study day of an event is calculated as: 
date of event – date of first dose + 1, if event is on or after Cycle 1 Day 1, OR 
date of event – date of first dose, if event is before Cycle 1 Day 1 
 
There is no Day 0. 
 
Days on Study 
Days on Study is the number of days from Day 1 to the date of study completion or early 
termination as recorded on the End of Study CRF.  


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Study Visit  
Study Visit is the nominal visit as recorded on the CRF.   
 
Change from Baseline  
Change from baseline for a given endpoint is defined as the Study Day X value minus the Baseline 
Value. 
 
Last Dose of Study Drug 
Last Dose of study drug is defined as the last date that the subject received SPH4336 as determined 
by last date of dosing as recorded on the End of Treatment CRF. 
Study Drug Exposure 
 
Study drug exposure will be summarized by duration of exposure (days), total dose received (mg) 
and daily dose (mg) received. 
 
Duration of exposure will be presented in days and is defined as the number of days from the date 
of First Dose to the date of Last Dose calculated as:  
(the date of last dose– date of first dose + 1) and corrected for any days dose was held. 
Total dose received (mg) will be calculated as the (sum of all tablets dispensed – sum of all tablets 
returned) x (100 mg) + (sum of all tablets dispensed – sum of all tablets returned) x (200 mg). If the 
number of tablets dispensed or returned is missing, it is assumed that the number of tablets returned 
was 0. 
 
Daily dose received (mg) will be calculated as total dose received (mg) / duration of exposure in 
days for each subject. 
 
Study Drug Treatment Compliance 
Treatment compliance will be calculated as a percentage based on the total dose received (mg) 
divided by the adjusted planned administration (mg) (extent of exposure after adjusting for any 
dose modifications or holds). 
 
Adjusted planned administration (mg) will be calculated based on the number of days of planned 
dose multiplied by 400 (mg). Number of days of planned dose will be defined as the cycle duration 
or days until end of treatment (whichever was smaller) for each planned dose per cycle minus the 
number of days dose held as reported on the Study Drug Administration CRF. 
 
Adverse Event 
An AE is any untoward medical event that occurs to a subject following signing of the study 
Informed Consent Form (ICF), whether or not the event is considered SPH4336-related. AEs will 
be recorded as those that occur following signing the ICF through the sooner of 28 days after the 
last dose of SPH4336 or until the start of additional anticancer therapy. 


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Treatment-emergent Adverse Event  
A TEAE will be an AE that occurred during the study after the first dose of study drug. Treatment-
emergent AEs will be recorded from the first administration of SPH4336 up to the sooner of 28 
days after the last dose of SPH4336 or until the start of additional anti-cancer therapy. 
Additionally, it is assumed that an Adverse Event which was reported to have started on Day 1 
occurred after the initiation of study drug. 
 
Serious Adverse Event (SAE) 
An SAE is any AE that results in any of the following outcomes: 
• 
Death 
• 
A life-threatening experience 
• 
An inpatient hospitalization or prolongation of an existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
An event that is not listed above, but that requires intervention to prevent one of the 
outcomes listed above also is considered a SAE 
 
The following will be excluded from the definition of an SAE: 
• 
Elective hospitalizations that are not in response to an AE 
• 
Hospitalizations that are of less than 24 hours duration 
• 
Hospitalization related to disease progression 
 
Concomitant Medications 
Concomitant medications are those medications taken on or after the initiation of SPH4336 and 
will be determined programmatically based on medication start date.  This definition includes 
medications started prior to the initiation of SPH4336, but continuing concomitantly with 
SPH4336. 
 
Prior Medications 
Prior medications are those medications taken and discontinued prior to the initiation of SPH4336 
and will be determined programmatically based on medication start date and end date.  
 
3.4. 
TIMING OF ANALYSES 
The final analysis of the study will occur when accrual has ceased and no patients remain on study 
treatment or if the study is stopped for safety reasons or lack of study drug efficacy. 
 
