Clinical trial NCT03416335
Conditions: Neoplasms
Keywords: DSP-0509 Toll-Like Receptor 7 (TLR-7) BLRM (Bayesian Logistic Regression Model)
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2018-06-01; Completion date: 2022-12-20
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center, Phase 1 / 2 clinical study for patients with advanced solid tumors. The study consists of 2 treatment arms - a monotherapy arm and a combination arm. The monotherapy arm has 1 part: Dose Escalation (Part A). The combination arm has Dose Escalation (Part B) only.

Detailed description:
The primary objective of Monotherapy Arm A is to determine the MTD or RP2D of DSP-0509 when administered as a single agent. Approximately 21 to 30 patients with advanced solid tumors will be enrolled. Several provisional dose levels of DSP-0509, with approximately 3 to 6 patients at each level may be tested in patients with advanced solid tumors. DSP-0509 will be administered as a single agent q2w beginning on Day 1.

The primary objective of Combination Therapy Arm B is to determine the RP2D of DSP-0509 when administered in combination with pembrolizumab, using a BLRM approach. The combination arm will enroll approximately 21 to 30 patients with advanced solid tumors that are (a) metastatic or unresectable and recurrent, and/or refractory to available therapy, (b) a condition for which pembrolizumab is an approved treatment, and (c) in patients who have shown either primary or acquired resistance to an ICI. DSP-0509 will be administered on Day 1 and then every 2 weeks thereafter. Pembrolizumab will be initiated on Day 1.

The primary objective of Combination Therapy Arm C is to determine preliminary efficacy in the form of the ORR of DSP-0509 when administered in combination with pembrolizumab to an expansion cohort of patients with HNSCC, using a Bayesian Adaptive design approach. Combination Arm C will enroll approximately 20 to 40 patients with HNSCC tumors that are (a) metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in patients who have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, and (c) who have subsequently shown either primary or acquired resistance to ICIs.

Dose escalation of DSP-0509 in combination with 400 mg pembrolizumab q6w will start at the same dose of DSP-0509 as the highest (not exceeding the MTD) level tested in the combination regimen with 200 mg pembrolizumab q3w. Upon completion of the DLT evaluation period for the first DSP-0509 dose level tested in combination with 400 mg pembrolizumab q6w in newly enrolled patients, if this dose level is found not to exceed the MTD, any ongoing patients receiving DSP-0509 in combination with pembrolizumab 200 mg q3w will be allowed, at the investigator's discretion, to transition to the 400 mg pembrolizumab q6w regimen, while maintaining the originally assigned DSP-0509 dose level.

Arms: arm 1: Dose Escalation Drug DSP-0509 arm 2: Dose Escalation Drug DSP-0509, Pembrolizumab arm 3: Dose Expansion, Drug DSP-0509, Pembrolizumab
Interventions: intervention 1: DSP-0509 intervention 2: DSP-0509, Pembrolizumab intervention 3: DSP-0509, Pembrolizumab
Intervention descriptions: intervention 1: Each patient treated will receive DSP-0509 at the dose fixed for that Part or cohort administered as a constant rate IV infusion over 10 minutes using a syringe pump. intervention 2: Each patient treated will receive DSP-0509 at the dose fixed for that Part or cohort administered as a constant rate IV infusion over 10 minutes using a syringe pump and is given in combination with pembrolizumab which should be administered following the dosing schedule of the approved label (200 mg IV q3w) intervention 3: Each patient treated will receive DSP-0509 at the Recommended Phase II Dose (RP2D) level as determined in Part B. It is given as a constant rate IV infusion over 10 minutes using a syringe pump and is given in combination with pembrolizumab which should be administered following the dosing schedule of the approved label (400 mg IV q6w)

Protocol documents:
Prot_000.pdf: 
Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 1 of 122 
CLINICAL STUDY PROTOCOL
AMENDMENT 7  
A First-in-Human Phase 1/2 Trial to Determine the Safety and the Pharmacokinetic Profile of DSP-0509, 
a Synthetic Toll-Like Receptor 7 (TLR-7) Agonist,  
Administered as Monotherapy and in Combination with Pembrolizumab  
in Adult Patients with Advanced Solid Tumors 
Protocol Number: 
BBI-DSP-0509-101 
EudraCT Number:
Not Applicable
Investigational Product: 
DSP-0509 
Phase:
Phase 1/2
Sponsor: 
Sumitomo Dainippon Pharma Oncology, Inc 
640 Memorial Drive 
Cambridge, MA 02139 
US
Contract Research 
Organization: 
Syneos Health 
3201 Beechleaf Court, Suite 600 
Raleigh, NC 27604-1547 
US 
Original Protocol (Version 1) 
Date: 
 
06 Dec 2017 
 
Amendment 1 (Version 2): 
18 Jan 2018 
Amendment 2 (Version 3): 
10 Jul 2018 
Amendment 3 (Version 4):
28 Feb 2019
Amendment 3.1 (Version 5):
19 Apr 2019 
Amendment 4 (Version 6): 
30 Apr 2020  
Amendment 5 (Version 7):
Amendment 6 (Version 8): 
Amendment 7 (Version 9): 
26 Mar 2021
04 May 2021 
15 September 2021 
The information contained in this document is confidential and the proprietary property of 
Sumitomo Dainippon Pharma Oncology, Inc. Any unauthorized use or disclosure of such 
information without the prior written authorization of Sumitomo Dainippon Pharma Oncology, 
Inc. is prohibited.


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
 
Confidential and Proprietary 
 
Page 2 of 122 
 
Signature Page 
Sponsor¶s Approval 
The protocol has been approved by Sumitomo Dainippon Pharma Oncology, Inc. 
 
Sponsor¶s Signatory: 
 
 
 
 
 
 
 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 3 of 122 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for DSP-0509. I have read the 
BBI-DSP-0509-101 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
Date 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 4 of 122 
1. 
CONTACT INFORMATION 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Leader
640 Memorial Drive
Cambridge, MA, 02139 
US 
 
 
Responsible Physician 
 
640 Memorial Drive
Cambridge, MA, 02139
US 
 
 
Drug Safety Physician 
 
640 Memorial Drive
Cambridge, MA, 02139 
US 
 
 
24-Hour Emergency Contact 
 
640 Memorial Drive
Cambridge, MA, 02139 
US 
 
 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 5 of 122 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sumitomo Dainippon Pharma Oncology, Inc 
Name of Investigational Product: 
DSP-0509  
Title of Study:  
A First-in-Human Phase 1/2 Trial to Determine the Safety and the Pharmacokinetic Profile of 
DSP-0509, a Synthetic Toll-Like Receptor 7 (TLR-7) Agonist, Administered as Monotherapy and in 
Combination with Pembrolizumab in Adult Patients with Advanced Solid Tumors 
Study Center(s):  
The study will be conducted in approximately 5 to 15 centers in the US.  
Phase of Development:  
1/2 
Indication: 
As this is a first-in-human (FIH) study, a final indication has not been determined. However, 
DSP-0509 will be studied for the following indications: 
 
Monotherapy Arm A (Dose Escalation, Phase 1)  
 Advanced solid tumors that are metastatic or unresectable, and recurrent and/or refractory 
to available therapy 
 
Combination Arm B (Dose Escalation, Phase 1)  
 Advanced solid tumors that are (a) metastatic or unresectable and recurrent and/or 
refractory to available therapy, (b) a condition for which pembrolizumab is an approved 
treatment; and (c) in patients who have shown primary or acquired resistance to immune 
checkpoint inhibitors (ICIs) 
 
Combination Arm C (Dose Expansion, Phase 2) 
Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) tumors that are (a) 
metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in 
patients who have been treated with pembrolizumab or other programmed cell death 
protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors in monotherapy, and 
(c) who have subsequently shown primary or acquired resistance to ICIs
Objectives and Criteria for Evaluation (Endpoints):  
Primary Objectives
Endpoints 
Monotherapy Arm A - Dose Escalation (Phase 1): 
To determine the safety, tolerability, and 
maximum tolerated dose (MTD) of 
DSP-0509 administered intravenously (IV) 
as a single agent in patients with advanced 
solid tumors  
 
To identify a recommended Phase 2 dose 
(RP2D) of DSP-0509 monotherapy for 
patients with advanced solid tumors.  
Incidence of dose-limiting toxicities (DLTs) 
within the first 6 weeks of dosing 
 
Incidence and severity of treatment-emergent 
adverse events (TEAEs) and serious adverse 
events (SAEs) using National Cancer Institute 
(NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 6 of 122 
Incidence of dose interruption, dose reduction, 
and dose intensity 
 
Changes in clinical laboratory values 
(hematology, clinical chemistry, urinalysis), 
electrocardiogram (ECG) parameters, 
multigated acquisition (MUGA) 
scan/echocardiograms (ECHO) parameters
Combination Arm B - Dose Escalation (Phase 1):
To determine the safety, tolerability, and 
MTD of DSP-0509 administered IV in 
combination with pembrolizumab for 
patients with advanced solid tumors who 
have shown primary or acquired resistance to 
immune checkpoint inhibitors (ICIs)  
 
To identify an RP2D of DSP-0509 when 
given in combination with pembrolizumab 
for such patients  
Incidence of DLTs within the first 6 weeks of 
dosing 
 
Incidence and severity of TEAEs and SAEs 
using NCI CTCAE 
 
Incidence of dose interruption, dose reduction, 
and dose intensity 
 
Changes in clinical laboratory values 
(hematology, clinical chemistry, urinalysis), 
ECG parameters, MUGA scan/ECHO 
parameters 
Combination Arm C – Dose Expansion (Phase 2): 
To evaluate the preliminary antitumor 
activity of DSP-0509 in combination with 
pembrolizumab in patients with HNSCC 
who have shown primary or acquired 
resistance to ICIs
Objective response rate (ORR), as assessed by 
Response Evaluation Criteria in Solid Tumors 
(RECIST), v1.1 and by Immune RECIST 
(iRECIST, modified RECIST for 
immunotherapy studies) 
Study Design:  
This is a Phase 1 dose-escalation study (with 2 treatment arms) with a Phase 2 dose expansion to 
evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of 
 with advanced solid tumors. 
 
 Monotherapy Arm  
 Arm A: Dose escalation, Phase 1  
 
Combination Arms  
 Arm B: Dose escalation (patients with advanced solid tumor with primary or acquired 
resistance to ICIs), Phase 1 
 Arm C: Dose expansion (patients with HNSCC with primary or acquired resistance to 
ICIs), Phase 2 
 
Monotherapy Arm A: The primary objective of Monotherapy Arm A is to determine the MTD or 
RP2D of DSP-0509 when administered as a single agent. Dose escalation uses a Bayesian logistic 
regression model (BLRM) approach. DSP-0509 will be administered on Day 1 and then every 2 weeks 
thereafter until discontinuation.  
Combination Therapy Arm B: The primary objective of Combination Arm B is to determine the 
RP2D of DSP-0509 when administered in combination with pembrolizumab. Dose escalation is guided 
by the BLRM approach. Combination Arm B will enroll patients with advanced solid tumors that are 
(a) metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) a condition for 
which pembrolizumab is an approved treatment, and (c) in patients who have shown either primary or 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 7 of 122 
acquired resistance to an ICI. Dose escalation of DSP-0509 in combination with 400 mg 
pembrolizumab every 6 weeks (q6w) will start at the same dose of DSP-0509 as the highest (not 
exceeding the MTD) level tested in the combination regimen with 200 mg pembrolizumab every 
3 weeks (q3w). Upon completion of the DLT evaluation period for the first DSP-0509 dose level tested 
in combination with 400 mg pembrolizumab q6w in newly enrolled patients, if this dose level is found 
not to exceed the MTD, any ongoing patients receiving DSP-0509 in combination with 200 mg 
pembrolizumab q3w will be allowed, at the investigator’s discretion, to transition to the 400 mg 
pembrolizumab q6w regimen, while maintaining the originally assigned DSP-0509 dose level.  
Combination Therapy Arm C: The primary objective of Combination Arm C is to determine the 
ORR of DSP-0509 when administered in combination with pembrolizumab. Combination Arm C will 
enroll patients with HNSCC tumors that are (a) metastatic or unresectable, and recurrent and/or 
refractory to available therapy, (b) in patients who have been treated with pembrolizumab or other 
PD-1 or PD-L1 inhibitors in monotherapy, and (c) who have subsequently shown either primary or 
acquired resistance to ICIs.  
DSP-0509 will be administered on Day 1 and q2w thereafter until discontinued. Pembrolizumab will 
be administered on Day 1 and q6w thereafter until discontinued. 
Number of Patients Planned: 
Dose escalation 
Monotherapy Arm A: approximately 21 to 30 patients   
Combination Arm B: approximately 21 to 30 patients  
Dose expansion 
Combination Arm C: approximately 20 to 40 patients
Inclusion Criteria: 
Each patient must meet the following criteria to be enrolled in this study: 
1. Must have a histologically or cytologically confirmed advanced solid tumor that meets the 
following additional specifications for the Arm/Phase in which they are to be treated: 
 Monotherapy Arm A (Dose escalation, Phase 1) – Advanced solid tumors that are metastatic or 
unresectable, and recurrent and/or refractory to available therapy 
 Combination Arm B (Dose escalation, Phase 1) – Advanced solid tumors that are (a) 
metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) a condition 
for which pembrolizumab is an approved treatment, and (c) in patients who have shown 
primary or acquired resistance to ICIs 
 Combination Arm C (Dose expansion, Phase 2) – Advanced HNSCC tumors of the 
oropharynx, oral cavity, hypopharynx, larynx, lip, or sinus that are (a) metastatic or 
unresectable, and recurrent and/or refractory to available therapy, (b) in patients who have 
been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, and (c) 
who have subsequently shown primary or acquired resistance to ICIs  
2. 
 
3. Should have all side effects of any prior therapy or procedures for any medical condition 
 1 (except alopecia) 
4. Must have at least 1 measurable lesion by computed tomography (CT) or magnetic resonance 
imaging (MRI) per RECIST v1.1 
5. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 8 of 122 
6. Female patients of childbearing age and women <12 months since the onset of menopause, except 
those who have been surgically sterilized (tubal ligation) or whose sexual partner(s) is surgically 
sterilized (vasectomy), must agree to use acceptable contraceptive methods for the duration of the 
study and for 9 months after the date of their last DSP-0509 infusion. If employing contraception, 
2 of the following precautions must be used: birth control pill, vaginal diaphragm, intrauterine 
system or device, condom, or vaginal spermicide. Female patients who are postmenopausal are 
 consecutive months. Male patients must be 
surgically sterilized (vasectomy) or their female sexual partner(s) must be surgically sterilized 
(tubal ligation) to avoid using contraception. If they do not meet this criterion, male patients must 
agree to use a condom as well as one of the acceptable contraceptive methods listed above with 
their female partner(s), who meets the criterion of either being of childbearing age or <12 months 
since the onset of menopause. Male patients and their female partner(s) must agree to use 
acceptable contraception methods for the duration of time the male patient is on the study and for 
9 months after the date of his last DSP-0509 infusion.  
7. Females of childbearing potential must have a negative serum pregnancy test at Screening 
8. Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
9. Must have adequate coagulation function at Screening as determined by: 
 Prothrombin international normalized ratio (INR) <1.5 
 Partial thromboplastin time (PTT) <1.5 times the upper limit of normal (ULN) 
10. Must have adequate hematologic function at Screening as determined by: 
 
 
 
,500/microliter (patient may not use granulocyte-colony 
stimulating factor [G-CSF] or granulocyte-macrophage-colony stimulating factor [GM-CSF] 
to achieve these WBC and ANC levels) 
 
3/microliter 
 
ansfuse or use erythropoietin to obtain this Hgb level) 
11. Must have adequate renal and hepatic function at Screening as determined by: 
 Serum creatinine <2.0 mg/dL or <1.5 times the ULN, whichever is lower 
 
patients with known Gilbert syndrome) 
 
metastases)  
 
metastases) 
12. Must be able to attend study visits as required by the protocol 
13. Prior to the first DSP-0509 infusion, the patient must be able to provide tumor tissue for baseline 
studies as (a) a block of archival tissue sufficient to provide the required number of slides, (b) a 
sufficient number of fixed, unstained slides of archival tissue, or (c) consent to undergo tumor 
biopsy to acquire sufficient tumor tissue. Sites need to refer to the current version of the 
“NeoGenomics "BBI-DSP-0509-101 Tissue Sample Collection and Shipping Instructions” 
manual to determine how many slides are required for each patient, as the number varies based on 
(a) the study Arm/Phase in which the patient is enrolled, and (b) whether the patient consented to 
optional future testing. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 9 of 122 
Additional Inclusion Criteria for Combination Arm C Only: 
In addition to the above criteria, patients must meet the following criteria to be eligible to enroll in 
Combination Arm C: 
14. Have at least one accessible tumor for biopsy. This accessible lesion must be considered as non-
measurable per RECIST criteria, v1.1. 
15. Be platinum refractory, PD-1 or PD-L1 exposed, and have no more than 3 lines of prior therapy 
for advanced/metastatic disease 
16. Have a known status of PD-L1 combined positive score (CPS) 
17. Have a known human papilloma virus (HPV) status
Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from the study:  
1. Has received prior therapy with a TLR agonist, excluding a topical TLR agonist 
2. Has received anticancer chemotherapy (including molecular-targeted drugs), radiotherapy, 
immunotherapy (eg, vaccines or cytokines), or investigational agents within the 3 weeks before 
the first dose of DSP-0509. Local palliative radiotherapy is permitted. 
3. Receives concurrent systemic (oral or IV) steroid therapy >10 mg prednisone daily or its 
equivalent 
4. Not fully recovered from major surgery before the first dose of DSP-0509  
5. Has central nervous system (CNS) metastases (including leptomeningeal or spinal metastases) or 
CNS primary tumors, eg, glioblastoma 
6. Has a history of seizures other than isolated febrile seizure in childhood; has a history of a 
cerebrovascular accident or transient ischemic attack less than 6 months ago  
7. Has effusions (pleural, pericardial, or ascites) requiring drainage 
8. Has a neurodegenerative disease, eg, motor neuron disease, Parkinson disease, Alzheimer disease, 
Huntington disease 
9. Has retinal detachment, ulcerative keratitis, uveitis, Vogt-Koyanagi-Harada syndrome, choroidal 
neovascularization, retinopathy/retinitis, thyroid-associated orbitopathy, idiopathic orbital 
inflammation, diabetic retinopathy, ischemic retinopathy (including glaucoma-associated 
retinopathy), retinal vein thrombosis, or a non-healing ocular or ophthalmic disease
10. Has a fever 
°C within 3 days before the first dose of study treatment
11. Has interstitial lung disease or active noninfectious pneumonitis 
12. Has a history of active autoimmune or immunologic disorder requiring immunosuppression with 
steroids or other immunosuppressive agents (eg, azathioprine, cyclosporine A), that, after 
discussion between the investigator and the Medical Monitor is considered not acceptable for the 
study. If the autoimmune status is questionable, and the patient is not at risk, the investigator may 
discuss the patient’s potential eligibility with the Medical Monitor. 
13. Has a known hypersensitivity to a component of the protocol therapy, DSP-0509, or another 
pyrimidine 
14. Has a history of another primary cancer within the 5 years before enrollment, except for the 
following: non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer, or 
other nonmetastatic carcinoma that has been in complete remission without treatment for more 
than 5 years


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 10 of 122 
15. Has abnormal ECGs that are clinically significant, such as QT prolongation (corrected QT 
interval [QTc] >480 msec)  
16. In the opinion of the treating investigator, has any concurrent conditions that could pose an undue 
medical hazard or interfere with interpretation of study results; these conditions include, but are 
not limited to, ongoing or active infection, clinically significant nonhealing or healing wounds, 
concurrent congestive heart failure (New York Heart Association Functional Classification Class 
II, III or IV), concurrent unstable angina, concurrent cardiac arrhythmia requiring treatment 
(excluding asymptomatic atrial fibrillation), recent (within the prior 12 months) myocardial 
infarction or acute coronary syndrome, significant pulmonary disease (shortness of breath at rest 
or on mild exertion, eg, due to concurrent severe obstructive pulmonary disease), concurrent 
hypertension requiring more than 2 medications for adequate control, or diabetes mellitus with 
more than 2 episodes of ketoacidosis in the prior 12 months 
17. Has an ejection fraction of 50% or less based on a MUGA scan or ECHO 
18. Has the presence of a known, active, acute or chronic infection, including human 
immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as 
determined by fourth-generation (HIV antibody and antigen) assay, hepatitis B surface antigen 
(HBsAg), and hepatitis C serology, respectively  
19. Has a cognitive, psychological, or psychosocial impediment that would impair the ability of the 
patient to receive therapy according to the protocol, or adversely affect the ability of the patient to 
comply with the informed consent process, protocol, or protocol-required visits and procedures  
20. Receives concurrent strong inhibitors of cytochrome P450 2C8  
21. Receives concurrent inhibitors of organic anion transporting peptide (OATP)1B1 and OATP1B3  
22. Is pregnant or breastfeeding 
23. Has active neurologic inflammatory or autoimmune disorders (eg, Guillain-Barre syndrome, 
amyotrophic lateral sclerosis)  
The following exclusion applies only to enrollment in Combination Arms B and C: 
24. Has a history of immune-related adverse events (irAEs) resulting in permanent discontinuation of 
prior ICI treatment  
Duration of Study and Duration of Treatment  
The duration of the study will be approximately 6 years.   
Patients in each Arm (Monotherapy Arm A, Combination Arm B, Combination Arm C) will undergo a 
Screening period of up to 28 days; a treatment period of up to127 days (approximately 4.5 months) or 
as long as the patient is benefitting from treatment; and a 30-day safety follow-up. Survival follow-up, 
if applicable, will occur every 6 months, following the 30-day safety follow-up. 
Treatment duration for each patient is unknown, as patients may continue therapy as long as they 
demonstrate clinical benefit. 
Safety Assessments:
Adverse events (AEs) will be collected from the time the patient signs informed consent to the 
End-of-Study (EoS) visit scheduled for 30 days after last dose of study drug. AEs will be assessed 
according to NCI CTCAE v5.0. Additional safety assessments will include MUGA scans, ECHO, 
12-lead ECGs, chest x-rays, vital signs, clinical laboratory tests, and ocular examinations (slit lamp, 
fundoscopy, visual field testing). 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 11 of 122 
Efficacy Assessments: 
The evaluation of efficacy will be based on the patient’s disease status, assessed using RECIST and 
iRECIST. Of note, in immunotherapy studies, if progressive disease (PD) as defined by RECIST is 
observed, then, per iRECIST, an additional scan for confirmation of PD is required 4 to 8 weeks later.  
The following additional efficacy variables will be evaluated: 
 