4. 
ANALYSIS POPULATIONS 
The populations for analysis will include the Safety Analysis Population and Efficacy-Evaluable 
Population.  A PK report describing the PK analysis will be included as an appendix in the clinical 
study report.  An analysis of the biomarkers was not performed.  Since the study ended prematurely 
because of futility, a limited analysis of efficacy will be performed. 


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4.1. 
SAFETY ANALYSIS POPULATION 
The Safety Population will include all subjects who receive at least one dose of SPH4336.  
4.2. 
EFFICACY-EVALUABLE POPULATION 
 
The protocol defined the Efficacy-Evaluable Population is to include all subjects who received at 
least 1 dose of SPH4336 and met at least one of the following 2 criteria: have at least 2 post-
baseline disease assessments (including at Week 12) and received study treatment for at least 12 
weeks without disease progression; or experience disease progression while on study treatment. 


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5. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study, with no 
hypothesis testing performed for the primary and other selected efficacy endpoints. Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (N), number of observations 
(n), mean, median, standard deviation (SD), interquartile range, minimum, and maximum for 
continuous data and frequencies and percentages for categorical data.  
 
Data required for an abbreviated clinical study report will be included in the data listings. Unless 
otherwise noted, the data will be sorted first by subject number, date, and time (as applicable). 
 
The statistical analyses will be conducted with the SAS® System version 9.4 or higher. 
5.1. 
SUBJECT DISPOSITION 
Subject disposition will be presented for the Safety Population in Tables and Listings. Summaries 
will include the reason(s) for discontinuation.  
 
Subject disposition, protocol deviations and inclusion / exclusion criteria (for screened subjects) 
will be presented in data listings. 
 
5.2. 
DEMOGRAPHIC CHARACTERISTICS 
Demographic characteristics will be summarized based on the Safety Population.  Demographic 
variables including age, sex, ethnicity and race will be summarized. Age at the time of informed 
consent, as collected on the eCRF, will be summarized using descriptive statistics. Sex, ethnicity 
and race will be summarized with the number and percentage of subjects in each parameter 
category. Demographic characteristics will be presented in a data listing. 
5.3. 
BASELINE CHARACTERISTICS AND CANCER HISTORY 
Baseline characteristics include weight (lb) and ECOG performance status score at baseline. 
Weight will be summarized using descriptive statistics. Frequency counts and percentages will be 
used to summarize subjects’ ECOG performance status score and cancer history. 
Baseline characteristics and cancer history data will be presented in data listings. 
5.4. 
MEDICAL HISTORY 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0 or later by preferred term (PT) and system organ classification (SOC). The number 
and percentage of subjects experiencing each medical history event will be summarized by SOC 
and PT for the Safety Population. A listing of medical history will also be provided.  


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5.5. 
PRIOR THERAPIES AND SURGERY 
Prior systemic cancer treatment, prior radiation therapy, and prior cancer surgery will be listed. The 
following will be presented in summary tables: 
• 
Number and % of subjects with any prior systemic cancer treatment 
• 
Number and % of subjects with any prior radiation therapy 
• 
Number and % of subjects with any prior cancer surgery 
 
5.6. 
EXPOSURE AND COMPLIANCE 
 
Exposure and compliance to SPH4336 will be summarized and listed for the Safety Population. 
Duration of exposure (days), total (mg) and daily dose (mg) received and treatment compliance (%) 
will be summarized using descriptive statistics as described in Section 3.3.9. 
 
Study drug administration, drug accountability, exposure, and compliance information will be 
presented in data listings. 
5.7. 
EFFICACY ANALYSIS 
 