ORR: the proportion of patients who achieved complete response (CR)/partial response (PR) per 
RECIST, or immune complete response (iCR)/immune partial response (iPR) per iRECIST 
 
Time to Progression (TTP): the time from first day of treatment to the date of PD per RECIST, 
or immune unconfirmed progressive disease (iUPD) if immune confirmed progressive disease 
(iCPD) is subsequently confirmed per iRECIST  
 
Duration of Response (DoR): the time from first documentation of a response until the date of 
the first documented PD per RECIST, or iUPD if iCPD is subsequently confirmed per iRECIST 
 
Progression Free Survival (PFS): the time from first day of treatment to either (a) the date of PD 
per RECIST, or iUPD if iCPD is subsequently confirmed per iRECIST, or (b) in the absence of 
documented PD, the date of death by any cause  
Pharmacokinetic Assessments: 
Blood and urine samples will be collected for the determination of plasma concentration of DSP-0509. 
On the days when blood samples are taken, the precise infusion start and stop time 
(hours:minutes:seconds) must be documented. Infusion start and stop times and PK sample times are to 
be based on the same clock. Blood samples for PK assessments are to be drawn from the arm 
contralateral to the site of drug administration. 
Note that urine samples to assess PK will be collected, but only in Monotherapy Arm A.  
Biomarker Assessments:  
The following samples will be collected for biomarker assessments: 
 
Plasma samples (eg, cytokine analysis)  
 
Peripheral blood mononuclear cells (PBMCs) (eg, lymphocyte immunophenotyping) 
 
Blood samples (eg, tumor-specific markers) 
 
Tumor tissue samples (eg, immune-related gene expression, CD8 immunohistochemistry 
(IHC), tumor-infiltrating lymphocytes (TIL) analysis, tumor mutational burden (TMB) 
analysis, PD-L1 IHC analysis [applicable only in the Combination Arms B and C])  
 
For patients who sign a separate consent, blood and tumor samples will be saved for future 
exploratory biomarker studies (this consent not required for study participation) 
In exploratory analyses, blood and tumor biomarkers will be correlated, as appropriate, with PK, dose 
level, safety, and efficacy outcomes. 
Statistical Methods:
Statistical analyses will be descriptive in nature. No formal sample size calculations will be performed 
for this study. Descriptive statistics (n, mean, standard deviation, median, and ranges for continuous 
variables; frequencies and percentages for categorical variables) will be provided by dose level and/or 
visit, if applicable. All data will be listed by patient, dose level, and visit where applicable. All 
summaries, statistical analyses, and individual patient data listings described below will be completed 
by using SAS v9.3 or later (SAS Institute, Inc, Cary, North Carolina, US). 
All anti-tumor parameters, including RECIST and iRECIST response, will be summarized using 
descriptive statistics. Analyses for response based on RECIST and iRECIST also will be performed for 
patients in the per protocol population with evaluable data. Data listings and summaries may include 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 12 of 122 
tumor markers, additional imaging, or other response data. Potential relationships between PK, 
pharmacodynamics, and other response data may be evaluated. Kaplan Meier estimates of PFS will be 
generated. 
Adverse events will be assessed based on the safety population, coded using the Medical Dictionary 
for Regulatory Activities (MedDRA; version to be specified in the Statistical Analysis Plan [SAP]) and 
graded according to CTCAE v5.0. AEs will be analyzed by grade, relatedness to study drug, and 
coding, with listings and tabulated summaries of TEAEs generated for each Arm/Phase by dose level 
and for patients overall. Additionally, the number treated, number evaluable for dose escalation, and 
number with DLTs will be described for each dose level and for the study overall. Vital signs, 
laboratory data, and ECG data (stratified by dose level and overall) will be summarized for changes 
over time on-study and each post-baseline visit, together with the change from baseline. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 13 of 122 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1.
CONTACT INFORMATION .......................................................................................... 4
2.
SYNOPSIS........................................................................................................................ 5
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13
LIST OF TABLES.............................................................................................................................. 18
LIST OF FIGURES ............................................................................................................................ 19
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 20
5.
INTRODUCTION ..........................................................................................................24
5.1.
Advanced Solid Tumors................................................................................................. 24
5.2.
Toll-Like Receptors as New Targets for Immunotherapy ........................................... 24
5.2.1. 
Recent Clinical Experience With TLR-4, -5, -9 Agonists ........................................... 25
5.2.2. 
Recent Clinical Experience With TLR-7 Agonists ...................................................... 26
5.2.3. 
DSP-0509 ........................................................................................................................ 26
5.2.3.1. 
General Overview ........................................................................................................... 26
5.2.3.2. 
Summary of Nonclinical Toxicology Data ................................................................... 27
5.2.3.3. 
Summary of Nonclinical Safety Pharmacology Data ................................................... 28
5.2.3.4. 
Summary of Nonclinical Pharmacodynamic Data ....................................................... 28
5.2.3.5. 
Summary of Nonclinical Data on Single-Agent In Vivo Antitumor Activity 
of DSP-0509 as Monotherapy and in Combination with Anti–Programmed 
Cell Death Protein 1 Antibody ....................................................................................... 29
5.2.4. 
Benefit/Risk Considerations .......................................................................................... 29
5.2.5. 
Rationale for Choosing Head and Neck Squamous Cell Carcinoma in the 
Dose-expansion Combination Arm C ........................................................................... 30
6.
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 31
6.1.
Primary Objectives and Endpoints ................................................................................ 31
6.2.
Secondary Objectives and Endpoints ............................................................................ 31
6.3.
Exploratory Objectives and Endpoints .......................................................................... 33
7.
INVESTIGATIONAL PLAN ........................................................................................ 35
7.1.
Overview of Study Design ............................................................................................. 35
7.1.1. 
Safety Monitoring in the Dose-escalation Cohorts....................................................... 35


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 14 of 122 
7.1.2. 
Dose Escalation - Monotherapy Arm A ........................................................................ 36
7.1.3. 
Dose Escalation - Combination Therapy Arm B .......................................................... 37
7.1.4.
Dose Expansion – Combination Therapy Arm C.........................................................38
7.2.
Rationale for Starting Dose ............................................................................................ 38
7.3.
Administration of Study Treatment ............................................................................... 39
7.4.
Dose Escalation Procedures ........................................................................................... 39
7.4.1. 
Application of BLRM to Dose Escalation .................................................................... 39
7.4.2.
Safety Review Committee..............................................................................................39
7.5.
Determination of the MTD and RP2D .......................................................................... 40
7.6.
Definition of Patients Evaluable for DLT ..................................................................... 41
7.7.
Definition of Dose-Limiting Toxicity ...........................................................................41
7.7.1. 
Immune-related DLTs .................................................................................................... 41
7.7.2. 
Hematologic DLTs ......................................................................................................... 41
7.7.3. 
Liver-related DLTs ......................................................................................................... 42
7.7.4. 
Other DLTs ..................................................................................................................... 42
7.8.
Monitoring of Potential Adverse Events ....................................................................... 42
7.9.
Guidance for Modifying or Discontinuing Study Treatment ....................................... 43
7.9.1. 
Guidance for Modifying or Discontinuing DSP-0509 ................................................. 43
7.9.2. 
Guidance for Modifying or Discontinuing Pembrolizumab ........................................ 44
7.9.3. 
Study Discontinuation .................................................................................................... 46
7.10.
Study Duration................................................................................................................47
7.11.
Selection of Study Population ........................................................................................ 47
7.11.1.
Inclusion Criteria ............................................................................................................ 47
7.11.2.
Exclusion Criteria ........................................................................................................... 49
7.12.
Investigational Product ................................................................................................... 51
7.12.1.
Identity of the Investigational Product DSP-0509 ........................................................ 51
7.12.2.
Combination Therapy – Pembrolizumab ...................................................................... 51
7.13.
Prior and Concomitant Therapy ..................................................................................... 51
7.13.1.
Allowed Concomitant Medications ............................................................................... 51
7.13.2.
Prohibited Medication/Therapy ..................................................................................... 51
8.
STUDY PROCEDURES................................................................................................ 53
8.1.
Schedule of Events ......................................................................................................... 53


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 15 of 122 
8.2.
Description of Study Procedures ................................................................................... 70
8.2.1. 
Telephone Contacts ........................................................................................................ 70
8.2.2.
Medical and Cancer History ..........................................................................................70
8.2.3. 
Eastern Cooperative Oncology Group Performance Status ......................................... 70
8.2.4. 
Clinical Laboratory Evaluation ...................................................................................... 71
8.2.4.1. 
Hematology..................................................................................................................... 71
8.2.4.2. 
Coagulation ..................................................................................................................... 71
8.2.4.3.
Clinical Chemistry..........................................................................................................71
8.2.4.4. 
Urinalysis ........................................................................................................................ 71
8.2.4.5. 
Pregnancy Testing .......................................................................................................... 72
8.2.4.6.
Serology Testing.............................................................................................................72
8.2.5. 
Vital Signs ....................................................................................................................... 72
8.2.6. 
Physical Examination ..................................................................................................... 72
8.2.7. 
Concomitant Medications and Procedures .................................................................... 72
8.2.8. 
Adverse Events ............................................................................................................... 72
8.2.9. 
Objective Disease Assessments ..................................................................................... 72
8.2.10.
Cardiac Assessments ...................................................................................................... 73
8.2.10.1.
12-lead Safety ECGs ...................................................................................................... 73
8.2.10.2.
Cardiodynamic Assessment ........................................................................................... 73
8.2.10.3.
MUGA Scan and ECHO Assessments .......................................................................... 73
8.2.11.
Chest X-rays ....................................................................................................................73
8.2.12.
Ocular Examinations ...................................................................................................... 73
8.2.13.
Pharmacokinetic Testing ................................................................................................ 74
8.2.13.1.
Infusion Procedure on PK Sampling Days.................................................................... 74
8.2.13.2.
Collection of PK Blood Samples ................................................................................... 74
8.2.13.3.
Collection of PK Urine Sample ..................................................................................... 75
8.2.14.
Blood Samples for Tumor Markers, Lymphocyte Phenotype, and Cytokines ........... 75
8.2.15.
Tumor Tissue Samples ................................................................................................... 75
8.2.15.1.
Tumor Tissue Samples to be Provided at Screening .................................................... 75
8.2.15.2.
Tumor Tissue Obtained On- or Post-Treatment ........................................................... 76
8.2.16.
Analysis of Tumor Samples ........................................................................................... 76
8.2.17.
Specimen Sampling for Future Exploratory Biomarker Analysis ............................... 76


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 16 of 122 
9.
EFFICACY ASSESSMENTS ....................................................................................... 77
9.1.
Efficacy Assessment ....................................................................................................... 77
9.2.
Biomarker Assessments ................................................................................................. 77
10.
PHARMACOKINETIC ASSESSMENTS ................................................................... 78
11.
SAFETY ASSESSMENTS ............................................................................................ 79
11.1.
Adverse Events and Serious Adverse Events ............................................................... 79
11.1.1.
Adverse Events: Definition ............................................................................................ 79
11.1.2.
Adverse Reactions and Suspected Adverse Reactions: Definition..............................79
11.1.3.
Serious Adverse Events: Definition .............................................................................. 79
11.2.
Procedures for Eliciting, Recording, and Reporting Adverse Events ......................... 80
11.2.1.
Relationship to Investigational Agent...........................................................................80
11.2.2.
Adverse Event Severity .................................................................................................. 81
11.2.3.
Assessment of Expectedness .......................................................................................... 82
11.2.4.
Specific Instructions for Recording Adverse Events on the eCRF.............................. 82
11.2.4.1.
Diagnosis versus Signs and Symptoms ......................................................................... 82
11.2.4.2.
Adverse Events Occurring Secondary to Other Events................................................ 82
11.2.4.3.
Medication Errors, Misuse, and Abuse of Investigational Agent ................................ 82
11.2.4.4.
Persistent or Recurrent Adverse Events ........................................................................ 83
11.2.4.5.
Abnormal Laboratory Values......................................................................................... 83
11.2.4.6.
New Cancers ................................................................................................................... 83
11.2.4.7.
COVID-19.......................................................................................................................84
11.2.4.8.
Death................................................................................................................................ 84
11.2.5.
Reporting of Expedited Safety Observations by the Investigator, Including 
Serious Adverse Events .................................................................................................. 84
11.2.5.1.
Immediate Reporting of Serious Adverse Events or Pregnancy by the 
Investigator to the Sponsor............................................................................................. 84
11.2.5.2.
Immediate Reporting of Adverse Events of Special Interest, Occupational 
Exposure, Overdose, or New Cancers ........................................................................... 85
11.2.5.3.
Reporting COVID-19 Infections ................................................................................... 85
11.2.5.4.
Reporting Pregnancies .................................................................................................... 85
11.2.5.5.
Expedited Reporting by the Sponsor to a Regulatory Health Authority ..................... 86
11.2.5.6.
Safety Notifications by the Sponsor to the Investigator ............................................... 86


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 17 of 122 
12.
STATISTICAL ANALYSIS.......................................................................................... 87
12.1.
Statistical Methods.......................................................................................................... 87
12.2.
Definition of Study Populations ....................................................................................87
12.3.
Determination of Sample Size ....................................................................................... 88
12.3.1.
Dose Escalation and Dose Expansion ........................................................................... 88
12.4.
Planned Analyses ............................................................................................................ 88
12.4.1.
Demographic and Other Baseline Characteristics ........................................................ 88
12.4.2.
Safety Endpoints.............................................................................................................88
12.4.3.
Efficacy Endpoints Analysis .......................................................................................... 89
12.4.4.
Pharmacokinetic Analyses (Secondary Endpoints) ...................................................... 89
12.4.5.
Pharmacodynamic Analyses (Secondary Endpoints)...................................................90
12.4.6.
ECG Analysis.................................................................................................................. 90
12.4.7.
Subgroup Analyses ......................................................................................................... 90
12.4.8.
Protocol Deviations ........................................................................................................ 90
13.
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ................................ 91
13.1.
Study Monitoring ............................................................................................................ 91
13.2.
Audits and Inspections ................................................................................................... 91
13.3.
Institutional Review Board/Independent Ethics Committee ........................................ 92
14.
QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 93
14.1.
Audit and Inspection....................................................................................................... 93
14.2.
Monitoring.......................................................................................................................93
14.3.
Data Management and Coding....................................................................................... 93
14.4.
Data Collection/Electronic Data Capture ...................................................................... 93
14.5.
Records and Supplies ..................................................................................................... 94
14.5.1.
Drug Accountability ....................................................................................................... 94
14.6.
Financing and Insurance................................................................................................. 94
14.7.
Compensation ................................................................................................................. 94
15.
ETHICS ........................................................................................................................... 95
15.1.
Independent Ethics Committee or Institutional Review Board ................................... 95
15.2.
Regulatory Authorities ................................................................................................... 95
15.3.
Ethical Conduct of the Study ......................................................................................... 95
15.4.
Informed Consent ........................................................................................................... 95


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 18 of 122 
15.5.
Patient Confidentiality .................................................................................................... 96
16.
REPORTING AND PUBLICATION, INCLUDING ARCHIVING .......................... 97
17.
REFERENCES ...............................................................................................................98
18.
APPENDICES .............................................................................................................. 100
18.1.
DSP-0509 Infusion Procedure ..................................................................................... 100
18.2.
RECIST 1.1 and iRECIST ........................................................................................... 103
18.3.
Extracts from NCCN Guidelines for irAEs ................................................................ 105
18.4.
Bayesian Logistic Regression Model..........................................................................107
LIST OF TABLES 
Table 1:
Abbreviations and Definitions.......................................................................................20
Table 2: 
List of Definitions ........................................................................................................... 23
Table 3: 
DSP-0509 Provisional Dose Levels in Arm A and Arm B .......................................... 37
Table 4: 
Monitoring of Potential Adverse Events ....................................................................... 43
Table 5: 
Modifications for Immune-related Adverse Events ..................................................... 45
Table 6: 
Prohibited Strong Inhibitors of CYP2C8 and OATP1B1/B3 ...................................... 52
Table 7: 
Schedule of Events – Screening and DLT Period - Monotherapy Part A ................... 54
Table 8: 
Schedule of Cardiodynamics, PK, and Cytokine Samples – Monotherapy 
Arm A .............................................................................................................................. 56
Table 9: 
Schedule of Events – Day 43 to End of Study – Monotherapy Arm A ...................... 57
Table 10:
Schedule for Sampling for PK, Cytokines– Monotherapy Arm A .............................. 59
Table 11:
Schedule of Events – Screening and DLT Period – Combination Arm B .................. 60
Table 12:
Schedule for Sampling for PK and Cytokines – Combination Arm B........................62
Table 13:
Schedule of Events – Day 43 to End of Study – Combination Arm B ....................... 63
Table 14:
Schedule for Sampling for PK and Cytokines – Combination Arm B ........................ 64
Table 15:
Schedule of Events – Screening and Treatment Periods - Combination Arm 
C ....................................................................................................................................... 65
Table 16:
Schedule for Sampling for PK and Cytokines – Combination Arm C ........................ 69
Table 17:
ECOG Performance Status Scale................................................................................... 71
Table 18:
Pharmacokinetic Parameters to be Assessed in DSP-0509 .......................................... 78
Table 19:
Comparison of RECIST 1.1 vs. iRECIST ................................................................... 103
Table 20:
Assignment of Timepoint Response using iRECIST ................................................. 104


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 19 of 122 
Table 21:
Principles of Routine Monitoring for Immune-Checkpoint Inhibitors ..................... 105
Table 22:
Assessment and Grading of Infusion-Related Reactions...........................................106
Table 23:
Prior Parameters for Bivariate Normal Distribution of Model Parameters............... 108
Table 24:
Prior Distribution Summaries Derived from Priors in Table 23 ................................ 109
Table 25:
True Underlying DLT Probabilities ............................................................................110
Table 26:
Summary Metrics of the Simulations Performed ....................................................... 112
Table 27:
Hypothetical Dose Allocation Scenarios in Early Cohorts ........................................ 113
Table 28:
Parameters of the Prior and Posterior Distributions for Agent 1...............................115
Table 29:
Parameters of the Prior Distribution for Agent 2........................................................ 116
Table 30:
Dose-Toxicity Scenarios (True DLT Probability at Each Dose) for Agent 1........... 118
Table 31:
Dose-Toxicity Scenarios (True DLT Probability) for Agent 2 .................................. 118
Table 32:
Dose-Toxicity Scenarios (True DLT Probability) for Agents 1 & 2 
Combined ...................................................................................................................... 119
Table 33:
Summary Metrics of the Simulations Performed ....................................................... 120
Table 34:
Hypothetical Dose Allocation Scenarios in Early Cohorts ........................................ 120
LIST OF FIGURES 
Figure 1: 
Downstream Signal Transduction Cascade ................................................................... 26
Figure 2: 
Study Design ................................................................................................................... 35
Figure 3: 
Dosing Schedule – Monotherapy Arm A ...................................................................... 36
Figure 4: 
Dosing Schedule – Combination Arms B and C .......................................................... 38
Figure 5: 
Prior Distribution of DLT Rates .................................................................................. 108


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 20 of 122 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1: 
Abbreviations and Definitions  
terminal elimination rate constant
Ae 
cumulative amount of unchanged drug excreted into the urine
ADL
activities of daily living
AE 
adverse event
AESI 
adverse event of special interest 
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC
area under the concentration-time curve
AUC24 
24-hour area under the concentration-time curve (daily exposure) 
AUCinf
area under the concentration-time curve from time 0 (dosing) extrapolated to infinity 
AUCt 
area under the concentration-time curve from time 0 (dosing) to the time of the last 
measurable concentration 
BLRM
Bayesian logistic regression model 
BOR
best overall response
C0 
initial concentration of DSP-0509 (time = 0)
cGCP
current Good Clinical Practice
CL
clearance
CLR
complete renal clearance from plasma 
Cmax 
maximal plasma concentration 
CNS 
central nervous system
CPS 
combined positive score
CR 
complete response 
CRC
colorectal carcinoma
CRP 
C-reactive protein
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T-lymphocyte 
CXCL10
chemokine C-X-C motif ligand 10 
CYP 
cytochrome P450 (enzyme) 
DAMP
damage-associated molecular pattern
DCR
disease control rate 
DLT 
dose-limiting toxicity
DoR 
duration of response 
ECG
electrocardiogram
ECHO 
echocardiogram
ECOG 
Eastern Cooperative Oncology Group (performance status)
eCRF 
electronic Case Report Form 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 21 of 122 
EDC
electronic data capture
EoS
end of study 
ES
Efficacy Set 
EWOC
escalation with overdose control 
FAS 
Full Analysis Set 
FDA
Food and Drug Administration
Fe(%)
percentage of the intravenously administered drug excreted into the urine
FIH
first in human
GCP 
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GM-CSF
granulocyte-macrophage-colony stimulating factor 
HBsAg 
hepatitis B surface antigen 
HBV
hepatitis B virus 
HCC
hepatocellular carcinoma
HCV
hepatitis C virus 
Hgb 
hemoglobin
HIV 
human immunodeficiency virus
HLA
human leukocyte antigen
HNSCC
head and neck squamous cell carcinoma
HPV
human papilloma virus
IB 
Investigator’s Brochure
ICH 
International Council on Harmonisation 
ICI 
immune checkpoint inhibitor
iCPD 
immune confirmed progressive disease
iCR
immune complete response
iDCR 
immune disease control rate 
iDoR 
immune duration of response
IEC
Independent Ethics Committee
IFN
interferon
interferon alpha
IHC 
immunohistochemistry
IL 
interleukin 
IL-1RA 
interleukin 1 receptor antagonist 
IL-6 
interleukin 6 
INR 
International Normalized Ratio
iORR 
immune objective response rate 
IP-10 
inducible protein 10
iPFS 
immune progression-free survival
iPR 
immune partial response 
irAE 
immune-related adverse event
IRB
Institutional Review Board


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 22 of 122 
iRECIST
Immune Response Evaluation Criteria in Solid Tumors; modified RECIST for 
immunotherapy studies 
iSD
immune stable disease
iUPD
immune unconfirmed progressive disease
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities
MEC 
minimum effective concentration
MRI 
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA 
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NF-
nuclear factor kappa B 
NSCLC
non-small cell lung cancer 
OATP 
organic anion transporting peptide
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease 
PD-1
programmed cell death protein 1
pDC 
plasmacytoid dendritic cell
PD-L1 
programmed death ligand 1
PFS
progression-free survival
PK
pharmacokinetic(s) 
PKS 
Pharmacokinetic Set
PPS
Per-Protocol Set 
PR
partial response
PT
prothrombin time 
PTT 
partial thromboplastin time
q1w 
once weekly 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
q6w 
every 6 weeks 
QTc 
corrected QT interval
QTcF 
QT interval corrected using Fridericia’s formula 
RBC
red blood cell
RECIST 
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase 2 dose
RSI
Reference Safety Information 
SAE 
serious adverse event
SAP 
Statistical Analysis Plan
SD
stable disease


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 23 of 122 
SDV
source document/data verify(ied)
SEAP
secreted alkaline phosphatase 
SJS 
Stevens-Johnson syndrome
SOC 
System Organ Class 
SoE
Schedule of Events 
SRC
Safety Review Committee
t1/2
terminal elimination half-life
TEAE 
treatment-emergent adverse event
Th2
T helper 2 
TEN 
toxic epidermal necrolysis
TIL
tumor-infiltrating lymphocyte
TLR 
Toll-like receptor 
TMB 
tumor mutational burden
tumor necrosis factor alpha
TTP 
time to progression 
ULN
upper limit of normal
US
United States
Vc 
initial volume of distribution (time 0)
Vz 
volume of distribution at the terminal phase
WBC 
white blood cell
Table 2: 
List of Definitions 
Acceptable toxicity 
dose level producing a DLT rate of approximately 16% to 33% 
Acquired ICI 
resistance
previous treatment with ICIs (PD-1 or PD-L1 inhibitors) accompanied by 
objective clinical benefit (stable disease [SD] for at least 24 weeks, PR, or CR, 
according to RECIST criteria, v1.1, as the best clinical response to ICIs), followed 
by systemic progression of disease during or within 3 months after the last dose of 
ICI treatment. Resistance to treatment of PD-1/PD-L1 with CTLA4 also is 
considered. 
End of Study 
date of last visit of the patient
Excessive toxicity
probability of a DLT rate greater than 33% (determined while applying BLRM and 
the principle of escalation with overdose control [EWOC])
Extent of exposure 
calculated as ([date last study treatment administered] - [date first study treatment 
administered] + 1) 
Postmenopausal
Primary ICI 
resistance 
previous treatment with ICIs with PD without prior objective clinical benefit, ie, 
without prior CR, PR, or SD (per RECIST criteria, v1.1) after 6 weeks or more of 
treatment.  
Treated patients
patients who have received at least one dose of study drug 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 24 of 122 
5. 
INTRODUCTION 
5.1. 
Advanced Solid Tumors 
In 2017, it was estimated that there would be more than 1.5 million persons diagnosed with 
advanced solid tumors, and more than half a million people with advanced solid tumors would 
die (American Cancer Society, 2017; Centers for Disease Control, 2017). Hence, there is an 
urgent unmet medical need for therapeutic innovations to treat advanced solid tumors. The 
primary goals of treatment of advanced solid tumors are to prolong survival and improve quality 
of life for patients. Although advanced solid tumors are generally not curable currently, 
meaningful improvements in survival have been seen, coincident with the introduction of newer 
systemic therapies. Especially important are those therapies that employ drugs with well-defined 
molecular targets that contribute to disease progression and chemotherapy resistance, and 
immuno-oncology drugs that boost the patient’s own immune system against the tumor cells. 
The development of immunotherapeutic strategies, such as the development of agonists of 
Toll-like receptors (TLRs) has been a focus in clinical research efforts to address the challenges 
of chemotherapeutic resistance in advanced solid tumors. 
5.2. 
Toll-Like Receptors as New Targets for Immunotherapy  
Immuno-oncology drugs, including TLR agonists, have been designed to activate 
cancer-targeting immune responses (Khalil, 2016; Galluzzi, 2012). TLRs are a family of 
pattern-recognition receptors that recognize pathogen-associated molecular patterns to activate 
innate immunity (Rakoff-Nahoum, 2009; Kawai, 2011; Gay 2014). These receptors are highly 
conserved from Drosophila to humans and share structural and functional similarities. More than 
10 types of TLRs have been identified (Kawai, 2011), and they are expressed on the cell surface 
or endosomal compartment. Toll-like receptors can be subdivided into 2 major categories, 
depending on their subcellular localization: (1) endosomal TLRs, including TLR-3, -7, -8, -9, 
and -10; and (2) plasma membrane-associated TLRs, including TLR-1, -2, -4, -5, and -6. Most 
endosomal and plasma membrane–associated human TLRs have been found to respond to 
conserved microbial products collectively known as microbe-associated molecular patterns, as 
well as to endogenous molecules collectively known as damage-associated molecular patterns 
(DAMPs) (Fucikova, 2015). Nonclinical and clinical evidence demonstrates that the release of 
TLR-activating DAMPs by dying cancer cells contributes to the elicitation of therapeutically 
relevant anticancer immune responses (Kroemer, 2013).  
The bacillus Calmette–Guérin, an attenuated variant of Mycobacterium bovis, is the best known 
TLR agonist, and it is approved by the United States (US) Food and Drug Administration (FDA) 
for the treatment of noninvasive transitional cell carcinomas of the bladder. Other approved TLR 
agonists for oncologic indications include (1) picibanil, a lyophilized preparation 
of Streptococcus pyogenes that is approved in Japan for the treatment of various carcinomas; 
(2) monophosphoryl lipid (MPL) A, a derivative of Salmonella minnesota lipopolysaccharide 
that is employed as an immunologic adjuvant in a peptide-based vaccine specific for cervical 
carcinoma–associated strains of human papillomavirus (HPV) (ie, HPV-16 and HPV-18), 
approved by FDA; and (3) imiquimod, an imidazoquinoline derivative that is used for the topical 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 25 of 122 
treatment of actinic keratosis and superficial basal cell carcinoma, approved by FDA 
(Aranda, 2014; Hoffman, 2005).  
5.2.1. 
Recent Clinical Experience With TLR-4, -5, -9 Agonists 
Studies of TLR-4, -5, and -9 agonists, alone or in combination with other current treatments, are 
in progress on multiple cancer types (Merkel cell carcinoma [Bhatia, 2015]; colorectal [CRC] 
and non-small-cell lung [NSCLC] cancers [Bakhribah, 2015]; and relapsed and/or metastatic 
squamous cell carcinoma of the head and neck [HNSCC] [Machiels, 2013; Smith, 2014; 
Burtness, 2019; Chan, 2015]), with preliminary evidence of antitumor activity and generally 
acceptable safety profiles. An unacceptable safety profile, with multiple serious adverse events 
(SAEs), 50% of which were deemed product-related, including 1 death, was reported for the 
study of TLR-9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and cetuximab 
(PFE) in patients with relapsed and/or metastatic HNSCC, and the study was terminated early. 
Additional studies of IMO-2055, in combination with a different set of therapies (erlotinib and 
bevacizumab; Smith, 2014) (folinic acid, 5-fluorouracil, irinotecan/cetuximab; Burtness, 2019; 
Chan, 2015) were conducted in advanced NSCLC and CRC, respectively, with limited antitumor 
activity and a mixed safety profile. 
In a further TLR-9 agonist study in metastatic CRC (Schmoll, 2014), the study was stopped early 
since MGN1703 significantly improved progression-free survival (PFS), measured from the start 
of induction therapy versus placebo, and since all adverse events (AEs) were transient, mild, and 
limited to injection site reaction or immune system activity.  
Additional achievement of preliminary antitumor and safety objectives was met in another study 
of MGN1703 (Weihrauch, 2015), with the majority of treatment-emergent AEs (TEAEs) less 
than Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), and fatigue and activated partial thromboplastin time (aPTT) prolongation 
being the only 2 cases of drug-related Grade 3 AEs. Twenty-five percent of patients had stable 
disease (SD) after 6 weeks of treatment; 3 of those remained in SD after 12 weeks, and 4 patients 
were further treated in a compassionate-use program that showed long-term disease stabilization 
for up to 18 months. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7 
Confidential and Proprietary
Page 26 of 122
5.2.2.
Recent Clinical Experience With TLR-7 Agonists
Among the various TLRs, TLR-7 is primarily expressed on 
the endosomes of plasmacytoid dendritic cells (pDCs) and, to 
some extent, in B cells, monocytes, and macrophages. It 
recognizes guanosine and/or uridine-rich single-stranded 
RNA derived from viruses such as hepatitis C virus (HCV) 
or hepatitis B virus (HBV) (Rakoff-Nahoum, 2009; Kawai, 
2011). TLR-7 activation in pDCs is responsible for the 
production of high levels of Type I interferon (IFN). TLR-7 
agonists modulate T helper 2 (Th2) responses in vitro 
well as through the upregulation of the costimulatory ligand 
DLL-4, and via the downregulation of the Th2 transcription 
factor, GATA-
-7 induces 
myeloid differentiation primary response gene 88 recruitment 
to endosomes and triggers a downstream signal transduction 
cascade (Figure 1). 
TLR-7 activation induces secretion of inflammatory 
-12, through 
nuclear factor kappa B (NF-
factor-7 pathways, and enhances dendritic cell maturation 
and antigen presentation, which are recognized by cytotoxic 
T-lymphocyte (CTL) precursors (Rakoff-Nahoum, 2009; 
Kawai, 2011). Subsequently, CTL precursors are instructed 
to develop into CTLs. As described above, activating innate 
immunity by TLR-7 signaling results in adaptive immune 
activation. Because of their immunostimulatory ability, 
TLR-7 agonists are expected to exhibit antitumor effects. It is 
reported that systemic delivery of a TLR-7 agonist leads to 
the priming of systemic immune responses capable of reducing both primary and metastatic 
tumor burden in nonclinical models (Chi, 2017).  
Recent Phase 1 studies of TLR-7 agonists have shown a mixed safety profile: limited, transient, 
mild to moderate TEAEs in a Glaxo-Smith-Kline study of GSK2245035 (Iribarren, 2016; 
Tsitoura, 2015); as well as a multiple ascending-dose study by AstraZeneca that was stopped 
after 2 healthy volunteers experienced severe influenza-like AEs. An additional study of a TLR-7 
agonist (MEDI9197, administered to patients with solid tumors and reported under clinical 
trials.gov number NCT02556463) has been terminated and no study data are available.
5.2.3.
DSP-0509 
5.2.3.1.
General Overview
Sumitomo Dainippon Pharma Oncology (SDP Oncology), Inc (formerly Boston Biomedical, Inc) 
is developing DSP-0509, a TLR-7 agonist, for the treatment of patients with advanced solid 
Figure 1: Downstream 
Signal 
Transduction 
Cascade


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 27 of 122 
tumors refractory to standard treatment, or patients who have contraindications to, are intolerant 
of, or have declined available therapy. DSP-0509 is a new molecular entity with TLR-7 agonist 
activity. The dosage form is a solution for intravenous (IV) administration.  
DSP-0509 is designed to have high water solubility, is optimized for IV administration, and also 
is designed to achieve rapid elimination from the body, partially due to excretion via organic 
anion transporting peptide (OATP) transporters. It is anticipated that the rapid elimination, 
combined with the promising TLR-7–selective activity profile will provide the basis for a safe 
immunotherapy capable of prolonging the lives of patients with advanced solid tumors, either as 
monotherapy or in combination with other immunotherapeutic or chemotherapeutic agents.  
This is the first clinical study with DSP-0509. Nonclinical toxicology and pharmacology studies 
have been conducted with DSP-0509, and the results from these studies support an acceptable 
safety profile for the initiation of the first-in-human (FIH) study of DSP-0509.  
5.2.3.2. 
Summary of Nonclinical Toxicology Data  
In accordance with its selective TLR-7–agonist activity, DSP-0509 did not exert any 
cytotoxicity, phospholipidosis, or mitochondrial toxicity in nonclinical studies. No genotoxic or 
phototoxic potential was found for DSP-0509 in vitro. A series of toxicology studies were 
performed to better understand the dose-effect relationships of the acute and subacute 
proinflammatory activity of DSP-0509. Rats and monkeys were selected as the principal species 
for toxicologic testing, consistent with literature reports of these 2 species being sensitive for 
TLR-7 agonists. Monkeys in repeated-dose studies received 5 once-weekly doses of DSP-0509, 
ranging from 2 mg/kg to 30 mg/kg. Animals were monitored during dosing and sacrificed at 
end-of-treatment (EoT; 1 week after last dose) or after recovery periods of 4 to 13 weeks. The 
pivotal toxicology studies were performed in full compliance with Good Laboratory Practice 
(GLP).  
These studies are described in detail in the Investigator’s Brochure (IB). A summary of clinical 
findings by System Organ Class (SOC) is presented below: 
Cardiac disorders: Increased heart rate on electrocardiogram (ECG) and decrease in pO2 blood 
 
Eye disorders: Uveitis, retinal detachment, and retinal atrophy were noted in monkeys at 
30 mg/kg. DSP-0509 caused histologically detectable inflammatory changes in multiple tissues, 
including the eyes, in both rats and monkeys.  
Nervous system disorders: Histopathologic changes were observed in cynomolgus monkeys 
revalent in animals dosed at 30 mg/kg. Histologic changes seen at 
EoT included mononuclear and inflammatory cell infiltrates in cerebrum (including choroid 
plexus), medulla, and pons; in some instances, the infiltrates were perivascular. Gliosis also was 
noted. Central nervous system (CNS) changes were persistent in recovery animals up to 
13 weeks. Similar changes in other organs typically resolved during recovery.   
Notable clinical findings included the following:  
 Tremors were observed in monkeys dosed a
 mg/kg and were present in the majority 
of animals dosed at 30 mg/kg.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 28 of 122 
Seizures were observed in 2 monkeys dosed at 30 mg/kg: 
– A female (#30, study SBL 198-323) had seizures observed on Day 21 
approximately 5 hours after dosing. The seizures were transitory; the animal 
completed treatment and was sacrificed as scheduled after a 4-week recovery 
period.  Histopathologic changes included the inflammatory infiltrates noted 
above, with no additional findings.  
– A male (#26, study SBL 198-323) had continuous clonic convulsions on 
Day 5 accompanied by a decrease in pO2 on blood gas analysis. The animal was 
euthanized and, at autopsy, CNS findings were notable for subarachnoid 
hemorrhages in cerebellum, cerebrum, and medulla; inflammatory changes were 
comparable to animals sacrificed after a course of 5 doses. The only notable 
finding outside the CNS was atrophy of mesenteric and mandibular lymph nodes 
and follicular atrophy in the spleen. In contrast, all males and females sacrificed 
after 5 doses had lymph node hyperplasia and moderate splenic hyperplasia.  
 One other animal dosed at 30 mg/kg was euthanized during treatment: 
– A female (#14, study SBL 198-324) was euthanized on Day 25 for severe clinical 
deterioration, including failure to eat and decreased movement. At autopsy, CNS 
findings of inflammation were modestly increased compared to other 30 mg/kg 
animals. Hemorrhages were observed in pons and medulla, but not in the 
cerebellum or cerebrum. Of note, mesenteric and mandibular lymph nodes and 
spleen in this animal also showed atypical follicular atrophy.  
Respiratory, thoracic, and mediastinal disorders: Inflammatory changes in the lung 
 mg/kg. These changes were typically not found at the end of the recovery periods.   
5.2.3.3. 
Summary of Nonclinical Safety Pharmacology Data 
Numerous in vitro and in vivo studies were performed to provide insight on the mechanism of 
action, active concentration, and schedule dependencies of DSP-0509. In vitro safety 
pharmacology studies demonstrated no human ether-à go-go (hERG)-related gene inhibition. 
Additional detailed information can be found in the IB.  
5.2.3.4. 
Summary of Nonclinical Pharmacodynamic Data 
Pharmacodynamic studies investigating DSP-0509 tumoricidal activity in syngeneic mouse 
tumor models demonstrated promising single-agent activity and enhanced potency when 
combined with other treatment modalities (eg, radiation therapy, immune checkpoint inhibitor 
[ICI] therapy).  
The TLR-7–specific agonist in vitro activity of DSP-0509 was evaluated using a reporter gene 
assay (ie, TLR-7/NF-
293 cells stably expressing human TLR-7 and a SEAP reporter gene under transcriptional control 
of an NF-
tent activation of human 
TLR-7 at nanomolar concentrations, with a mean negative logarithm of 50% effective 
concentration (pEC50) of 6.5 ± 0.25 nM. Similar experience in cells expressing mouse, rat, or 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 29 of 122 
cynomolgus monkey TLR-7 demonstrated activity at pEC50 concentrations of 7.5, 6.6, and 
6.5 nM, respectively. 
The minimum effective concentrations (MECs) of DSP-0509 that induced production of the 
-X-C motif ligand 10 (CXCL10), and IL-1 receptor 
antagonist (IL-1RA) in plasma from healthy volunteers were determined to be 125, 63, and 
125 nM, respectively. Similarly, the MECs of DSP-
-10, IL-12p40, IL-12p70, IL-
-1RA, IL-6, CXCL10, and tumor necrosis factor 
y human plasma were 117, 234, 1,875, 1,875, 3,750, 234, 117, 117, 59, and 
117 nM, respectively. In vivo, DSP-
cynomolgus monkeys were 1, 0.3, and 0.3 mg/kg, respectively. See the IB for further details. 
5.2.3.5. 
Summary of Nonclinical Data on Single-Agent In Vivo Antitumor Activity of 
DSP-0509 as Monotherapy and in Combination with Anti–Programmed Cell 
Death Protein 1 Antibody 
The effects of DSP-0509 on tumor progression and lung metastasis were evaluated in 
LM8-bearing C3H/HeN mice. After mice were inoculated with LM8 cells, DSP-0509 (1 mg/kg) 
was administered IV once weekly (q1w) for 3 weeks. DSP-0509 significantly suppressed both 
tumor volume and lung metastasis compared with treatment with the vehicle. These results 
indicate that DSP-0509 monotherapy possesses antitumor activity not only in primary tumors but 
also in metastatic tumors. Antitumor activity of DSP-0509 in combination with anti-programmed 
cell death protein 1 (PD-1) antibody was evaluated in BALB/c mice bearing mouse colon 
carcinoma CT26 (CT26-bearing mice). DSP-0509 (5 mg/kg) or anti–PD-1 antibody 
(200 
-bearing mice once or twice weekly for 3 weeks, 
respectively, alone or in combination. DSP-0509 alone showed significant antitumor effect, and 
mouse anti–PD-1 antibody alone had little effect on tumor growth. On the other hand, 
combination therapy with DSP-0509 and anti–PD-1 antibody significantly suppressed tumor 
growth compared with treatment with the vehicle, DSP-0509 alone, or anti–PD-1 antibody alone. 
These results indicated that DSP-0509 has synergistic antitumor activity when combined with 
anti–PD-1 antibody. 
5.2.4. 
Benefit/Risk Considerations 
Immuno-oncology drugs, including TLR agonists, have been designed to activate 
cancer-targeting immune responses. Nonclinical and clinical evidence shows that the release of 
TLR-activating DAMPs by dying cancer cells contributes to the elicitation of therapeutically 
relevant anticancer immune responses. 
SDP Oncology, Inc is developing DSP-0509, a TLR-7 agonist, for the treatment of patients with 
advanced solid tumors refractory to standard treatment or for whom no effective therapy exists. 
DSP-0509 is a new molecular entity with TLR-7 agonist activity. 
Study BBI-DSP-0509-101 is a FIH study. In addition to the AEs observed to date, potential AEs 
that may be encountered with administration of DSP-0509 alone or in combination with ICIs 
include those previously observed with the administration of other TLR agonists and ICI (see IB 
for detailed presentation). Details of immune-related AEs (irAEs) and guidelines for monitoring 
and managing these potential events are described in Sections 7.8 and 7.9. In consideration of the 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 30 of 122 
anticipated benefits of DSP-0509 administration and potential safety concerns, the benefit-risk 
profile of DSP-0509 in patients with advanced solid tumors is considered favorable. 
5.2.5. 
Rationale for Choosing Head and Neck Squamous Cell Carcinoma in the 
Dose-expansion Combination Arm C  
The decision to focus on patients with advanced and/or metastatic, recurrent and/or refractory 
HNSCC in the added dose-expansion Combination Arm C was made after careful review of the 
potential treatment space for such solid tumors. For newly diagnosed patients with 
relapsed/metastatic HNSCC, the standard of care consists of pembrolizumab alone or in 
combination with platinum-based chemotherapy (Burtness, 2019). Currently, different strategies 
to overcome resistance to ICIs are under investigation. The combination of DSP-0509 and 
pembrolizumab attempts to overcome resistance in patients with HNSCC after disease 
progression following previous therapy. 
For patients with advanced HNSCC who have progressed to chemotherapy and pembrolizumab, 
the prognosis remains poor, with overall survival (OS) around 6 to 8 months (Burtness, 2019). 
Thus, there is a high unmet medical need for new treatment options for these patients. 
The patient population selected for enrollment into Combination Arm C will have resistance to 
ICIs, either as a primary or acquired resistance, defined as: 
 Primary resistance: patients who experience disease progression without clinical response 
to the ICI after 6 weeks or more of treatment 
 Acquired resistance: patients who experience clinical response (complete response [CR], 
partial response [PR], and/or SD for at least 24 weeks on ICI therapy, but subsequently 
experience progressive disease (PD) during or within 3 months after the last dose of ICI 
treatment. Resistance to treatment of PD-1/PD-L1 with CTLA4 also is considered. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 31 of 122 
6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives and Endpoints 
Primary Objectives 
Endpoints 
Monotherapy Arm A - Dose Escalation (Phase 1):
 