5.7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint was to be the number and percentage of Efficacy-Evaluable subjects 
who had Progression-Free Survival (PFS) at 12 weeks. PFS is defined as the time interval from the 
date of the first dose of the SPH4336 until the first date at which disease progression is documented 
as assessed by the Investigator or date of death due to any cause, whichever occurs first. Subjects 
who were alive and progression-free at the time of data analysis were to be censored at the time of 
their last tumor assessment. Progression was evaluated by the investigator according to RECIST 
v1.1. 
5.7.2. 
Primary Efficacy Analysis 
Limited efficacy analyses (tabulations) will be performed because this study ended prematurely 
due to futility (lack of efficacy).  A by-patient listing of the objective responses evaluated by the 
investigators will be included in the report.  The listing and table displaying duration of dosing will 
display the number of subjects who were dosed for 12 weeks or more without disease progression, 
and subjects who experienced disease progression at any time during the study, which were the 
criteria for inclusion in the Efficacy-Evaluable analysis dataset. 
After 13 patients were enrolled in the study, too few Efficacy-Evaluable patients had reached 12 
weeks of dosing without disease progression (2 of 10) to obtain a positive result for the primary 
study objective (see Section 3.1 Sample Size and Power). A futility analysis was performed, and it 
showed that the study would most likely not reach the threshold for a positive signal, even if 
additional patients were enrolled. A fourteenth patient was enrolled, but the study was closed (due 
to futility) before week 12. 


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Bayesian Evaluation of Futility 
# Efficacy-Evaluable Patients 
Stop Study if #Responses ≤ 
10 
2 
11 
3 
12 
3 
13 
4 
14 
4 
15 
5 
16 
5 
17 
6 
18 
6 
29 
13 
 
The analysis above was performed using available software (BOP2: Bayesian Optimal Phase II 
Design with Simple and Complex Endpoints (mdanderson.org)) and a simulation was conducted 
evaluating different sample sizes between current enrollment at the time of the evaluation (n=8) 
and full protocol enrollment (n=29). 
5.7.3. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints were to include: 
• 
Median PFS 
• 
Best Overall Response (BOR) 
• 
Overall Response Rate (ORR) 
• 
Duration of Response (DOR) 
• 
Time to Response (TTR) 
• 
Overall Survival (OS) 
 
BOR will be tabulated, and overall response will be recorded in listings, but otherwise, analyses of 
secondary efficacy endpoints will not be performed because this study was prematurely ended due 
to a lack of efficacy.   
 


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5.8. 
SAFETY 
Data from all subjects that receive at least one dose of SPH4336 (Safety Population) will be 
included in the safety analyses. 
5.8.1. 
Adverse Events 
Treatment emergent adverse events (TEAEs) will be coded by System Organ Class and preferred 
term using MedDRA version 23.0 or higher. The investigator grades the severity/intensity of each 
AE with National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0 and categorizes the relatedness of the AE to SPH4336.  
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending incidence of system organ class and preferred term within each system organ class. 
Summaries of the following types will be presented: 
• 
Overall Summary of Treatment-Emergent Adverse Events; 
• 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term; 
• 
Related Treatment-Emergent Adverse Events by CTCAE Grade, System Organ Class and 
Preferred Term; 
• 
CTCAE Grade 3 or Higher Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term; 
• 
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term; 
• 
Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term; 
• 
Treatment-Emergent Adverse Events Leading to Discontinuation of SPH4336 by System 
Organ Class and Preferred Term; 
Summaries of AEs will include the number and percentages of subjects with each preferred term 
and SOC unless specified otherwise. Missing onset dates will be imputed as previously outlined in 
Section 3.3.5.1 as required to determine treatment-emergent events. 
All adverse events reported will be listed for individual subjects showing both verbatim and 
preferred terms. All adverse events that occurred prior to the initiation of study drug or more than 
28 days after last dose of study drug will be excluded from the tables, but will be included in the 
listings. No imputation for missing severity or relationship will be applied for listings. 
5.8.2. 
Clinical Laboratory Assessments 
Results from both local laboratories and the central laboratory used in this study are included in all 
data displays. 
All descriptive summaries of laboratory results will be presented in Système International (SI) 
units, as suggested by the Center for Biologics Evaluation and Research and the Center for Drug 
Evaluation and Research Position on Use of SI Units for Lab Tests (Oct 2013). Descriptive 


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statistics of chemistry, hematology, and coagulation clinical laboratory results and their 
corresponding change from baseline will be presented at each visit where parameters were 
scheduled to be collected per the clinical study protocol.  
Where applicable, hematology, chemistry and coagulation results for select parameters will be 
assigned a toxicity grade based on the U.S. Department of Health and Human Services Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0 (27 Nov 2017). If the quantitative 
criteria for grading are equivalent for two grades and the differentiation is described by clinical 
interventions, the clinical intervention component will not be considered and the highest CTCAE 
grade will be assigned. Similarly, death related to AE (i.e., Grade 5) cannot be determined with 
available laboratory-based data collection and, thus, will not be summarized as a category. 
Laboratory parameters that include multiple sets of criteria for each direction (e.g., separate criteria 
for potassium measures to assess hyperkalemia and hypokalemia) will be summarized separately to 
reflect each set of criteria. 
Five-by-five contingency tables will be presented for lab tests where toxicity grading can be 
applied, to summarize the shift from the baseline grade to the worst post-baseline grade. Grades 
will be presented as none (Grade 0; i.e., measurements did not meet any CTCAE criteria for Grades 
1 through 4), mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4). 
Summary results will include the count and percentage of subjects within each shift category. 
Hematology, chemistry and coagulation parameters will be presented in data listings. 
5.8.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug Dictionary (WHODD) 
Global B3 March 2022 or later. Medications entered on the eCRF will be mapped to Anatomic 
Therapeutic Chemical (ATC) drug class and drug name.  
Concomitant medications will be summarized. The number and percentage of subjects receiving 
any medication will be summarized, as will the number and percentage receiving any medication 
by ATC drug class and generic drug name. Subjects reporting use of more than one medication at 
each level of summarization (any medication received, ATC class, and generic drug name) will be 
counted only once. ATC class terms will be displayed by descending order of incidence, as will 
generic drug names within each ATC class.  
All medications will be listed.  
5.8.1. 
Concomitant Procedures 
Concomitant procedures will be coded using MedDRA Version 22.0 or later. Concomitant 
procedures will be summarized. The number and percentage of subjects receiving any procedures 
will be summarized, as will the number and percentage receiving any procedures by system organ 
class (SOC) and preferred term. Subjects reporting more than one procedure at each level of 
summarization (any procedure, SOC, and preferred term) will be counted only once. All 
procedures will be listed.  


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5.8.1. 
Electrocardiogram (ECG) 
Descriptive statistics of heart rate/pulse (beats/min), RR interval (msec), PR interval (msec), QRS 
interval (msec), QT interval (msec) and QTcF (msec) interval and changes from baseline will be 
summarized, as well shift tables for overall interpretation. ECG parameters will be presented in 
data listings. 
5.8.2. 
Vital Signs 
Descriptive statistics for vital signs including heart rate (beats per minute), respiratory rate (breaths 
per minute), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and temperature 
(Fahrenheit) values and changes from baseline will be summarized. 
Vital signs parameters will be presented in data listings.  
5.8.1. 
ECOG 
The number and percentage of subjects with each ECOG performance status (0, 1, 2, 3, 4, 5) will 
be summarized categorically. Change from baseline for each post-baseline visit will also be 
summarized. 
 
A listing of ECOG performance status results will be presented.  
6. 
PROTOCOL DEVIATIONS 
Subjects with protocol deviations will be presented in data listings. 
7. 
CHANGES IN THE PLANNED ANALYSES 
The study ended prematurely because of a lack of efficacy in study patients.  Therefore, a formal 
analysis of efficacy will not be performed.  Biomarker analysis was also not performed. 
No other changes in the planned analysis are anticipated.  Should any deviations from the analyses 
specified in the authorized statistical analysis plan arise, such deviations will be documented in the 
final clinical study report. 
8. 
REFERENCES 
E. L. Kaplan & Paul Meier (1958) Nonparametric Estimation from Incomplete 
Observations, Journal of the American Statistical Association, 53:282, 457-481 


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9. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
 