To determine the safety, tolerability, and 
maximum tolerated dose (MTD) of 
DSP-0509 administered IV) as a single agent 
in patients with advanced solid tumors 
To identify a recommended Phase 2 dose 
(RP2D) of DSP-0509 monotherapy for 
patients with advanced solid tumors  
Incidence of dose-limiting toxicities (DLTs) 
within the first 6 weeks of dosing
Incidence and severity of TEAEs and SAEs 
using NCI CTCAE  
 
Incidence of dose interruption, dose reduction, 
and dose intensity 
 
Changes in clinical laboratory values 
(hematology, clinical chemistry, urinalysis), 
ECG parameters, multigated acquisition 
(MUGA) scan/electrocardiogram (ECHO) 
parameters 
Combination Arm B - Dose Escalation (Phase 1):
 
To determine the safety, tolerability, and 
MTD of DSP-0509 administered IV in 
combination with pembrolizumab for 
patients with advanced solid tumors who 
have shown primary or acquired resistance 
to ICIs 
 
To identify an RP2D of DSP-0509 when 
given in combination with pembrolizumab 
for such patients  
Incidence of DLTs within the first 6 weeks of 
dosing 
 
Incidence and severity of TEAEs and SAEs 
using NCI CTCAE 
 
Incidence of dose interruption, dose reduction, 
and dose intensity 
 
Changes in clinical laboratory values 
(hematology, clinical chemistry, urinalysis), 
ECG parameters, MUGA scan/ECHO 
parameters 
Combination Arm C – Dose Expansion (Phase 2):
 
To evaluate the preliminary antitumor 
activity of DSP-0509 in combination with 
pembrolizumab in patients with HNSCC 
who have shown primary or acquired 
resistance to ICIs 
Objective response rate (ORR), as assessed by 
Response Evaluation Criteria in Solid Tumors 
(RECIST), v1.1 and by Immune RECIST 
(iRECIST, modified RECIST for 
immunotherapy studies)
6.2. 
Secondary Objectives and Endpoints 
Secondary Objectives 
Endpoints 
Monotherapy Arm A - Dose Escalation (Phase 1):
 
To evaluate pharmacokinetic (PK) 
parameters of DSP-0509 administered as a 
single agent in patients with advanced 
solid tumors
Area under the concentration-time curve (AUC), 
maximal plasma concentration (Cmax), and other 
parameters described in Table 18. Additional 
parameters may be added as needed.


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 32 of 122 
 
To evaluate the preliminary antitumor 
activity of DSP-0509 administered as a 
single agent in patients with advanced 
solid tumors 
Using RECIST and iRECIST: 
 
ORR 
 
Time to progression (TTP) 
 
PFS, defined as the time from the date of the first 
dose of study treatment to the earlier date of 
assessment of progression by RECIST (v.1.1), or 
death by any cause 
 
Duration of response (DoR), defined as the time 
from the first documentation of a response (CR or 
PR) until time of first documentation of disease 
progression by RECIST (v.1.1), or death by any 
cause
To assess DSP-0509–induced changes in 
plasma cytokine levels in patients with 
advanced solid tumors treated with 
DSP-0509 as a single agent 
Measurement of cytokines in plasma including but 
interleukin 1 receptor agonist (IL-1RA), tumor 
(IL-6) 
Combination Arm B - Dose Escalation (Phase 1):
 
To evaluate PK parameters of DSP-0509 
given in combination with pembrolizumab 
in patients with advanced solid tumors
AUC, Cmax, and other parameters described in 
Table 18. Additional parameters may be added as 
needed.
 
To evaluate the preliminary antitumor 
activity of DSP-0509 in combination with 
pembrolizumab in patients with advanced 
solid tumors 
Using RECIST and iRECIST: 
 
ORR 
 
TTP 
 
PFS 
DoR
 
To assess changes in plasma cytokine 
levels induced by DSP-0509 in 
combination with pembrolizumab in 
patients with advanced solid tumors
Measurement of cytokines in plasma, including but 
-10, IL-
IL-6 
Combination Arm C – Dose Expansion (Phase 2):  
 
To evaluate the preliminary antitumor 
activity of DSP-0509 in combination with 
pembrolizumab in patients with HNSCC 
 
DoR  
 
Disease control rate (DCR), defined as the 
percentage of patients who have achieved best 
overall response (BOR) of CR, PR, or SD, per 
RECIST v1.1 
 
PFS  
 
6-month PFS rate, defined as the proportion of 
patients who neither progress by RECIST v1.1 nor 
die before 6 months (24 weeks) from first study 
treatment  
 
OS, defined as the time from date of first dose of 
study treatment to date of death by any cause


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 33 of 122 
 
To evaluate the preliminary antitumor 
activity of DSP-0509 in combination with 
pembrolizumab, in patients with HNSCC, 
using iRECIST criteria  
 
immune ORR (iORR), defined as proportion of 
patients who have achieved confirmed immune 
complete response (iCR) or immune partial 
response (iPR), evaluated using iRECIST, based 
on investigator assessment  
 
immune DCR (iDCR), defined as the percentage of 
patients who have achieved BOR of iCR, iPR, or 
immune stable disease (iSD) per iRECIST 
 
immune PFS (iPFS), defined as the time from the 
date of the first dose of study treatment to the 
earlier date of assessment of progressiona by 
iRECIST, or death by any cause 
 
immune DoR (iDoR), defined as the time from the 
first documentation of response (iCR or iPR) until 
time of first documentation of disease progression 
by iRECIST, or death by any cause 
 
To further evaluate the safety and 
tolerability of DSP-0509 administered with 
pembrolizumab
 
Frequency and intensity of AEs/SAEs using NCI 
CTCAE v5.0 
 
To assess changes in plasma cytokine 
levels induced by DSP-0509 in 
combination with pembrolizumab in 
patients with advanced solid tumors
Measurement of cytokines in plasma including, but 
-10, IL-
IL-6 
a The event date to be used for calculation of PFS should be the first date on which progression criteria are met (ie, 
the date of immune unconfirmed progressive disease [iUPD]), provided that immune confirmed progressive disease 
[iCPD] is confirmed at the next assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, 
that iUPD date should not be used as the progression event date 
6.3. 
Exploratory Objectives and Endpoints 
Exploratory Objectives
Endpoints
Monotherapy Arm A - Dose Escalation (Phase 1):
To evaluate the effect of DSP-0509 
administered as a single agent on cardiac 
parameters in patients with advanced solid 
tumors
 
Assessment of single agent QT 
interval/corrected QT interval (QTc) 
prolongation effect by continuous 25-hour ECG 
recording
 
To profile potential metabolites of DSP-0509 
in plasma and possibly in urine samples of 
patients treated with DSP-0509  
Detection of metabolites from DSP-0509 in 
pooled plasma and urine samples using liquid 
chromatography-tandem mass spectrometry
Monotherapy Arm A and Combination Arm B – Dose Escalation (Phase 1): 
 
To evaluate biomarkers potentially 
predictive of the clinical efficacy, immune 
activation, and/or toxicity associated with 
DSP-0509  
Examples include:  
 
Immune-related gene expression  
 
CD8+ immunohistochemistry (IHC) 
 
Lymphocyte immunophenotyping  
 
Tumor infiltrating lymphocytes (TILs) 
Human leukocyte antigen (HLA)-ABC (IHC) 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 34 of 122 
Tumor mutational burden (TMB)
 
Programmed death ligand 1 (PD-L1+) IHC 
(Combination Arms B and C only) 
Combination Arm C – Dose Expansion (Phase 2):
 
To determine the PFS rate as an evaluation 
of treatment benefit of DSP-0509 
administered with pembrolizumab 
PFS rate is defined as PFS1/PFS (-1) ratio using 
RECIST (v.1.1) 
PFS1 is defined as the time from the date of 
the first dose of study treatment to the earlier 
date of assessment of progression by RECIST 
(v.1.1), or death by any cause 
 PFS (-1) is defined as the date of initiation of 
the previous (penultimate) treatment regimen 
to the date of assessment of progression by 
RECIST (v.1.1) 
 
To evaluate biomarkers potentially 
predictive of the clinical efficacy, immune 
activation, and/or toxicity associated with 
DSP-0509 
Examples include:  
 
Immune-related gene expression  
 
CD8+ IHC 
 
Lymphocyte immunophenotyping  
 
TILs 
 
HLA-ABC (IHC)  
 
TMB 
 
PD-L1+ IHC (Combination Arms B and C only) 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7 
Confidential and Proprietary
Page 35 of 122
7.
INVESTIGATIONAL PLAN
7.1.
Overview of Study Design
This is a multicenter, Phase 1/2 clinical study for patients with advanced solid tumors. The study 
has 3 parts: a dose-escalation monotherapy Arm A, a dose-escalation combination therapy Arm 
B, and a dose-expansion combination therapy Arm C. The study structure is summarized in 
Figure 2.
Figure 2: 
Study Design
See Section 7.4 and Appendix 18.4 for details regarding Bayesian Adaptive Design 
Abbreviations: BLRM = Bayesian logistic regression model; DLT = dose-limiting toxicity; 
HNSCC = head and neck squamous cell carcinoma; ICI = immune checkpoint inhibitor; IV 
= intravenous; qXw = every X weeks (2 or 6); RP2D = recommended Phase 2 dose   
7.1.1.
Safety Monitoring in the Dose-escalation Cohorts
The guiding principles for dose escalation are to maximize patient safety and achieve precise 
dose selection. To accomplish this, the following provisions will be applied to all dose-escalation 
cohorts: 
Criteria for DLT events (see Section 7.7) include potential risks of immunotherapy, in 
general, and TLR agonists, in particular 
Dose escalation will be performed using a design based on Bayesian logistic regression 
model (BLRM) methods applied with the escalation with overdose control (EWOC) 
principle to limit the risk of exposing patients to excessive toxicity, defined as a DLT rate 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7 
Confidential and Proprietary
Page 36 of 122
greater than 33%. Based on this approach, a dose-escalation level is considered 
After all patients in a newly escalated cohort have completed the DLT evaluation period 
(Days 1 through 42), the BLRM model will be updated and a recommendation for the 
next dose level will be provided. 
PK is monitored closely (ie, real time by cohort) for patients in the dose-escalation 
cohorts to assure correct application of a Cmax cap; this cap specifies that dose escalation 
is contingent on the mean unbound Day 1 Cmax for DSP-0509 for the prior cohort being 
<43.5 nM (22.3 ng/mL unbound, or 378.6 ng/mL total) (observed drug binding in human 
serum is 94.1%). 
A Safety Review Committee (SRC; Section 7.4.2) will review available clinical data and 
integrate that with PK data and guidance for dose escalation by the BLRM method. The 
SRC will make a recommendation for the next cohort in the study (Section 7.4.2). 
Within each cohort, enrollment will be staggered, ie, there will be at least 48 hours 
between initiation of treatment in successive patients.
During the DLT period (Days 1 through 42), in the intervals that patients have no 
required study visits for infusions, a telephone safety check will be made to maintain 
close monitoring. These calls will be made (±1 day) on Days 8, 22, and 36 for both the 
Monotherapy Arm A and the Combination Therapy Arm B 
Dose levels assessed as tolerated based on the SRC review may, with the approval of the SRC 
and Sponsor, be opened to enroll an additional 3 to 6 patients (referred to as enrichment cohorts).
7.1.2.
Dose Escalation - Monotherapy Arm A 
The primary objective of Monotherapy Arm A is to determine the MTD or RP2D of DSP-0509 
when administered as a single agent. Approximately 21 to 30 patients with advanced solid 
tumors will be enrolled. Several provisional dose levels of DSP-0509, with approximately 3 to 
6 patients at each level may be tested in patients with advanced solid tumors, with dose 
escalation contingent on the mean Cmax for the prior cohort being below the Cmax cap described 
in Section 7.1.1.
DSP-0509 will be administered as a single agent q2w beginning on Day 1. Within each cohort, 
patients will be entered in a staggered fashion as an additional safety measure. That is, treatment 
of a new patient will be delayed at least 48 hours after the first dose of the most recent patient 
entered within each cohort. See Figure 3 for details.
Figure 3: 
Dosing Schedule – Monotherapy Arm A 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 37 of 122 
The provisional dose levels presented in Table 3 may be evaluated for both Arm A and Arm B. 
Intermediate dose levels may be added, or certain provisional dose levels may be skipped, based 
on the BLRM results. Every dose escalation will not be more than 100% higher than the previous 
dose in all dose levels above 3.0 mg. Enrollment of additional cohorts will be based on the 
dose -escalation procedures detailed in Section 7.4. Real-time DSP-0509 PK data (by dose 
cohort) will be obtained to support dose-escalation decisions. 
Table 3: 
DSP-0509 Provisional Dose Levels in Arm A and Arm B 
Provisional Dose Level 
Dose of DSP-0509 (mg) 
1 
0.3
2 
1.0
3 
3.0 
4 
6.0 
5 
9.0 
6 
12.0 
7 
16.0 
8 
20.0 
9 
25.0 
10
30.0 
7.1.3.
Dose Escalation - Combination Therapy Arm B 
The primary objective of Combination Therapy Arm B is to determine the RP2D of DSP-0509 
when administered in combination with pembrolizumab, using a BLRM approach. The 
combination arm will enroll approximately 21 to 30 patients with advanced solid tumors that are 
(a) metastatic or unresectable and recurrent, and/or refractory to available therapy, (b) a 
condition for which pembrolizumab is an approved treatment, and (c) in patients who have 
shown either primary or acquired resistance to an ICI. DSP-0509 will be administered on Day 1 
and then every 2 weeks thereafter. Pembrolizumab will be initiated on Day 1 and administered at 
a dose of 400 mg IV every 6 weeks (q6w) (Merck and Co, 2020) (Figure 4). 
To maximize patient safety, enrollment in the first combination-escalation cohort will begin at a 
dose level of 0.3 mg DSP-0509 after safety and tolerability of DSP-0509 monotherapy has been 
confirmed in patients receiving DSP-0509 at least 1 dose level higher. The provisional doses 
described in Section 7.1.2 also may be evaluated in Combination Therapy Arm B. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7 
Confidential and Proprietary
Page 38 of 122
Figure 4: 
Dosing Schedule – Combination Arms B and C
7.1.4.
Dose Expansion – Combination Therapy Arm C 
The primary objective of Combination Therapy Arm C is to determine preliminary efficacy in 
the form of the ORR of DSP-0509 when administered in combination with pembrolizumab to an 
expansion cohort of patients with HNSCC, using a Bayesian Adaptive design approach. 
Combination Arm C will enroll approximately 20 to 40 patients with HNSCC tumors that are (a) 
metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in patients 
who have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, 
and (c) who have subsequently shown either primary or acquired resistance to ICIs.  
Dose escalation of DSP-0509 in combination with 400 mg pembrolizumab q6w will start at the 
same dose of DSP-0509 as the highest (not exceeding the MTD) level tested in the combination 
regimen with 200 mg pembrolizumab q3w. Upon completion of the DLT evaluation period for 
the first DSP-0509 dose level tested in combination with 400 mg pembrolizumab q6w in newly 
enrolled patients, if this dose level is found not to exceed the MTD, any ongoing patients 
receiving DSP-0509 in combination with pembrolizumab 200 mg q3w will be allowed, at the 
investigator’s discretion, to transition to the 400 mg pembrolizumab q6w regimen, while 
maintaining the originally assigned DSP-0509 dose level. See Figure 4.  
7.2.
Rationale for Starting Dose
Data from nonclinical studies, together with the data from recent clinical studies with other 
TLR-7 agonists, have informed the Phase 1/2 study design. 
The minimal anticipated biologic effective level, based on human whole blood cytokine 
induction activity, has been used to select a starting dose of 0.3 mg in Monotherapy Arm A. 
Based on nonclinical studies, the unbound Cmax at the initial dose level in this FIH study is 
estimated to be in the range of 1.0 nM to 3.9 nM. 
To maximize patient safety, the starting dose in Combination Arm B will be at least 1 dose level 
below that of the second dose level tested and tolerated in the Monotherapy Arm A. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 39 of 122 
7.3. 
Administration of Study Treatment  
Each patient treated will receive DSP-0509 at the dose fixed for that Arm or Phase administered 
as a constant-rate IV infusion over 10 minutes using a syringe pump; see Appendix 18.1 for the 
detailed procedure.  
Patients in Combination Arms B and C also will receive pembrolizumab administered as a 
30-minute IV infusion. In both Arms B and C, pembrolizumab will be administered at a dose of 
400 mg every 6 weeks, in accordance with the updated prescribing information (Merck and Co, 
2020). On all occasions when patients are scheduled to receive both agents on the same day, the 
following procedures will apply:  
 DSP-0509 will be administered first 
 After 4 hours of observation, vital signs will be obtained 
 After the investigator has assessed that the patient is clinically stable, including vital 
signs, infusion of pembrolizumab may be initiated  
 Vital signs must be obtained 30 to 60 minutes after completion of the pembrolizumab 
infusion, just prior to discharge 
7.4. 
Dose Escalation Procedures  
7.4.1. 
Application of BLRM to Dose Escalation 
As indicated in Section 7.1, dose-escalation procedures include BLRM models 
(Neuenschwander, 2008) that incorporate the EWOC principle (Babb , 1998). Details of 
statistical methodology and the specific BLRM models in this study are provided in 
Appendix 18.4.  
The use of Bayesian adaptive models for Phase 1 dose-escalation studies has been advocated by 
the European Medicines Agency (EMA) in their guidelines on clinical studies in small 
populations (EMA, 2006). The BLRM method similarly provides guidance on the MTD and 
RP2D dose levels (see Section 7.5).  
Intrapatient dose escalation is not allowed at any time in either of the dose-escalation treatment 
arms. 
7.4.2. 
Safety Review Committee 
The SRC will consist of the principal investigators (or delegates) and the Sponsor’s Medical 
Monitor, Statistician, Pharmacovigilance Safety Lead, and PK Lead. The SRC will meet after all 
patients in a new cohort have completed the DLT evaluation period. The SRC may have 
unscheduled meetings on an as-needed basis to review results of routine signal detection efforts, 
unexpected toxicities, and/or other information that may be relevant to the conduct of this study 
or to patient safety. 
At dose-escalation meetings, the SRC will review the following:  
 Dose recommendation based on BLRM (treated as guidance and integrated into an 
overall clinical assessment) 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 40 of 122 
Available clinical and safety data, including assessments of AE severity/causality, action 
taken with study treatment, and action taken for AE management (including 
administration of systemic corticosteroids)  
 Available PK and pharmacodynamics data 
The SRC final recommendation may include, but is not limited to, the following:  
 Dose escalation 
 Dose de-escalation 
 Enrollment of additional patients at the same dose level 
 Proposal of the RP2D dose level, as detailed in Section 7.5  
The SRC recommendation will be recorded in meeting minutes and reviewed by the Sponsor. 
SRC recommendations and the Sponsor's decision will be provided to investigators before 
dosing any new patients. 
7.5. 
Determination of the MTD and RP2D  
The RP2D is usually the highest dose with acceptable toxicity, generally defined as the dose 
level producing a DLT rate of approximately 16% to 33%.  
In the current study, the unbound plasma Cmax steady-state level or systemic exposure level 
(AUC) of DSP-0509 may be incorporated into the determination of the RP2D, especially if an 
association is found between toxicity and these PK parameters. The RP2D will be defined as the 
MTD, provided the MTD is not associated with a potentially toxic Cmax or systemic exposure 
level of DSP-0509.  
Determination of the RP2D will be performed in consultation with the SRC, based on safety and 
other data available at the time of the RP2D decision.  
Dose escalation will continue until identification of the MTD or a suitable lower dose for 
expansion (the RP2D). This will occur when the following conditions are met: 
 At least 6 patients have been treated at this dose 
 This dose satisfies one of the following conditions: 
 The posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or 
 A minimum of 21 patients already have been treated in the dose-escalation part of 
the study 
 It is the dose recommended for patients, either per the model or by review of all 
available clinical data in the SRC meeting 
Of note, dose escalation could be stopped earlier by a joint decision between the Sponsor and 
investigators during a dose-escalation meeting, by considering the model estimations and a 
global assessment of safety, PK, pharmacodynamics, and preliminary activity data. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 41 of 122 
7.6. 
Definition of Patients Evaluable for DLT 
The DLT period for dose-escalation review is from Study Days 1 through 42. During this period, 
treated patients will be monitored closely for AEs in general and for DLTs in particular.  
A patient will be considered evaluable for DLT if observed for 42 days following the first dose 
of DSP-0509 in monotherapy and with pembrolizumab in combination. Patients discontinued 
during the DLT period due to DLTs are considered as evaluable for DLT.   
Patients who do not meet the above criteria will be considered nonevaluable for DLT and may be 
replaced to provide sufficient evaluable patients to fully assess a given dose level.  
7.7. 
Definition of Dose-Limiting Toxicity  
DLTs are defined below, including both irAEs and other AEs, grouped by SOC. Severity of the 
events will be graded based on NCI CTCAE version 5.0. Within each category, specific events 
not considered DLTs also will be indicated.   
The TEAEs listed below will be considered DLTs if they meet all of the following criteria: 
 Have onset from Days 1 through 42 
 Are assessed as treatment-related, unless causality is determined to be related to 
pembrolizumab alone  
 Meet criteria defined in Sections 7.7.1 through 7.7.4  
7.7.1. 
Immune-related DLTs 
 Any Grade 4 irAE (except immune-mediated endocrinopathies) 
 Grade 3 pneumonitis and nephritis 
 Grade 3 infusion-related reaction, except first occurrence without steroid prophylaxis and 
resolved within 6 hours with appropriate clinical management 
 Recurrent Grade 2 pneumonitis 
 Recurrent Grade 3 irAE 
 
 
7.7.2. 
Hematologic DLTs 
 Neutropenia Grade 4 (absolute neutrophil count [ANC] <500/mm3
 
 
000/mm3) associated with infection or requiring 
granulocyte-colony stimulating factor (G-CSF) 
 Febrile neutropenia (ANC <1000/mm3 with a temperature of >38.3ºC once or 
1 hour)  
 Thrombocytopenia Grade 4 (platelet count <25,000/mm3
 
 Thr
3) associated with bleeding or 
requiring platelet transfusion 
 Anemia Grade 4 (requires urgent intervention)  
 Anemia Grade 3 (hemoglobin [Hgb] <8 g/dL; requires blood transfusion) 
The following hematologic event is NOT considered a DLT:  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 42 of 122 
Grade 3 or 4 lymphopenia (lymphocyte count <500/mm3) 
7.7.3. 
Liver-related DLTs 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 x the upper 
limit of normal (ULN) 
 Total bilirubin >5 x ULN 
 Cases that meet all 3 of the following criteria (ie, are consistent with Hy’s law):  
– ALT or 
 
– Serum total bilirubin >2 x ULN without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
– Have no other reason identified to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; 
pre-existing or acute liver disease; or another drug capable of causing the 
observed injury  
The following liver-related events are NOT considered DLTs: 
 Patients without liver metastases: isolated Grade 3 increases of ALT and/or AST 
(>5 x 
 
 Patients with liver metastases: isolated Grade 3 increases of ALT and/or AST 
(>5 x 
within 10 days 
7.7.4. 
Other DLTs 
 
-
(a) leads to hospitalization, (b) 
 
 Any of the following eye-
uveitis, choroidal neovascularization, retinopathy/retinitis, thyroid-associated 
orbitopathy, idiopathic orbital inflammation  
 Any seizure, regardless of the grade  
The following events are NOT considered DLTs:  
 
 
 Grade 3 nausea and/or vomiting  
 Grade 3 hypertension that is controlled within 7 days with medical management  
 Grade 3 fatigue t
 
 Isolated Grade 3 electrolyte abnormalities that are (a) not associated with clinical signs or 
symptoms and (b) reversed within 3 days with medical intervention  
 Isolated Grade 3 amylase or lipase abnormalities that are not associated with clinical 
signs or symptoms or with findings on imaging consistent with pancreatitis 
7.8. 
Monitoring of Potential Adverse Events 
The following materials are provided as guidance and reference for monitoring for potential 
events:  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 43 of 122 
National Comprehensive Cancer Network [NCCN, 2020] guidelines for monitoring 
immunotherapy-related toxicities and cytokine release syndrome, and assessing infusion-
related- reactions (Appendix 18.3)  
 Guidelines for monitoring potential AEs associated with DSP-0509 (Table 4)   
Table 4: 
Monitoring of Potential Adverse Events 
Potential AE 
Monitoring 
Ask Patients to Report Promptly
Postinfusion events 
associated with 
TLR-mediated 
cytokine induction  
Monitor signs/symptoms post infusion for 
cytokine-related symptoms (eg, flulike 
symptoms, decreased blood pressure)  
Observe patients for 1 to 2 hours post 
infusion (at Day 1, then as needed)  
Shortness of breath, chills or shaking, fever, 
wheezing, flushing, headache, itching, skin 
rash, dizziness, or feeling like passing out 
Cardiac disorders
Monitor signs/symptoms of cardiac 
disorders; perform ECG monitoring, 
MUGA/ECHO monitoring; perform 
cardiodynamic assessments as scheduled    
Pressure or tightness in the chest, chest pain, 
shortness of breath, sweating, fast heart rate, 
dizziness, cough, nausea and/or vomiting  
Nervous system 
disorders 
Monitor for signs/symptoms of nervous 
system disorders, eg, tremor, convulsions, 
mental status changes, encephalitis  
Sudden, irregular/uncontrolled shaking of an 
arm or leg or of the body, involuntary 
contraction of muscles, stiffness, confusion, a 
sudden feeling of fear or panic, loss of 
consciousness   
Eye disorders 
Monitor signs/symptoms of eye disorders 
(eg, uveitis, retinal atrophy, retinal 
detachment); perform Slit Lamp exam, 
visual field testing, fundoscopy, as 
scheduled; ad hoc exams performed at 
investigator’s discretion
Any visual changes  
Pneumonitis
Monitor for signs and symptoms of 
pneumonitis; if suspected, perform 
appropriate evaluations
Shortness of breath, chest pain, new or 
worsening cough  
Abbreviations: AE = adverse event(s); ECG = electrocardiogram; ECHO = echocardiogram; MUGA = multigated 
acquisition; TLR = Toll-like receptor  
7.9. 
Guidance for Modifying or Discontinuing Study Treatment  
For the clinical management of urgent or severe events (eg, acute infusion-related reactions, 
cardiopulmonary distress, seizures), investigators should follow applicable institutional 
standards, clinical practice guidelines, and their own judgement.  
Refer to the latest NCCN guideline for management of immunotherapy-related toxicities in 
patients with irAEs and cytokine-release syndrome. 
7.9.1. 
Guidance for Modifying or Discontinuing DSP-0509  
DSP-0509 will be withheld for a given patient for: 
 Any treatment-related Grade 3 or greater non-irAE: if recovered to Grade 2 or 
Grade 1 within 6 weeks after the last dose, treatment may be restarted at a lower dose 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 44 of 122 
level (after discussion with Medical Monitor); if not recovered, permanently 
discontinue DSP-0509 
In case of treatment-related irAE, refer to withholding conditions listed in Table 5
DSP-0509 will be permanently discontinued for a given patient for: 
 Use of a prohibited treatment for a concomitant illness or TEAE (exception: use of 
corticosteroids for an irAE) 
 Toxicities meeting the DLT definition 
 Any Grade 3 or higher allergic reaction or anaphylaxis  
 Any symptomatic congestive heart failure, or decreased left ventricular ejection 
fraction of >10% from baseline, based on a MUGA scan or ECHO  
 Corrected QT interval according to Fridericia’s formula (QTcF) prolongation of 
greater than 500 msec 
7.9.2. 
Guidance for Modifying or Discontinuing Pembrolizumab  
Pembrolizumab will be withheld or permanently discontinued according to irAEs in Table 5. The 
dose of pembrolizumab cannot be modified.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 45 of 122 
Table 5:
Modifications for Immune-related Adverse Events 
Adverse Reaction 
Severity 
Dose Modification 
Immune-mediated 
pneumonitis 
Grade 2
Withholda
Recurrent Grade 2
Grade 3 or 4
Permanently discontinue 
Immune-mediated colitis 
Grades 2 or 3 
Withholda
Grade 4
Permanently discontinue
Immune-mediated hepatitis 
in patients without 
hepatocellular carcinoma 
(HCC) 
AST or ALT 3 to 5 x ULN or 
Total bilirubin 1.5 to 3 x ULN 
Withhold a
Immune-mediated hepatitis 
in patients with HCC 
 
ULN 
Total bilirubin >2.0 mg/dL if baseline 
<1.5 mg/dL; or 
Total bilirubin >3.0 mg/dL, regardless of 
baseline levels
Withholdb
ALT or AST >10 x ULN or
Child-
 
Gastrointestinal bleeding suggestive of 
portal hypertension or new onset of clinically 
detectable ascites or encephalopathy
Permanently discontinue 
Immune-mediated 
endocrinopathies 
Grades 3 or 4 
 
Withhold until clinically 
stable 
Immune-mediated nephritis
Grade 2
Withhold a
Grade 3 or 4
Permanently discontinue 
Immune-mediated skin 
adverse reactions 
Grade 3 or suspected Stevens-Johnson Syndrome 
(SJS) or Toxic Epidermal Necrolysis (TEN) 
Withhold a
Grade 4 or confirmed SJS or TEN 
Permanently discontinue 
Other immune-mediated 
adverse reactions 
Grades 2 or 3 based on severity and type of 
reaction 
Withhold a
Grade 3 based on severity and type of reaction, 
or Grade 4
Permanently discontinue 
Recurrent immune-mediated 
adverse reactions 
Recurrent Grade 3 or 4
Recurrent Grade 2 pneumonitis 
Permanently discontinue 
Infusion-related reactions 
Grades 1 or 2 
Interrupt or slow the rate of 
infusionc 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 46 of 122 
Adverse Reaction 
Severity 
Dose Modification 
Grade 3 or 4
Permanently discontinue 
Inability to taper 
corticosteroid
for >12 weeks after last dose of study drug 
Permanently discontinue 
Persistent Grade 2 or 3 AE 
(excluding endocrinopathy)
Permanently discontinue 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular 
carcinoma; SJS = Stevens-Johnson Syndrome; TEN = Toxic Epidermal Necrolysis; ULN = upper limit of normal 
Guidelines based on approved pembrolizumab label with minimal modifications for patients eligible for this study 
a 
 
b 
 
c If symptoms resolve within one hour of stopping drug infusion, infusion may be restarted at 50% of original 
infusion rate; otherwise, dosing will be held until symptoms resolve. Patient should be premedicated for the next 
scheduled dose. 
 
If DSP-0509 is discontinued permanently, dosing with pembrolizumab may continue, provided 
the investigator considers it to be safe and potentially beneficial for the patient. If 
pembrolizumab is discontinued permanently, dosing with DSP-0509 may continue, provided the 
investigator considers it to be safe and potentially beneficial for the patient. 
7.9.3. 
Study Discontinuation 
Patients must be discontinued from this study if any of the following occurs: 
 Patient withdraws consent 
 Investigator decision to withdraw patient from treatment 
 Pregnancy in a female patient 
 Confirmed PD per iRECIST criteria (Appendix 18.2): initial PD should be confirmed 
within 4 to 8 weeks. Study treatment may continue after confirmed progression if 
there is potential benefit for the patient, following discussion between the investigator 
and the Medical Monitor. 
 Loss to follow-up 
 Unacceptable toxicities, described in Section 7.9, or other toxicities according to 
investigator 
 Noncompliance with study treatment or procedures 
 Initiation of other anticancer therapy 
 Sponsor terminates the study 
In the event of premature discontinuation, the patient should return to the study site within 
30 days (±7 days) after last dose of study treatment to have the end-of-study (EoS) assessments 
performed. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 47 of 122 
7.10.
Study Duration 
The duration of the study will be approximately 6 years.  
Patients in each Arm (Monotherapy Arm A, Combination Arm B, Combination Arm C) will 
undergo a Screening period of up to 28 days; a treatment period of up to 127 days 
(approximately 4.5 months) or as long as the patient is benefitting from treatment; and a 30-day 
safety follow-up. Survival follow-up, if applicable, will occur every 6 months, following the 
30-day safety follow-up. 
Treatment duration for each patient is unknown, as patients may continue therapy as long as they 
demonstrate clinical benefit. 
7.11.
Selection of Study Population
7.11.1. 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study: 
1. Must have a histologically or cytologically confirmed advanced solid tumor that meets the 
following additional specifications for the Arm/Phase in which they are to be treated: 
a. Monotherapy Arm A (Dose Escalation), Phase 1 – Advanced solid tumors that are 
metastatic or unresectable, and recurrent and/or refractory to available therapy 
b. Combination Arm B (Dose Escalation), Phase 1 – Advanced solid tumors that are (a) 
metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) a 
condition for which pembrolizumab is an approved treatment, and (c) in patients who 
have shown either primary or acquired resistance to ICIs 
c. Combination Arm C (Dose Expansion), Phase 2 – Advanced HNSCC tumors of the 
oropharynx, oral cavity, hypopharynx, larynx, lip, or sinus that are (a) metastatic or 
unresectable, and recurrent and/or refractory to available therapy, (b) in patients who 
have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in 
monotherapy, and (c) who have subsequently shown primary or acquired resistance to 
ICIs 
2. 
 
3. Should have all side effects of any prior therapy or procedures for any medical condition 
 1 (except alopecia) 
4. Must have at least 1 measurable lesion by computed tomography (CT) or magnetic resonance 
imaging (MRI) per RECIST v1.1 
5. 
 
6. Female patients of childbearing age and women <12 months since the onset of menopause, 
except those who have been surgically sterilized (tubal ligation) or whose sexual partner(s) is 
surgically sterilized (vasectomy), must agree to use acceptable contraceptive methods for the 
duration of the study and for 9 months after the date of their last DSP-0509 infusion. If 
employing contraception, 2 of the following precautions must be used: birth control pill, 
vaginal diaphragm, intrauterine system or device, condom, or vaginal spermicide. Female 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 48 of 122 
patients who are postmenopausal are defined as those with an absence of menses for 
 consecutive months. Male patients must be surgically sterilized (vasectomy) or their 
female sexual partner(s) must be surgically sterilized (tubal ligation) to avoid using 
contraception. If they do not meet this criterion, male patients must agree to use a condom as 
well as one of the acceptable contraceptive methods listed above with their female partner(s) 
who meets the criterion of either being of childbearing age or <12 months since the onset of 
menopause. Male patients and their female partner(s) must agree to use acceptable 
contraception methods for the duration of time the male patient is on the study and for 
9 months after the date of his last DSP-0509 infusion.  
7. Females of childbearing potential must have a negative serum pregnancy test at Screening 
8. Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
9.  Must have adequate coagulation function at Screening as determined by: 
a. Prothrombin time (PT) international normalized ratio (INR) <1.5 
b. Partial thromboplastin time (PTT) <1.5 times the ULN 
10. Must have adequate hematologic function at Screening as determined by: 
a. White blood cell (WBC) count 
 
b. 
-CSF or GM-CSF to achieve these 
WBC and ANC levels) 
c. 
3/microliter 
d. 
 
11. Must have adequate renal and hepatic function at Screening as determined by: 
a. Serum creatinine <2.0 mg/dL or <1.5 times the ULN, whichever is lower 
b. 
 mg/dL for patients with known Gilbert syndrome) 
c. AST 
 
d. 
 
12. Must be able to attend study visits as required by the protocol 
13. Prior to the first DSP-0509 infusion, the patient must be able to provide tumor tissue for 
baseline studies as (a) a block of archival tissue sufficient to provide the required number 
of slides; (b) a sufficient number of fixed, unstained slides of archival tissues; or (c) 
consent to undergo tumor biopsy to acquire sufficient tumor tissue. (Sites need to refer to 
the current version of the “Sample Collection & Shipment Instructions” manual to 
determine how many slides are required for each patient, as the number varies based on (a) 
the study Arm/Phase in which the patient is enrolled, and (b) whether the patient 
consented to optional future testing) 
Additional Inclusion Criteria for Combination Arm C Only: 
In addition to the above criteria, patients must meet the following criteria to be eligible to enroll 
in Combination Arm C: 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 49 of 122 
14. Have at least one accessible tumor for biopsy. This accessible lesion must be considered 
as nonmeasurable per RECIST criteria, v1.1. 
15. Be platinum refractory, PD-1 or PD-L1 exposed, and have no more than 3 lines of prior 
therapy for advanced/metastatic disease 
16. Have a known status of PD-L1 combined positive score (CPS) 
17. Have a known HPV status  
7.11.2.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study: 
1. Has received prior therapy with a TLR agonist, excluding a topical TLR agonist 
2. Has received anticancer chemotherapy (including molecular-targeted drugs), 
radiotherapy, immunotherapy (eg, vaccines or cytokines), or investigational agents 
within the 3 weeks before the first dose of DSP-0509. Local palliative radiotherapy is 
permitted 
3. Receives concurrent systemic (oral or IV) steroid therapy >10 mg prednisone daily or its 
equivalent 
4. Not fully recovered from major surgery before the first dose of DSP-0509  
5. Has CNS metastases (including leptomeningeal or spinal metastases) or CNS primary 
tumors, eg, glioblastoma 
6. Has a history of seizures other than isolated febrile seizure in childhood; has a history of 
a cerebrovascular accident or transient ischemic attack less than 6 months ago  
7. Has effusions (pleural, pericardial, or ascites) requiring drainage 
8. Has a neurodegenerative disease, eg, motor neuron disease, Parkinson disease, 
Alzheimer disease, Huntington disease 
9. Has retinal detachment, ulcerative keratitis, uveitis, Vogt-Koyanagi-Harada syndrome, 
choroidal neovascularization, retinopathy/retinitis, thyroid-associated orbitopathy, 
idiopathic orbital inflammation, diabetic retinopathy, ischemic retinopathy (including 
glaucoma-associated retinopathy), retinal vein thrombosis, or a non-healing ocular or 
ophthalmic disease  
10. Has a fever 38°C within 3 days before the first dose of study treatment 
11. Has interstitial lung disease or active noninfectious pneumonitis 
12. Has a history of active autoimmune or immunologic disorder requiring 
immunosuppression with steroids or other immunosuppressive agents (eg, azathioprine, 
cyclosporine A), that, after discussion between the investigator and the Medical Monitor 
is considered not acceptable for the study. If the autoimmune status is questionable, and 
the patient is not at risk, the investigator may discuss the patient’s potential eligibility 
with the Medical Monitor. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 50 of 122 
13. Has a known hypersensitivity to a component of the protocol therapy, DSP-0509, or 
another pyrimidine  
14. Has a history of another primary cancer within the 5 years before enrollment except for 
the following: non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder 
cancer, or other nonmetastatic carcinoma that has been in complete remission without 
treatment for more than 5 years 
15. Has abnormal ECGs that are clinically significant, such as QT prolongation (QTc 
>480 msec)  
16. In the opinion of the treating investigator, has any concurrent conditions that could pose 
an undue medical hazard or interfere with interpretation of study results; these 
conditions include, but are not limited to, ongoing or active infection, clinically 
significant non-healing or healing wounds, concurrent congestive heart failure (New 
York Heart Association Functional Classification Class II, III or IV), concurrent 
unstable angina, concurrent cardiac arrhythmia requiring treatment (excluding 
asymptomatic atrial fibrillation), recent (within the prior 12 months) myocardial 
infarction or acute coronary syndrome, significant pulmonary disease (shortness of 
breath at rest or on mild exertion, eg, due to concurrent severe obstructive pulmonary 
disease), concurrent hypertension requiring more than 2 medications for adequate 
control, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 
12 months 
17. Has an ejection fraction of 50% or less based on a MUGA scan or ECHO 
18. Has the presence of a known, active, acute or chronic infection, including human 
immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), 
as determined by fourth-generation (HIV antibody and antigen) assay, hepatitis B 
surface antigen (HBsAg), and hepatitis C serology, respectively  
19. Has a cognitive, psychological, or psychosocial impediment that would impair the 
ability of the patient to receive therapy according to the protocol, or adversely affect the 
ability of the patient to comply with the informed consent process, protocol, or 
protocol-required visits and procedures  
20. Receives concurrent strong inhibitors of cytochrome P450 (CYP)2C8 (see 
Section 7.13.2) 
21. Receives concurrent inhibitors of OATP1B1 and OATP1B3 (see Section 7.13.2) 
22. Is pregnant or breastfeeding 
23. Has active neurologic or inflammatory or auto immune disorders (eg, Guillain-Barre 
syndrome, amyotrophic lateral sclerosis) 
The following exclusion applies only to enrollment in Combination Arms B and C: 
24. Has a history of irAEs resulting in permanent discontinuation of prior ICI treatment 
 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 51 of 122 
7.12.
Investigational Product 
7.12.1. 
Identity of the Investigational Product DSP-0509 
The investigational product is formulated as a sterile solution for injection. Each vial contains 
8.5 mL of DSP-0509 at the concentration of 0.3 mg/mL. The assigned fixed dose of DSP-0509 
will be administered as an IV constant-rate infusion over 10 minutes using a syringe pump; see 
Appendix 18.1 for a detailed description of the procedure. For patients who have indwelling 
ports, it is acceptable to use this access for DSP-0509 administration. For full information about 
drug storage, preparation, and handling, please refer to the Pharmacy Manual. 
7.12.2. 
Combination Therapy – Pembrolizumab 
In Combination Therapy Arms B and C, pembrolizumab will be administered in the clinic at 
400 mg IV q6w over 30 minutes, in accordance with pembrolizumab labeling, unless otherwise 
specified. See Section 7.3 for details related to administration of both pembrolizumab and 
DSP-0509 on the same day.  
7.13.
Prior and Concomitant Therapy 
7.13.1. 
Allowed Concomitant Medications 
Patients may receive concomitant medications, including supportive care drugs, during treatment 
for all intercurrent medical conditions or TEAEs (whether assessed as related or not related to 
study treatment) at the discretion of the investigator, in conformance with community or 
institutional medical standards. Use of megestrol acetate for treatment of loss of appetite and 
weight loss due to disease is allowed. 
Patients on the study will be permitted to receive COVID-19 vaccinations that are authorized for 
use by the Health Authorities of the country/region. 
7.13.2. 
Prohibited Medication/Therapy 
 There are no scheduled premedications.  
– Patients in the dose-escalation cohorts may not, during the DLT period, receive 
prophylactic medications aimed at preventing TEAEs, unless it is required as per 
Table 4    
– After the DLT period, prophylactic treatments, including antiemetics, may be 
given with the approval of the Medical Monitor  
 During the study, patients may not receive any other anticancer therapy, including 
therapeutic radiotherapy   
– Local palliative radiotherapy is permitted but, if to a target lesion, that lesion must 
be excluded from tumor response assessments  
– Therapy with denosumab and bisphosphonates for bone metastases may continue 
if a patient is taking this medication before starting study treatment 
 Patients may not receive immunosuppressive agents, including systemic corticosteroids 
with the following exceptions: 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 52 of 122 
– Intranasal corticosteroids at a physiologic dose not to exceed 10 mg/day of 
prednisone or equivalent 
– A course of systemic corticosteroids given for the treatment of an irAE. Note that 
if the response is not adequate to permit tapering of the steroids within the time 
indicated, the patient must be discontinued from study treatment (see Table 5)  
 Patients should not receive live vaccines (eg, FluMist®); vaccines containing killed 
organisms or purified products are permitted. 
 Herbal preparations/medications are prohibited including, but not limited to, 
dehydroepiandrosterone, ephedra (ma huang), gingko biloba, ginseng, kava, saw 
palmetto, St. John’s wort, and yohimbe 
 Patients with renal cell carcinoma being considered for combination therapy must 
discontinue axitinib before starting study treatment due to increased risks of hepatic 
toxicity in combinations with pembrolizumab 
 The strong inhibitors of CYP2C8 and of OATP1B1 and OATP1B3 transporters indicated 
in Table 6 are prohibited: 
 
Table 6: Prohibited Strong Inhibitors of CYP2C8 and OATP1B1/B3 
Target 
Prohibited Strong Inhibitorsa 
CYP2C8 
clopidogrel 
gemfibrozil 
OATP1B1 and OATP1B3 
clarithromycin 
erythromycin 
rifampin 
gemfibrozil 
cyclosporine 
a Additional strong inhibitors of OATP1B1 and OATP1B3 transporters include atazanavir, lopinavir, 
ritonavir, and simeprevir. These are antiviral agents for the treatment of HIV and HBV. However, 
patients with HIV or HBV (whether previously known or found at Screening) are excluded from the 
study. Patients diagnosed with those infections while on study treatment should be discontinued.   