Number 
Title 
Population 
Tables 
14.1.1 
Subject Disposition 
Safety 
14.1.2 
Demographic Characteristics 
Safety 
14.1.3 
Baseline Characteristics and Cancer History 
Safety 
14.1.4 
Medical History 
Safety 
14.1.5 
Prior Therapies and Surgery 
Safety 
14.1.6 
Study Drug Exposure and Compliance 
Safety 
14.2.1 
Best Overall Response 
Efficacy 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety 
14.3.1.3 
Related Treatment-Emergent Adverse Events by CTCAE Grade, 
System Organ Class and Preferred Term 
Safety 
14.3.1.4 
CTCAE Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety 
14.3.1.5 
Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
Safety 
14.3.1.6 
Treatment-Emergent Adverse Events Leading to Death by System 
Organ Class and Preferred Term 
Safety 
14.3.1.7 
Treatment-Emergent Adverse Events Leading to Discontinuation of 
SPH4336 by System Organ Class and Preferred Term 
Safety 
14.3.2.1 
Listing of Deaths 
Safety 
14.3.2.2 
Listing of Serious Adverse Events 
Safety 
14.3.2.3 
Listing of Grade 3 or Higher Adverse Events 
Safety 
14.3.2.4 
Listing of Adverse Events Leading to Discontinuation of SPH4336 
Safety 
14.3.3.1 
Hematology Results and Changes from Baseline 
Safety 
14.3.3.2 
Shift in Hematology Laboratory Values in CTCAE Toxicity Grade 
to the Worst Abnormal Value  
Safety 
14.3.3.3 
Chemistry Results and Changes from Baseline 
Safety 
14.3.3.4 
Shift in Chemistry Laboratory Values in CTCAE Toxicity Grade to 
the Worst Abnormal Value  
Safety 
14.3.3.5 
Coagulation Results and Changes from Baseline 
Safety 
14.3.3.6 
Shift in Coagulation Laboratory Values in CTCAE Toxicity Grade  
to the Worst Abnormal Value  
Safety 


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14.3.4.1 
Concomitant Medications 
Safety 
14.3.4.2 
Concomitant Procedures 
Safety 
14.3.5.1 
Vital Signs Results and Changes from Baseline 
Safety 
14.3.5.2 
12-Lead Electrocardiogram - Univariate Summary by Parameter and 
Visit 
Safety 
14.3.5.3 
12-Lead Electrocardiogram Interpretation - – Shift from Baseline to 
Worst Post-Baseline Value 
Safety 
14.3.6 
Summary of ECOG Performance Status 
Safety 
Listings 
16.2.1 
Subject Disposition 
Safety, 
Screened 
16.2.2 
Inclusion/Exclusion Criteria  
Screened 
16.2.3 
Protocol Deviations  
Safety 
16.2.4.1 
Demographic Characteristics 
Safety 
16.2.4.2 
Medical History 
Safety 
16.2.4.3 
Baseline Characteristics and Cancer History 
Safety 
16.2.4.4 
Prior Systemic Cancer Treatment 
Safety 
16.2.4.5 
Prior Radiation Therapy 
Safety 
16.2.4.6 
Prior Cancer Surgery 
Safety 
16.2.4.7 
Prior and Concomitant Medications 
Safety 
16.2.4.8 
Concomitant Procedures 
Safety 
16.2.5.1 
Study Drug Administration 
Safety 
16.2.5.2 
Drug Accountability 
Safety 
16.2.5.3 
Study Drug Exposure and Compliance 
Safety 
16.2.6.1 
Overall Response 
Safety 
16.2.6.2 
Target Lesion Assessment 
Safety 
16.2.6.3 
Non-Target Lesion Assessment 
Safety 
16.2.6.4 
New Lesion Assessment 
Safety 
16.2.7 
Adverse Events  
Safety 
16.2.8.1.1 
Hematology 
Safety 
16.2.8.1.2 
Chemistry 
Safety 
16.2.8.1.3 
Coagulation 
Safety 
16.2.8.2 
Vital Signs 
Safety 
16.2.8.3 
ECOG Performance Status 
Safety 
16.2.8.4 
12-Lead Electrocardiogram 
Safety 
16.2.8.5 
Physical Examination 
Safety