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 53 of 122 
8. 
STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
performed. 
8.1.
Schedule of Events
The planned schedules of events (SoE), including treatment, procedures, and assessments, for the 
Monotherapy Arm A and for Combination Therapy Arms B and C are presented in Table 7 
through Table 16.  
 For each part, events during Screening and the DLT period (Days 1 through 42) and 
during ongoing treatment (Day 43 to EoS) are presented separately by study day  
 Additional detailed tables are provided for events that have hourly schedules, including 
collection of blood and urine samples for PK, cytokines, and cardiodynamic assessments 
Following the SoEs, a detailed description of each study procedure and assessment to be 
performed is provided (Section 8.2).  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 54 of 122 
Table 7:
Schedule of Events – Screening and DLT Period - Monotherapy Part A
Tests and Procedures 
Screening 
DLT Period
Day
-28 
to -1 
-7 
to -1 
1
8
15
22
29
36
Window 
–
± 1 d
± 1 d
± 1 d
± 1 d
±1 d
Informed Consenta 
X
 
 
 
Assess Eligibility 
X
 
 
 
Demographics 
X
 
 
 
Medical and Cancer History 
X
 
 
 
Hospitalizationb 
 
X
 
 
DSP-0509 Infusion
 
X
 
X
X
Telephone Safety Callc  
 
X 
 
X
X
Physical Examination
X
 
X
 
X
X
Pregnancy Test, if Necessary
X
 
 
 
ECOG Performance Status
X 
X
 
X
X
Vital Signs 
X 
X
 
X
X
Body Weight
X 
X
 
X
X
Height 
X 
 
 
Hematology Tests
X 
X d
 
X
X
Chemistry Tests 
X 
X d
 
X
X
Coagulation Tests (PT & PTT only)
X 
 
 
Urinalysis 
X 
X d
 
X
X
Serum Virology (HBV, HCV, HIV)e  
X
 
 
 
Chest X-ray 
X
 
 
 
MRI scan of brainf 
X
 
 
 
Bone scan (if indicated)g  
X
 
 
 
MUGA Scan or ECHO 
X
 
 
 
X
Eye Examination by an Ophthalmologisth 
X
 
 
 
X
12-Lead Safety ECGsi
X
 
X
 
 
X
Cardiodynamic Assessment by Holter Monitorj 
 
X
 
 
Pharmacokineticsk  
 
X
 
X
X
Plasma for Cytokinesk  
 
X
 
X
X
Blood for PBMC Lymphocyte Markers 
X
 
 
 
Blood for Tumor Markersl 
X
 
 
 
Blood for Future Biomarker Analysism  
X
 
 
 
Tumor Samples for TMB Analysis 
X
 
 
 
Tumor Samples for Immune-Related Biomarkers 
X
 
 
 
Tumor Samples for Future Biomarker Analysism
X
 
 
 
Objective Disease Assessmentn
X
 
 
 
Concomitant Medications 
<---------- Continuously from Consent to EoS --------->
Adverse Events
<---------- Continuously from Consent to EoS --------->


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 55 of 122 
d = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; HbsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; HIV = 
IHC = immunohistochemistry; iRECIST = Immune Response Evaluation Criteria in Solid Tumors; min = minutes; 
MUGA = multigated acquisition; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetics; PR = partial 
response; PT = Prothrombin time; PTT = Partial thromboplastin time; SOI = start of infusion   
a Informed consent is to be obtained before performing any study-specific procedures; begin AE collection after 
informed consent is obtained. 
b Hospitalization extends into Day 2 to at least 24 hours post infusion to allow completion of the events in Table 8. 
c On Days 8, 22, and 36 (±1 day) during the dose-limiting toxicity (DLT) period, when there are no required visits, 
telephone calls will be made to maintain close safety monitoring of patients. 
d Day 1 laboratory assessments do not need to be repeated if done within the previous 3 days. 
e Viral serology tests include HbsAg, anti-HCV, and HIV Ag and Ab screening tests (ie, fourth-generation) 
f A brain MRI will be performed at baseline to rule out brain metastases, and at subsequent time points if clinically 
indicated 
g A bone scan will be conducted when clinically indicated 
h Eye exam includes slit lamp exam, visual field testing, and fundoscopy 
i Manual 12-lead ECGs are to be performed after 10 minutes rest, in triplicate, at least 5 minutes apart at Screening, 
predose on Day 1, at 24 hours postdose on Day 2, and predose on Day 29 
j Cardiodynamic assessments: On Day 1, a Holter monitor will be placed on the patient 1 hour prior to start of DSP-
0509 infusion and will remain in place until 24 hours (Day 2) after the end of infusion. On Day 1, patients should be 
supine and at rest from at least 10 minutes before to 5 minutes after (a) the interval from start of infusion (SOI) to 
30 minutes post-SOI; and (b) for similar periods around each subsequent timepoint shown in Table 8. Concurrent 
PK samples should be obtained on time, and the exact times for the SOI and the start and end of the rest periods 
recorded to permit ECG extraction by the Holter vendor. 
k See Table 8 for a detailed schedule of collection times for blood and urine for PK and cytokines 
l Tumor markers in blood will be assessed as appropriate for those cancers for which markers are known to exist, 
eg, CA-125, PSA, AFP, CA19-9, CEA 
m An additional separate informed consent is needed at the prestudy evaluation to permit collection and storage of 
blood and tumor tissues (archival and/or fresh biopsy) for future exploratory biomarker analyses 
n Objective disease assessment (tumor imaging) pretreatment represents the baseline study for the patient's response 
to treatment evaluated using RECIST and iRECIST. The same imaging modality must be used throughout the study 
for an individual patient. See Table 9 for timepoints of subsequent post-treatment evaluations. 
 


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
 
 
Confidential and Proprietary
Page 56 of 122
Table 8: 
Schedule of Cardiodynamics, PK, and Cytokine Samples – Monotherapy Arm A 
Day
Day 1
Day 2
Day 15 and Day 29
Time After Start of 
Infusion 
Predo
se
0 
8  
min
11 
min
15 
min
20 
min
30 
min
1  
hr 
2  
hr 
4  
hr 
6  
hr 
8  
hr 
12  
hr 
24 
hr 
Predose 
0
1 hr 
4 hr 
6 hr 
Acceptable Range 
for Blood Sampling
-2 hr 
to  
-2 
min 
- 
± 0.5 
min
± 0.5 
min
± 1 
min
± 1 
min
± 1 
min
± 3 
min
± 5 
min
± 10 
min
± 15 
min
± 20 
min
± 20 
min
± 1 
hr 
-2 hr to 
-2 min
NA
±3 
min
±10 
min
±15 
min
DSP-0509 Infusion  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Plasma for Cytokines  
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Xc 
Plasma for PK 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Cardiodynamic 
Assessment, Holter 
Monitora
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Collectionb
X 
<--------------------- 0 to 4 hr -------------------------
> 
4 to 8hr 
8–12 
hr 
12–24 
hr
a Cardiodynamic assessments: On Day 1, a Holter monitor will be placed on the patient 1 hour prior to start of DSP-0509 infusion and will remain in place until 
24 hours (Day 2) after the end of infusion. On Day 1, patients should be supine and at rest from at least 10 minutes before to 5 minutes after (a) the interval from 
start of infusion (SOI) to 30 minutes post-SOI; and (b) for similar periods around each subsequent timepoint shown in Table 9. Concurrent PK samples should be 
obtained on time, and the exact times for the SOI and the start and end of the rest periods recorded to permit ECG extraction by the Holter vendor. 
b Urine collections for PK: Predose urine samples may be collected any time on Day 1 prior to DSP-0509 dosing (ie, they are not limited to be within 2 hours 
before treatment). After start of infusion of DSP-0509, urine should be collected during the following intervals: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 12 to 
24 hours (ie, into Day 2).  
c Optional blood collection for cytokine and PK is at 6 hours


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 57 of 122 
Table 9: 
Schedule of Events – Day 43 to End of Study – Monotherapy Arm A 
Tests and Procedures
Ongoing Treatment 
End of 
Study
Day 
43
57
71
85
99
113
127
Subse-
quenta
30 days 
after last 
dose of 
DSP-0509
Window ± 3 d ± 3 d ± 3 d ± 3 d ± 7 d ± 7 d 
± 7 d 
± 7 d 
+ 7 d 
Hospitalization 
X  
 
 
 
 
 
 
DSP-0509 Infusion 
X 
X 
X 
X 
X 
X 
X 
q2w
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
q2w
X 
Pregnancy Testb 
 
 
 
 
 
 
 
 
X
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
q2w
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
q2w
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
q2w
X 
Hematology Tests
X 
X 
X 
X 
X 
X 
X 
q2w
X 
Clinical Chemistry Tests 
X 
X 
X 
X 
X 
X 
X 
q2w
X 
Urinalysisc  
X 
X 
X 
X 
X 
X  
X  
q4w
X 
MUGA Scan or ECHO 
 
 
 
 
 
 
 
 
X 
Eye Exam by an Ophthalmologistd 
 
X 
X 
 
 
X 
q6w 
X 
12-Lead Safety ECGe
 
 
 
 
 
 
X 
Pharmacokineticsf  
X 
 
 
 
 
 
 
Plasma for Cytokines f
X 
 
X 
 
 
 
 
 
Blood for PBMC Lymphocyte Markersg
X 
 
  
 
 
X 
 
Blood for Tumor Markersh
X 
 
X 
 
 
X 
Xi
X 
Blood for Future Biomarker Analysisg, j  
X 
 
X 
 
 
X 
X 
Tumor Samples for Immune-Related 
Biomarkersj, k
 
 
 
X 
 
 
 
X  
Tumor Samples for Future Biomarker 
Analysisj, k
 
 
 
X 
 
 
 
X  
Objective Disease Assessmentl
X 
 
X 
 
 
X 
X  
X  
Concomitant Medications 
<------------------ Continuously from Consent to EoS -------------------->
Adverse Events
<------------------ Continuously from Consent to EoS -------------------->


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 58 of 122 
a Entries in the "Subsequent" column indicate the interval at which procedures need to be repeated after Day 127, if 
the patient remains on treatment. For additional details, see the specific footnote for the procedure 
b A pregnancy test (serum) is to be performed on all females of child-bearing potential at Screening and at the End-
of-Study visit as scheduled, and at other times as judged appropriate by the investigator 
c After the Day 127 visit, urinalysis will be performed every 4 weeks (ie, every other visit)
d Eye exam includes slit lamp exam, visual field testing, and fundoscopy 
e Manual 12-lead ECGs are to be performed after 10 minutes rest, in triplicate, at least 5 minutes apart at the 
End-of-Study visit 
f See Table 10 for a detailed schedule of blood sampling for cytokines on Days 43, 44, and 85, and of blood and 
urine sampling for PK on Days 43 and 44 
g Blood sampling for PBMC lymphocyte markers and future biomarkers will be performed as shown. (Note: the 
schedule for each item is different.). Samples to be collected will include whole blood (for PBMCs), whole blood 
and plasma (see Laboratory Manual for details) 
h Tumor markers in blood will be assessed as appropriate for those cancers for which markers are known to exist, 
eg, CA-125, PSA, AFP, CA19-9, CEA 
i Subsequent samples are to be collected on Day 169 and then every 12 weeks to coincide with objective evaluation 
(radiologic imaging; see footnote “l”) 
j An additional separate informed consent is needed at the pre-study evaluation to collect and store blood and 
archival and/or fresh biopsy tumor tissues for future exploratory biomarker analyses 
k Optional tumor sample collections if medically feasible. See Section 8.2.15.2 for further details 
l Objective disease assessments by tumor imaging are used to assess the patient's response to treatment according to 
RECIST and iRECIST. The same modality for tumor imaging must be used throughout the study for an individual 
patient. Post-treatment imaging will be performed every 6 weeks through Day 127 (18 weeks), as shown, also on 
Day 169, and subsequently, every 12 weeks until PD is observed. Imaging should be performed at the end of study 
unless it has been done in the previous 8 weeks 
 
   


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
 
 
Confidential and Proprietary
Page 59 of 122
Table 10: 
Schedule for Sampling for PK, Cytokines– Monotherapy Arm A 
Day
Day 43
Day 
44
Day 85
Time After Start of 
Infusion 
Predos
e
0 
8 
min
11 
min
15 
min
20 
min
30 
min
1  
hr
2  
hr
4  
hr
6  
hr
8  
hr
12  
hr
24 
hr
Predo
se
0 
1 hr 
2 hr 
4 hr 
6 hr 
Acceptable Range 
for Blood Sampling
-2 hr
to  
-2 min  
-
± 0.5 
min 
± 0.5 
1min 
± 1 
min 
± 1 
min 
± 1 
min 
± 3 
min 
± 5 
min 
± 10 
min 
± 15 
min 
± 20 
min 
± 20 
min 
± 1 
hr 
-2 hr 
to -2 
min 
NA
±3 
min 
±5 
min 
±10 
min 
±15 
min 
DSP-0509 Infusion  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Plasma for Cytokines  
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for PK  
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Collectiona
X 
<------------------ 0 to 4 hr ----------------------> 
4 to 8 hr 
8–12 
hr
12– 24 
hr
CR = complete response; d = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; ELISA = enzyme-linked 
immunosorbent assay; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA = 
-1RA = interleukin 1 receptor antagonist; IL-6 = interleukin 6; 
IP-10 = inducible protein 10; iRECIST = Immune Response Evaluation Criteria in Solid Tumors; min = minutes; MUGA = multigated acquisition; PBMC = 
peripheral blood mononuclear cell; PD = progressive disease; PK = pharmacokinetics; PR = partial response; PT = Prothrombin time; PTT = Partial 
thromboplastin time; SD = stable disease; TIL = tumor infiltrating lymphocyte; TMB = 
 tumor necrosis factor alpha 
a Urine collections for PK: Predose urine samples may be collected any time on Day 43 prior to DSP-0509 administration (ie, they are not limited to be within 
2 hours before treatment.) After start of infusion of DSP0509, urine should be collected for the following intervals: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 
12 to 24 hours (ie, into Day 44)


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 60 of 122 
Table 11: 
Schedule of Events – Screening and DLT Period – Combination Arm B 
Tests and Procedures
Screening  
DLT Period 
Day
-28 to -1 
-7 to -1
1
8
15
22
29
36
Window 
–
± 1 d ± 1 d ± 1 d ± 1 d ± 1 d
Informed Consenta 
X
 
 
 
 
Assess Eligibility  
X
 
 
 
 
Demographics
X
 
 
 
 
Medical and Cancer History
X
 
 
 
 
Hospitalization
X
 
 
 
Telephone Safety Callb 
 
X
 
X
X 
DSP-0509 Infusion
X
 
X
 
X
Pembrolizumab Infusionc, d  
Xc,d 
 
 
 
Physical Examination
X
X
 
X
 
X
Pregnancy Teste 
X
 
 
 
 
ECOG Performance Status
X
X
 
X
 
X
Vital Signs 
X
Xd
 
X
 
X
Body Weight
X
X
 
X
 
X
Height 
X
 
 
 
 
Hematology Tests 
X
Xf 
 
X
 
X
Clinical Chemistry Tests
X
Xf 
 
X
 
X
Coagulation Tests (PT & PTT only)
X
 
 
 
 
Urinalysis  
X
Xf 
 
X
 
X
Serum Virology (HBV, HCV, HIV)g 
X
 
 
Chest X-ray 
X
 
 
MRI scan of brainh 
X
 
 
Bone scan (if indicated)i
X
 
 
MUGA Scan or ECHO 
X
 
 
 
 
X
Eye Examination by an Ophthalmologistj
X
X
12-Lead Safety ECGsk 
X
X
 
 
 
X
Pharmacokineticsl
X
 
X 
X
Plasma for Cytokinesl
X
 
X 
X
Blood for PBMC Lymphocyte Biomarkers
X
 
 
Blood for Tumor Markersm
X
 
 
Blood for Future Biomarker Analysisn
X
 
 
Tumor Samples for TMB Analysiso
X
 
 
Tumor Samples for Immune-related Biomarkerso 
X
 
 
Tumor Samples for Future Biomarker Analysisn
X
 
 
Objective Disease Assessmentp
X
 
 
Concomitant Medications 
<------ Continuously from Consent to EoS ------->
Adverse Events
<-------- Continuously from Consent to EoS -------> 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 61 of 122 
CR = complete response; d = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; ELISA = enzyme-linked immunosorbent assay; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunohistochemistry; IL-1RA = interleukin 1 receptor antagonist; IL-6 = interleukin 6; IP-10 = inducible protein 
10; iRECIST = Immune Response Evaluation Criteria in Solid Tumors; IV = intravenous; min = minutes; MUGA 
= multigated acquisition; PBMC = peripheral blood mononuclear cell; PD = progressive disease; PK = 
pharmacokinetics; PR = partial response; PT = prothrombin time; PTT = partial thromboplastin time; SD = stable 
disease; TIL = tumor infiltrating lymphocyte; TMB = 
 tumor necrosis factor alpha 
 
a Informed consent is to be obtained before performing any study-specific procedures; begin collection of AEs after 
consent is obtained 
b On Days 8, 22, and 36 (±1 day) during the DLT period when there are no required visits, sites will make a 
telephone call to the patients to ensure ongoing close safety monitoring of patients 
c Pembrolizumab treatment (400 mg intravenous [IV]) will start on Day 1 and thereafter will be administered every 
6 weeks as detailed in Section 7.3, in accordance with the US Package Insert 
d On days when both DSP-0509 and pembrolizumab are administered, vital signs will be taken (a) prior to 
DSP-0509 infusion; (b) 4 hours after DSP-0509 infusion and, if assessed as stable by the investigator, then 
pembrolizumab will be infused; and (c) 30 to 60 minutes after the end of the pembrolizumab infusion, prior to 
discharge from the site 
e A pregnancy test (serum) is to be performed on all females of child-bearing potential at Screening and at the End-
of-Study visit as scheduled, and at other times as judged appropriate by the investigator 
f Day 1 laboratory assessments do not need to be repeated if done within the previous 3 days 
g Viral serology tests include HBsAg, anti-HCV, and HIV Ag & Ab screening test 
h A brain MRI will be performed at baseline to rule out brain metastases, and at subsequent time points if clinically 
indicated 
i A bone scan will be conducted when clinically indicated 
j Eye exam includes slit lamp exam, visual field testing, and fundoscopy    
k Manual 12-lead ECGs are to be performed after 10 minutes rest, in triplicate, at least 5 minutes apart, at Screening, 
predose on Day 1, at 24 hours postdose on Day 2, and predose on Day 29  
l See Table 12 for a detailed schedule of blood sampling for PK and for cytokines 
m Tumor markers in blood will be assessed as appropriate for those cancers for which markers are known to exist, 
eg, CA-125, PSA, AFP, CA19-9, CEA 
n An additional separate informed consent is needed at the prestudy evaluation to permit collection and storage of 
blood and tumor tissues (archival and/or fresh biopsy) for future exploratory biomarker analyses 
o Tumor samples are required at the Screening evaluation; either archival tissue samples or fresh biopsy samples are 
acceptable 
p Objective disease assessment (tumor imaging) pretreatment represents the baseline study for the patient's response 
to treatment evaluated using RECIST and iRECIST. The same imaging modality must be used throughout the study 
for an individual patient. See Table 13 for timepoints of subsequent evaluations 
 


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
 
 
Confidential and Proprietary
Page 62 of 122
Table 12: 
Schedule for Sampling for PK and Cytokines – Combination Arm B 
Day
Day 1
Da
y 2
Day 15
Day 29
Time 
After 
Start of 
Infu-
sion 
Predos
e
0 
8 
mi
n 
11 
mi
n 
15 
mi
n 
20 
mi
n 
30 
mi
n 
1  
hr
2  
hr
4  
hr
6  
hr
 
24  
hr
Predos
e
0 
1 
hr
4 
hr
6 
hr
Predos
e
0 
8 
min
11 
min
15 
mi
n
20 
mi
n
30 
mi
n 
1 
hr
2 
hr
4 
hr
6 
hr
Accept-
able 
Range 
for 
Blood 
Samp-
ling
-2 hr to 
-2 min  
± 
0.5 
mi
n
± 
0.5 
mi
n
± 1 
mi
n
± 1 
mi
n
± 1 
mi
n
± 3 
mi
n
± 5 
mi
n
± 
10 
mi
n
± 
15 
mi
n
± 1 
hr 
-2 hr to 
-2 min 
±3 
mi
n
±1
0 
mi
n
±1
5 
mi
n
-2 hr to 
-2 min 
±0.
5 
min
±0.
5 
min
±1 
mi
n
±1 
mi
n
±1 
mi
n
±3 
mi
n
±5 
mi
n
±1
0 
mi
n
±1
5 
mi
n
DSP-0509 
Infusion  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Plasma for 
PK  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for 
Cytokine
s  
X
X
X
X
X
X
X
X
X
Xa
X
X
X
X
X
a Optional blood collection for cytokine and PK is at 6 hours


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
Page 63 of 122 
Table 13: 
Schedule of Events – Day 43 to End of Study – Combination Arm B 
Tests and Procedures 
Day 43 and Ongoing 
End of 
Study
Day
43 
57 
71 
85 
99 
113 
127 
Subseq
uenta 
30 Days 
After Last 
Dose of 
DSP-0509
Window  
± 3 d 
± 3 d 
± 3 d ± 3 d 
± 7 d ± 7 d ± 7 d 
± 7 d 
+ 7 d 
DSP-0509 Infusion
X
X
X 
X
X 
X 
X 
q2w
 
Pembrolizumab Infusionb, c
X
X
X
q6wc
Physical Examination
X
X
X
X
X
X
X
q2w
X
Pregnancy Testd
X
ECOG Performance Status
X
X
X 
X
X 
X 
X 
q2w
X
Vital Signs 
Xc 
X
X 
Xc
X 
X 
Xc 
q2w
X
Body Weight
X
X
X 
X
X 
X 
X 
q2w
X
Hematology Tests 
X
X
X 
X
X 
X 
X 
q2w
X
Clinical Chemistry Tests
X
X
X 
X
X 
X 
X 
q2w
X
Urinalysis  
X
X
X 
X
X 
X 
X 
q4w
X
MUGA Scan or ECHO 
 
 
 
 
 
X
Eye Exam by 
Ophthalmologiste
 
X 
X 
 
X 
q6w 
X 
12-Lead Safety ECGf 
 
 
 
 
 
X
Pharmacokineticsg 
X
 
 
Plasma for Cytokinesg
X
X
 
Blood for PBMC 
Lymphocyte Markersh
X 
 
  
 
 
X 
 
Blood for Tumor Markersi
X
X
X 
Xj
X
Blood for Future Biomarker 
Analysish, k 
X 
X 
X 
X 
Tumor Samples for Immune-
related Biomarkersl
 
X 
 
 
X 
Tumor Samples for Future 
Biomarker Analysisl, k
 
X 
 
 
X 
Objective disease 
Assessmentm
X 
X 
 
X 
X 
X 
Concomitant Medications 
<------ Continuously from Consent to EoS -------> 
Adverse Events
<------ Continuously from Consent to EoS -------> 
ECG = electrocardiogram; ECHO = echocardiogram; HLA = human leukocyte antigen; IHC = 
immunohistochemistry; iRECIST = Immune Response Evaluation Criteria in Solid Tumors; MUGA = multigated 
acquisition; PBMC = peripheral blood mononuclear cell; TIL = tumor infiltrating lymphocyte 
a Entries in the "Subsequent" column indicate the interval at which procedures need to be repeated after Day 127, if 
the patient remains on treatment. For additional details, see the specific footnote for the procedure 
b Pembrolizumab treatment (400 mg IV) will start on Day 1 and thereafter will be administered every 6 weeks as 
detailed in Section 7.3 in accordance with the US Package Insert


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
Page 64 of 122 
c On days when both DSP-0509 and pembrolizumab are administered, vital signs will be taken (a) prior o DSP-0509 
infusion, (b) 4 hours after DSP-0509 infusion and, if assessed as stable by the investigator, pembrolizumab will be 
infused, and (c) 30 to 60 minutes after the end of the pembrolizumab infusion, prior to discharge from the site 
d A pregnancy test (serum) is to be performed on all females of child-bearing potential at Screening and at the End-
of-Study visit as scheduled, and at other times as judged appropriate by the investigator 
e Eye exam includes slit lamp exam, visual field testing, and fundoscopy 
f Manual 12-lead ECGs are to be performed after 10 minutes rest, in triplicate, at least 5 minutes apart at the 
End-of-Study visit 
g See Table 14 for detailed schedule of blood sampling for cytokines on Days 43 and 85, and of blood sampling for 
PK on Day 43 
h Blood sampling for PBMC lymphocyte markers and future biomarkers will be performed as shown. (Note: the 
schedule for each item is different.). Samples to be collected will include whole blood (for PBMCs), whole blood 
and plasma (see Laboratory Manual for details) 
i Tumor markers in blood will be assessed as appropriate for those cancers for which markers are known to exist, 
eg, CA-125, PSA, AFP, CA19-9, CEA 
j Subsequent samples are to be collected on Day 169 and then every 12 weeks to coincide with objective evaluation 
(radiologic imaging; see footnote “l”) 
k An additional separate informed consent is needed at the prestudy evaluation to collect and store blood and 
archival and/or fresh biopsy tumor tissues for future exploratory biomarker analyses 
l Optional tumor sample collections if medically feasible. See Section 8.2.15.2 for further details 
m Objective disease assessments by tumor imaging are used to assess the patient's response to treatment according to 
RECIST and iRECIST. The same modality for tumor imaging must be used throughout the study for an individual 
patient. Post-treatment imaging will be performed every 6 weeks through Day 127 (18 weeks), as shown, also on 
Day 169, and subsequently, every 12 weeks until PD is observed. Imaging should be performed at the end of study 
unless it has been done in the previous 8 weeks 
 
Table 14: 
Schedule for Sampling for PK and Cytokines – Combination Arm B 
Day 
Day 43
Day 85
Time After End of Infusion 
Predose
0 
1 hr
4 hr
6 hr
Predose
0
1 hr
2 hr
4 hr 
6 hr
Acceptable Range for 
Blood Sampling
-2 hr to 
-2 min  
± 3 
min 
± 10 
min 
± 15 
min 
-2 hr to 
-2 min  
 
± 3 
min 
± 5 
min 
± 10 
min 
± 15 
min 
DSP-0509 Infusion  
X
 
 
 
X 
 
Plasma for Cytokines  
X 
X 
X 
Xa
X 
 
X
X 
X 
X
Plasma for PK 
X 
 
X 
 
 
 
a Optional blood collection for cytokine at 6 hours 
 


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
Amendment 7 
 
Confidential and Proprietary
Page 65 of 122
Table 15:
Schedule of Events – Screening and Treatment Periods - Combination Arm C
Tests and Procedures
Screening 
Dose-expansion Treatment Period
End of 
Study
Day 
-28 to 
-1 
-7 to 
-1 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Subsequent 
EoS 30 days 
after last 
DSP-0509 
infusion
Survival 
Follow-up 
every 6 
months
Window 
–
±1 d
±1 d
±3 d
±3 d
±3 d
±3 d
±7 d
±7 d
±7 d
±7 d
+7 d
±7 d
 
 
 
 
 
 
 
 
 
 
 
(DSP-0509 
q2w) 
(Pembro 
q6w) 
 
 
Informed Consenta 
X 
 
 
 
 
Assess Eligibility  
X 
 
 
 
 
Demographics 
X
Medical and Cancer History 
X
Hospitalization 
 
X
DSP-0509 Infusion
 
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Infusionb, c
 
X c
X c
X c
X c
X c
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
q2w
X
Pregnancy Testd
X
X
ECOG Performance Status
 
X
X
X
X
X
X
X
X
X
X
X
q2w
X
Vital Signsc 
 
X
Xc
X
X
Xc
X
X
Xc
X
X
Xc
q2wc
X
Body Weight
 
X
X
X
X
X
X
X
X
X
X
X
q2w
Height
 
X
Hematology
X
Xe
X
X
X
X
X
X
X
X
X
q2w
X


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
Amendment 7 
 
Confidential and Proprietary
Page 66 of 122
Tests and Procedures 
Screening  
Dose-expansion Treatment Period 
End of 
Study
Day
-28 to 
-1
-7 to 
-1
1
15
29
43
57
71
85
99
113
127
Subsequent
EoS 30 days 
after last 
DSP-0509 
infusion 
Survival 
Follow-up 
every 6 
months
Window 
–
±1 d
±1 d
±3 d
±3 d
±3 d
±3 d
±7 d
±7 d
±7 d
±7 d
+7 d
±7 d
Clinical Chemistry 
X
Xe
X
X
X
X
X
X
X
X
X
q2w
X
Coagulation (PT and PTT only)
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q4w 
X 
 
Serum Virology (HBV, HCV, 
HIV)f
X
 
Chest X-ray
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI of braing
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan (if indicated)h
X
 
MUGA or ECHO 
X
X
X
Eye Exam by Ophthalmologisti
X
X
X
X
X
q6w
X
 
12-Lead Safety ECGj
X
X
X
X
PKk
 
 
X
X
X
Plasma for Cytokinesk
 
 
X
X
X
X
Blood for PBMC Lymphocyte 
Biomarkers 
X
X
X
X
X
Blood for Tumor Markersl
X
X
X
X
X
X
Blood for Future Biomarker 
Analysism
X
X
X
X
X


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
Amendment 7 
 
Confidential and Proprietary
Page 67 of 122
Tests and Procedures 
Screening  
Dose-expansion Treatment Period 
End of 
Study
Day
-28 to 
-1 
-7 to 
-1 
1
15
29
43
57
71
85
99
113
127
Subsequent
EoS 30 days 
after last 
DSP-0509 
infusion 
Survival 
Follow-up 
every 6 
months
Window 
– 
±1 d
±1 d
±3 d
±3 d
±3 d
±3 d
±7 d
±7 d
±7 d
±7 d
+7 d 
±7 d
Blood for ctDNA Analysis 
X 
Tumor Samples for TMB 
Analysisn
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Samples for Immune-
related Biomarkersn
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Tumor Samples for Future 
Biomarker Analysism,n 
X 
X 
X 
Objective Disease Assessmento
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Survival Follow-up 
Xp
Concomitant Medications 
-------------- Continuously from Consent to EoS ------------
Adverse Events 
-------------- Continuously from Consent to EoS ------------
CR = complete response; d = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; ELISA = enzyme-linked 
immunosorbent assay; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA = 
-1RA = interleukin 1 receptor antagonist; IL-6 = interleukin 6; 
IP-10 = inducible protein 10; iRECIST = Immune Response Evaluation Criteria in Solid Tumors; min = minutes; MUGA = multigated acquisition; PBMC = 
peripheral blood mononuclear cell; PD = progressive disease; PK = pharmacokinetics; PR = partial response; PT = prothrombin time; PTT = partial 
thromboplastin time; q2wk = every 2 weeks; q3wk = every 3 weeks; q4wk = every 4 weeks; q6wk = every 6 weeks; SD = stable disease; TIL = tumor infiltrating 
lymphocyte; TMB = 
 tumor necrosis factor alpha.  
a Informed consent is to be obtained before performing any study-specific procedures; begin collection of AEs after consent is obtained
b Pembrolizumab treatment (400 mg IV) will start on Day 1 and thereafter will be administered every 6 weeks as detailed in Section 7.3, in accordance with the 
US Package Insert 
c On days when both DSP-0509 and pembrolizumab are administered, vital signs will be taken (a) prior to DSP-0509 infusion, (b) 4 hours after DSP-0509 
infusion and, if assessed as stable by the investigator, pembrolizumab will be infused, and (c) 30 to 60 minutes after the end of the pembrolizumab infusion, prior 
to discharge from the site 


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
Amendment 7 
 
Confidential and Proprietary
Page 68 of 122
d A pregnancy test (serum) is to be performed on all females of child-bearing potential at Screening and at EoS visit as scheduled, and at other times as judged 
appropriate by the Investigator 
e Day 1 laboratory assessments do not need to be repeated if done within the previous 3 days 
f Viral serology tests include HBsAg, anti-HCV, and HIV Ag & Ab screening test 
g A brain MRI will be performed at baseline to rule out brain metastases, and at subsequent time points if clinically indicated
h A bone scan will be conducted when clinically indicated.   
i Eye exam includes slit lamp exam, visual field testing, and fundoscopy.    
j Manual 12-lead ECGs are to be performed after 10 min rest, in triplicate, at least 5 min apart, at Screening, predose on Day 1, at 24 hours postdose on Day 2, 
and predose on Day 29.    
k See Table 16 for detailed schedule of blood sampling for pharmacokinetics and for cytokines 
l Tumor markers in blood will be assessed as appropriate for those cancers for which markers are known to exist, eg, CA-125, PSA, AFP, CA19-9, CEA
m An additional, separate informed consent is needed at the prestudy evaluation to permit collection and storage of blood and tumor tissues (archival and/or fresh 
biopsy) for future exploratory biomarker analyses 
n Tumor samples are required at the Screening evaluation; either archival tissue samples or fresh biopsy samples are acceptable. See Section 8.2.15 for further 
details. 
o Objective disease assessment by tumor imaging are used to assess the patient's response to treatment evaluated using RECIST and iRECIST. The same 
modality for tumor imaging must be used throughout the study for an individual patient. Post-treatment imaging will be performed every 6 weeks up to the 
Day 547 visit (18 months), and subsequently every 12 weeks until PD is observed. Imaging should be performed at the End-of-Study visit unless it has been done 
in the previous 6 weeks for patients coming off study prior to or on Day 547, or in the previous 12 weeks for patients who come off study after the Day 547 visit. 
p A phone call to the last phone numbers provided by the patient will be made every 6 months (±7 days) starting from the date of the final dose of DSP-0509, to 
determine overall survival (OS) until the patient is known to be no longer alive or withdraws consent. A date of death should be obtained, and any anticancer 
treatments, whether systemic, surgical, or radiation, also should be collected and reported on the Survival Follow-up eCRF. 


Sumitomo Dainippon Pharma Oncology, Inc 
BBI-DSP-0509-101 Protocol 
Amendment 7 
 
Confidential and Proprietary
Page 69 of 122
Table 16: 
Schedule for Sampling for PK and Cytokines – Combination Arm C 
Day 
Day 1
Day 29
Day 43
Day 85
Time 
After 
Start of 
Infusion
Predos
e 
0
8 
min 
11 
min 
30 
mi
n 
2 
hr 
4 
hr 
Predos
e 
0
8 
min 
11 
min 
30 
mi
n 
2 
hr 
4 
hr 
Predos
e 
0
8 
min 
11 
min 
30 
mi
n
2 
hr 
4 
hr 
Predos
e 
0
8 
min 
11 
min 
30 
mi
n
2 
hr 
4 
hr 
Accept-
able 
Range 
for 
Blood 
Samplin
g 
-2 hr 
to -2 
min
 ±0.
5 
min
±0.
5 
min
±1 
mi
n
±5 
mi
n
±1
0 
mi
n 
-2 hr 
to -2 
min
 
±0.
5 
min
±0.
5 
min
±1 
mi
n
±5 
mi
n
±1
0 
mi
n 
-2 hr 
to -2 
min
 ±0.
5 
min
±0.
5 
min
±1 
mi
n
±5 
mi
n
±1
0 
mi
n 
-2 hr 
to -2 
min
 ±0.
5 
min
±0.
5 
min
±1 
mi
n
±5 
mi
n
±1
0 
mi
n
DSP-0509 
Infusion  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X
 
 
 
 
 
Plasma 
for PK  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma 
for 
Cytokin
es  
X 
 
 
 
 
X 
X
X
 
 
 
 
X 
X 
X 
 
 
 
 
X
X 
X 
 
 
 
 
X
X


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 70 of 122 
8.2. 
Description of Study Procedures 
Please see the SoEs for study visits when the procedures are to be performed in the individual 
study Arms and Phases.  
8.2.1. 
Telephone Contacts 
Patients will be asked to provide telephone numbers for both themselves and a close family 
member or caregiver. This primary purpose for this information is for use in the following 
contexts: 
 Follow-up of an AE reported by the patient at a visit  
 A clinically significant abnormal test result or finding is returned after a visit 
 The patient misses a scheduled visit without informing the site 
 During the DLT period (Days 1 through 42), a telephone safety check will be done on the 
following days (±1) when there is no clinic visit scheduled for infusion:  
– Monotherapy Arm A: Days 8, 22, and 36 
– Combination Therapy Arm B: Days 8, 22, and 36 
 To determine OS via phone call every 6 months, starting from the date of the final dose 
of DSP-0509, until the patient is known to no longer be alive or withdraws consent. A 
date of death should be obtained, and any anticancer treatments, whether systemic, 
surgical, or radiation, also should be collected and reported on the Survival Follow-up 
electronic Case Report Form (eCRF).  
8.2.2. 
Medical and Cancer History 
The medical history will include all pertinent aspects of the patient’s past health, as well as 
aspects of the underlying tumor, including date of diagnosis, extent of surgery, dose of 
radiotherapy administered, duration of chemotherapy, and date of recurrence or progression.  
8.2.3. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status (Table 17) is a scale used to assess the progress of a patient’s 
disease, evaluate how the disease affects the patient’s daily living abilities, and determine 
appropriate treatment and prognosis.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 71 of 122 
Table 17: 
ECOG Performance Status Scale  
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity; fully active; able to carry on all predisease 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 (eg, 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 out any self-care; totally confined to bed or chair
5
Dead
ECOG = Eastern Cooperative Oncology Group.
8.2.4. 
Clinical Laboratory Evaluation 
The hematology, coagulation parameters (only required at Screening visit; prothrombin time 
(PT) and partial PTT needed for inclusion criteria), and clinical chemistry laboratory analyses 
will be performed at a local laboratory. Reference ranges will be supplied and used by the 
investigator to assess the laboratory data for clinical significance and pathological changes. 
Day 1 laboratory assessments do not need to be repeated if done within the previous 3 days. 
8.2.4.1. 
Hematology 
A complete blood count will include red blood cell (RBC) count, Hgb, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, WBC count with differential, absolute and percent neutrophils, absolute and 
percent lymphocytes, absolute and percent monocytes, absolute and percent eosinophils, and 
absolute and percent basophils; and platelet count.  
8.2.4.2. 
Coagulation 
Coagulation parameters (PT and PTT) will be collected at Screening for eligibility purposes. 
8.2.4.3. 
Clinical Chemistry 
Serum chemistry tests will include measurements of sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen, creatinine, glucose, AST, ALT, alkaline phosphatase, lactate 
dehydrogenase, amylase, gamma glutamyl transpeptidase, total bilirubin, conjugated bilirubin, 
unconjugated bilirubin, uric acid, total protein, albumin, globulin, creatinine kinase, cholesterol, 
triglycerides, calcium, magnesium, and phosphate; also C-reactive protein (CRP), thyroid 
stimulating hormone (TSH), and free thyroxine (free T4). 
8.2.4.4. 
Urinalysis 
A urinalysis will include measurements of pH, specific gravity, and dipstick determinations of 
protein, nitrite, glucose, ketones, RBCs, WBCs, and urobilinogen. If any dipstick determinations 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 72 of 122 
are 2+ or greater, a microscopic examination of urine will be performed. If a dipstick 
determination of protein is 2+ or higher, a 24-hour urine collection must be done. 
8.2.4.5. 
Pregnancy Testing 
Pregnancy testing in women of childbearing potential may be obtained with a serum beta human 
chorionic gonadotropin test at Screening. A pregnancy test also will be performed by serum at 
the EoS visit, and if clinically indicated per the investigator’s judgment. 
8.2.4.6. 
Serology Testing 
Testing for HBsAg, HCV antibody, and HIV.  
8.2.5. 
Vital Signs 
Vital signs will include systolic and diastolic blood pressures, pulse, respiratory rate, 
temperature, and weight. Height is assessed at Screening only. Blood pressure and heart rate will 
be recorded after the patient has rested in the sitting position for at least 5 minutes. 
8.2.6. 
Physical Examination 
A physical examination will include examination of the skin; head, eyes, ears, nose, and throat; 
and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic 
systems.  
8.2.7. 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded from Screening through the EoS visit. See Section 7.13.2 for a list of medications and 
therapies that are prohibited during the study. 
8.2.8. 
Adverse Events 
Monitoring of AEs, serious and nonserious, will be conducted from signing of the informed 
consent form through 30 days after last dose of investigational therapy. Refer to Section 11 for 
details regarding definitions, documentation, reporting, and follow-up of AEs and SAEs, 
including information on Adverse Events of Special Interest (AESIs), such as COVID-19. 
8.2.9. 
Objective Disease Assessments  
Tumor lesions will be evaluated radiologically by CT or MRI scans while on study so that 
response to treatment can be assessed according to RECIST and iRECIST. At the EoS visit, 
CT/MRI scans will be performed according to the SoE. The same modality must be used 
throughout the study for an individual patient. PET-CT scans may be used for patients with 
non-small-cell lung cancer (NSCLC), breast cancer, HNSCC, renal cancer, and melanoma, but 
only if this imaging procedure is approved by the health insurance company of the patient.  
An MRI scan of the brain will be done primarily to rule out brain metastases. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 73 of 122 
8.2.10. 
Cardiac Assessments 
8.2.10.1. 12-lead Safety ECGs 
A 12-lead ECG will be obtained in triplicate with the patient having rested in a supine position 
for at least 10 minutes before the first recording, and with at least 5-minute intervals between 
recordings. The following intervals should be determined for each recording either by the 
machine used or manually: PR interval, QRS complex duration, QT interval, and QTcF. If any 
results outside normal ranges are deemed clinically significant by the investigator or 
appropriately qualified designee, these should be recorded as AEs. 
8.2.10.2. Cardiodynamic Assessment 
The 12-lead Holter and associated laptop computer equipment will be supplied to the study sites. 
Holter devices will be required only for Day 1 of the Monotherapy Arm A. 
On Day 1, a Holter monitor will be placed on the patient 1 hour prior to start of DSP-0509 
infusion and remain in place until 24 hours (Day 2) after the end of infusion. On Day 1, patients 
should be supine and at rest from at least 10 minutes before to 5 minutes after (a) the interval 
from start of infusion to 30 minutes post-start of infusion; and (b) for similar periods around each 
subsequent timepoint shown in Table 8. Concurrent PK samples should be obtained on time, and 
the exact times for the start of infusion and the start and end of the rest periods recorded to 
permit ECG extraction by the Holter vendor. 
The continuous 12-lead digital ECG data are stored on memory cards in the device. After the 
Holter is removed, the memory card is collected, placed in the laptop provided, the data is 
transferred via internet to the central vendor and analyzed as follows: up to 13 triplicate 12-lead 
ECGs will be extracted at the nominal time points detailed in Table 7 using the precisely 
recorded times indicating the start of infusion and the start of the rest interval. The procedures 
for ECG extraction, interval measurements, and statistical analysis will be provided separately. 
8.2.10.3. MUGA Scan and ECHO Assessments 
Either MUGA scan or ECHO may be used to perform cardiac assessments, which should include 
left ventricular ejection fraction (%), presence or absence of pericardial effusion and, if done by 
ECHO, interventricular septum thickness. Additionally, any abnormalities will be noted, as well 
as their clinical significance. 
8.2.11. 
Chest X-rays 
Chest x-rays will be performed at Screening to assess for pulmonary disorders and patient 
eligibility. Any clinically significant findings will be noted in history.  
After consent, chest x-rays can be performed at the investigator’s discretion on an as-needed 
basis. Clinically significant changes (new or worsening) will be recorded as AEs.  
8.2.12. 
Ocular Examinations 
Ocular examinations, including Slit Lamp examinations, visual field testing, and fundoscopy, 
will be performed as indicated on the SoE by a qualified ophthalmologist to monitor for potential 
ophthalmologic toxicity.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 74 of 122 
Should any ocular symptoms occur between scheduled exams, the patient should be referred 
immediately to an ophthalmologist for diagnostic work-up, and the Medical Monitor is to be 
notified. Symptoms may include, but are not limited to, sudden appearance of floaters, flashes of 
light in one or both eyes (photopsia), blurred or distorted vision, gradually reduced peripheral 
vision, a curtain-like shadow over visual field, and/or lost vision. 
Ocular examinations will note any abnormalities and, if present, whether the abnormalities are 
new, the same as noted at baseline, or worsening.  
8.2.13. 
Pharmacokinetic Testing 
Blood and urine samples will be collected for the determination of plasma concentration of 
DSP-0509. On the days when blood samples are taken, the morning dose of DSP-0509 must be 
administered at the site, and the precise infusion start and stop times (hours:minutes:seconds) 
must be documented. Infusion start and stop times and PK sample times are to be based on the 
same clock.  
Blood samples for PK assessments are to be drawn from the arm contralateral to the site of drug 
administration.  
Note that urine samples to assess PK will be collected, but only in Monotherapy Arm A.  
8.2.13.1. Infusion Procedure on PK Sampling Days 
The procedure for administering DSP-0509 as a 10-minute infusion by syringe infusion pump is 
detailed in Appendix 18.1. On days when PK samples are to be collected, it is essential that the 
procedure be followed exactly as described to avoid artifactual levels.  
 Of critical importance: At the end of infusion, solution remaining in the catheter 
connecting the syringe in the pump to the patient must not be manually flushed into the 
patient.  
8.2.13.2. Collection of PK Blood Samples  
Please note the following items regarding timing of collection of all PK samples. DSP-0509 is to 
be administered as a 10-minute infusion using a syringe infusion pump (see Appendix 18.1 for 
full details)  
 Time zero (t=0) is defined as the infusion start time.  
 PK collection times are specified as time relative to the start of infusion, eg,: 
– 8-minute sample occurs 8 minutes after start of infusion, ie, 2 ± 0.5 minutes 
before end of infusion  
– 11-minute sample occurs 11 minutes after start of infusion, ie, 1 ± 0.5 minutes 
after end of infusion 
 Collection times (and windows) for all PK blood samples are detailed in the SoE 
Critical elements of the procedure for collecting valid PK samples are the following:  
 PK blood samples must be collected from the arm contralateral to DSP-0509 infusion 
 Immediately prior to collecting each PK sample, a volume of blood equal to or slightly 
greater than the void volume of the sampling catheter must be drawn and discarded to 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 75 of 122 
assure no dilution of the sample by fluid in the sampling catheter. (The latter assumes the 
PK sampling catheter remains in the patient’s vein between PK samples.)   
 Please refer to the Study Laboratory manual for required sample blood volumes, 
collection tube specifications, sample processing, specimen storage, and other details of 
the procedures for collecting PK blood samples. 
Please refer to the Study Laboratory manual for further details and guidance on obtaining PK 
samples in an indwelling line.  
8.2.13.3. Collection of PK Urine Sample  
The times for collection of a urine sample for PK analysis on Day 1 and Day 43 of Monotherapy 
Arm A are detailed on the SoE for those days. On the day of dosing, the predose urine sample is 
collected as convenient before the start of infusion of DSP-0509 and the time recorded. The time 
of the last void before the start of infusion also should be recorded. For each of the collection 
intervals, the volume of urine collected and the times of the first and last voids within each 
collection interval will be recorded.  
8.2.14. 
Blood Samples for Tumor Markers, Lymphocyte Phenotype, and Cytokines  
Blood samples for serum, plasma, and peripheral blood mononuclear cells (PBMCs) will be 
collected to assess the following: 
 Tumor markers for those cancers for which markers have been established, eg, CA-125, 
PSA, AFP, CA19-9, CEA  
 Lymphocyte immunophenotype, eg, activated lymphocytes, effector memory cells, 
myeloid cells, T cell proliferation  
 
-10, IL-
-6 
 ctDNA (in Combination Arm C, dose-expansion patients only) 
8.2.15. 
Tumor Tissue Samples 
8.2.15.1. Tumor Tissue Samples to be Provided at Screening 
Prior to initiation of study treatment, tumor tissue samples are required of all patients and may be 
obtained in one of the 3 forms described below. Please refer to the NeoGenomics 
"BBI-DSP-0509-101 Tissue Sample Collection and Shipping Instructions" manual for 
requirements relating to each form (eg, size of the tissue block; number of fixed, unstained 
slides; handling of fresh biopsy tissue) as well as details regarding handling and shipping.   
 Preferred archival material is a block of formalin-fixed tumor tissue embedded in 
paraffin. The block of tissue must be of sufficient size to provide the required number of 
slides needed for baseline assessments. The remaining part of the tumor block will be 
returned to the site upon request.  
 As an alternative to a block of tumor tissue, required number of slides may be provided 
as fixed, unstained archival tumor tissue mounted on positively charged glass slides.  
 If archival tumor tissue is unavailable, an attempt should be made to obtain a fresh biopsy 
of tumor tissue.   


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 76 of 122 
8.2.15.2. Tumor Tissue Obtained On- or Post-Treatment 
After start of treatment, obtaining fresh tumor tissue requires a biopsy procedure, which is 
optional, and should be performed only if medically feasible. The timepoints and conditions at 
which tumor tissue should be obtained are:  
 EoS, if the patient discontinues study treatment before Day 43 (Combination Arm C 
patients) or before Day 85 (Monotherapy Arm A or Combination Arm B patients) 
– Should be obtained as soon as feasible after study treatment is discontinued  
 Day 43 (Combination Arm C patients) or Day 85 (Monotherapy Arm A or Combination 
Arm B patients) unless the patient has achieved CR (whichever comes first) 
 After Day 43 or Day 85 under the following conditions: 
o Patients with SD at Day 43 or Day 85 who show PR in subsequent disease 
assessment; biopsy will be performed when PR is confirmed (= iPR according to 
iRECIST) 
o Patients with suspected pseudo-progression at Day 43 or Day 85 who show PR or SD 
in subsequent disease assessment; biopsy will be performed when PR or SD is 
confirmed (= iPR or iSD according to iRECIST) 
Details of sample collection, processing, shipping, and storage are described in the "Sample 
Collection and Shipping Instructions" manual.  
8.2.16. 
Analysis of Tumor Samples 
Tumor tissue samples obtained before study drug treatment (archival or fresh) may be analyzed 
for immune-related gene expression and additional biomarkers, eg, CD8 (by IHC), TMB, TIL, 
and HLA-ABC (by IHC). Biopsies from patients in the Combination Arms B and C also may be 
analyzed for PD-L1.  
8.2.17. 
Specimen Sampling for Future Exploratory Biomarker Analysis 
If consent is given, both blood samples and tumor tissue may be collected and stored long-term 
for future analysis of as-yet unidentified exploratory biomarkers (eg, protein and gene expression 
analysis) that may be important to the understanding of DSP-0509 mechanism of action. 
Providing informed consent for storage of samples for this purpose is optional and is not a 
requirement for participation in the study. 
 
 
 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 77 of 122 
9. 
EFFICACY ASSESSMENTS 
9.1. 
Efficacy Assessment 
The evaluation of efficacy will be based on the patient’s measurable disease, using RECIST and 
iRECIST. If PD is determined by RECIST, an additional scan for confirmation of PD is required 
(per iRECIST) 4 to 8 weeks later.  
Additional efficacy variables include the following:  
 ORR – the proportion of patients who achieve CR/PR per RECIST or iCR/ iPR per 
iRECIST 
 TTP – time from date of enrollment to date of first documented PD per RECIST, or iUPD 
if iCPD is subsequently confirmed per iRECIST  
 DOR – time from first documentation of response until time of first documentation of PD 
per RECIST, or iUPD if iCPD is subsequently confirmed per iRECIST 
 PFS – time from first day of treatment to either (a) date of PD per RECIST, or iUPD if 
iCPD is subsequently confirmed per iRECIST, or (b) in the absence of documented PD, 
the date of death by any cause 
9.2. 
Biomarker Assessments
Plasma cytokines will be correlated with dose level and safety outcomes. 
Blood and tumor exploratory biomarkers will be correlated with efficacy outcomes.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 78 of 122 
10. 
PHARMACOKINETIC ASSESSMENTS 
The pharmacokinetics of DSP-0509 will be evaluated in this study and will include those 
parameters described in Table 18, data permitting. Additional parameters may be added. PK data 
may be analyzed in conjunction with data from other studies (for example, for population PK 
analyses).
Table 18: 
Pharmacokinetic Parameters to be Assessed in DSP-0509 
terminal elimination rate constant
Ae 
cumulative amount of unchanged drug excreted in urine
AUCt 
area under the concentration-time curve from time 0 (dosing) to the time of the last 
measurable concentration 
AUC24 
area under the concentration-time curve from time 0 (dosing) through 24 hours 
post-dosing (ie, daily exposure)
AUCinf
area under the concentration-time curve from time 0 (dosing) extrapolated to infinity
CL
clearance 
CLR
complete renal clearance from plasma 
Cmax 
maximal plasma concentration
C0 
initial concentration of DSP-0509 at time 0 (dosing)
Fe (%)
Percentage of the intravenously administered drug excreted into the urine
t1/2 
terminal elimination half-life 
Vc 
initial volume of distribution (time 0) 
Vz 
volume of distribution at the terminal phase


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 79 of 122 
11. 
SAFETY ASSESSMENTS 
Safety will be evaluated using scheduled assessments, reported AEs, and unscheduled 
assessments performed to evaluate AEs.  
 Scheduled assessments include physical examinations, vital signs, clinical laboratory 
tests, ECGs, imaging studies (MUGA scans, ECHO, chest x-ray, CT/MRI) and ocular 
examinations (slit lamp, fundoscopy, visual field testing)   
 Patients will be asked about AEs at all scheduled and unscheduled contacts. Events will 
be collected from the time the patient signs his or her informed consent through 30 days 
after the last dose of study treatment. As detailed in Section 12.4.2, all events will be 
reported in data listings; treatment-emergent AEs (TEAEs), defined as events with onset 
after start of the first infusion of investigational agent, also will be summarized in tables.  
11.1.
Adverse Events and Serious Adverse Events 
11.1.1. 
Adverse Events: Definition 
An AE is any untoward medical occurrence in a clinical study patient administered an 
investigational agent that does not necessarily have a causal relationship with the treatment 
administered. An AE can be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the investigational 
agent, whether or not considered related to the investigational agent. An AE can arise from any 
use of the investigational agent, and from any route of administration, formulation, or dose, 
including an overdose. 
 AEs may be new events or may be pre-existing conditions that have become aggravated 
or have worsened in severity or frequency.  
 AEs may be clinically significant changes from baseline in physical examination, 
laboratory tests, or other diagnostic investigations (eg, laboratory results, x-ray findings). 
See Section 11.2.4.5 for further guidance on clinically significant laboratory findings. 
Pregnancy is not an AE; however, if a female patient or partner of a male patient becomes 
pregnant during the study, the investigator must notify the Sponsor according to the procedures 
provided in Section 11.2.5.1. 
11.1.2. 
Adverse Reactions and Suspected Adverse Reactions: Definition 
All noxious and unintended responses to an investigational agent related to any dose should be 
considered adverse drug reactions. Suspected adverse reactions are any AEs for which there is a 
reasonable possibility that the investigational agent caused the AE. Adverse reactions also may 
include medication errors and uses outside of what is foreseen in the protocol, including misuse, 
abuse, and overdose (intentional or unintentional) of the investigational agent. 
11.1.3. 
Serious Adverse Events: Definition 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any 
of the following outcomes: 
 Death 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 80 of 122 
 Life-threatening experience 
Note: “Life-threatening” refers to a situation in which the patient was at risk of death at 
the time of the event as it occurred; it does not refer to an event that might have caused 
death if it were more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization, unless the 
hospitalization is for the following: 
o Elective or preplanned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent form (ICF) (as documented as medical history on the eCRF) 
 Results in congenital anomaly or birth defect 
 Results in persistent or significant disability or incapacity 
 Is considered to be an important medical event 
Note: Important medical events are those that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition, above. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
11.2.
Procedures for Eliciting, Recording, and Reporting Adverse Events 
Patients will be instructed to report all AEs and will be asked a general health status question at 
each study visit. 
 All AEs occurring from the signing of informed consent through 30 days after the last 
dose of the investigational agent will be recorded in the eCRF 
An AE will be followed until it is either resolved, has returned to baseline status, or is 
determined to be a stable or chronic condition. 
All SAEs occurring from the signing of informed consent through 30 days after the last 
investigational agent administration will be reported to the Sponsor or designee, as outlined in 
Section 11.2.5.1. 
At each required visit during the study, all AEs that have occurred since the previous visit must 
be reviewed. The investigator or appropriate designee must determine if the AE is serious or 
nonserious. 
11.2.1. 
Relationship to Investigational Agent 
A medically qualified investigator must assess the relationship of any AE to the use of the 
investigational agent as not related, unlikely related, possibly related, probably related, or 
definitely related, based on clinical judgment, and using all available information, and may 
include consideration of the following factors:  
 Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors 
 The temporal association between investigational agent exposure and onset of the AE 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 81 of 122 
 Whether the manifestations of the AE are consistent with known mechanism of action or 
toxicities associated with the investigational product 
 Dechallenge: the AE resolved or improved with decreasing the dose or stopping use of 
the investigational agent. Judgment should be used if multiple products are discontinued 
at the same time. 
Rechallenge: the AE recurred or worsened upon re-exposure to the investigational agent
The causal relationship between the investigational agent and the AE will be assessed using one 
of the following categories: 
Not Related to the Study Drug 
 Not Related/Unrelated: suggests that there is no causal association between the 
investigational agent and the reported event 
 Unlikely Related: suggests that the clinical picture is highly consistent with a cause other 
than the investigational agent, but attribution cannot be made with absolute certainty, and 
a relationship between the investigational agent and the AE cannot be excluded with 
complete confidence 
Related to the Study Drug 
 Possibly Related: suggests that treatment with the investigational agent may have caused 
or contributed to the AE (ie, the event follows a reasonable temporal sequence from the 
time of drug administration and/or follows a known response pattern to the 
investigational agent, but also could have been produced by other factors) 
 Probably Related: suggests that a reasonable temporal sequence of the event with the 
investigational agent administration exists, and that the likely causal association of the 
event with the investigational agent exists as well. This will be based upon the known 
pharmacologic action of the investigational agent, known or previously reported adverse 
reactions to the investigational agent or class of drugs, or judgment based on the 
investigator’s clinical experience. 
 Definitely Related: temporal relationship to the investigational agent. Other conditions 
(concurrent illness, concurrent medication reaction, or progression/expression of disease 
state) do not appear to explain the event, which corresponds with the known 
pharmaceutical profile, improvement on discontinuation, or reappearance upon 
rechallenge. 
11.2.2. 
Adverse Event Severity 
The severity of AEs will be assessed according to NCI CTCAE, version 5.0. For events not 
specifically found in CTCAE, the following definitions will be used to estimate the grade of 
severity:  
 Grade 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 Grade 2: Moderate: minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 82 of 122 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
 Grade 4: life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
The term “severe” is used often to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious” (outlined in 
Section 11.1.3), which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning. 
11.2.3. 
Assessment of Expectedness 
The Reference Safety Information (RSI) for assessing the expectedness of an AE in this study is 
to be the section identified as the RSI in the most recent DSP-0509 Investigator’s Brochure (IB). 
The RSI for assessing the expectedness of an AE for a co-suspect drug in this study is to be the 
US full prescribing information for pembrolizumab. 
11.2.4. 
Specific Instructions for Recording Adverse Events on the eCRF 
11.2.4.1. Diagnosis versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, the diagnosis rather than the individual signs and 
symptoms should be recorded in the eCRF (eg, record only hepatitis rather than the elevated 
transaminases, bilirubin, or jaundice). However, if a constellation of signs and/or symptoms 
cannot be characterized medically as a single diagnosis or syndrome, each individual event 
should be recorded as an AE or SAE on the eCRF. If a diagnosis is established subsequently, it 
should be reported as follow-up and should replace the individual signs and/or symptoms with 
the event term on the eCRF. 
11.2.4.2. Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, clinical sequelae or a cascade of events) 
should be identified by their primary cause. However, medically significant AEs occurring 
secondary to an initiating event that are separated in time should be recorded as independent 
events on the eCRF (eg, dehydration secondary to diarrhea). 
11.2.4.3. Medication Errors, Misuse, and Abuse of Investigational Agent 
Overdose, medication error, misuse, off-label use, abuse, and occupational exposure are defined 
as follows: 
 Overdose: refers to the administration of a quantity of investigational agent given per 
administration or cumulative that is above the maximum dose according to the protocol. 
Clinical judgement always should be applied. 
 Medication error: refers to an unintentional error in dispensing or administration of the 
investigational agent not in accordance with the protocol 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 83 of 122 
 Off-label use: relates to situations where the investigational agent is used intentionally 
for medical purpose not in accordance with the protocol 
 Misuse: refers to situations where the investigational agent is used intentionally and 
inappropriately not in accordance with the protocol 
 Abuse: corresponds to the persistent or sporadic, intentional, excessive use of the 
investigational agent that is accompanied by harmful physical or psychological effects 
 Occupational exposure: refers to exposure to the investigational agent as a result of one’s 
professional or nonprofessional occupation  
Overdoses, medication errors, abuse, or misuse, regardless of whether there was an associated 
AE, will be collected as part of the investigational agent dosing information and/or as a protocol 
violation, as required. 
Any AE associated with an overdose, medication error, misuse, or abuse of the investigational 
agent should be recorded on the AE eCRF with the diagnosis of the AE. 
11.2.4.4. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such events should be recorded only once on the SAE Report form and/or the AE 
eCRF. If a persistent AE increases in severity, it should be recorded as a new AE on the eCRF. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. Each individual instance of a recurrent AE should be recorded on an SAE 
Report form and/or AE eCRF. 
11.2.4.5. Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered to be additional information that must be collected on the 
relevant eCRF. If the laboratory abnormality is a sign of a disease or syndrome, only the 
diagnosis needs to be recorded on the SAE Report form and/or AE eCRF. Abnormal laboratory 
values assessed as not clinically significant (NCS) should be documented as such in the source 
document. 
Abnormal laboratory values will be reported as AEs if the laboratory result: 
 requires an adjustment in the investigational agent(s) or discontinuation of treatment 
 meets seriousness criteria 
 requires additional testing or surgical intervention 
 is associated with accompanying symptoms 
11.2.4.6. New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least 1 of the seriousness criteria (Section 11.1.3). New primary cancers are those that are not 
the primary reason for administration of study treatment and have developed after inclusion of 
the patient in the study. They do not include metastases of the original cancer. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 84 of 122 
Symptoms of metastasis or the metastasis of the disease under study should not be reported as 
AEs/SAEs unless fatal. 
11.2.4.7. COVID-19 
Because much is still unknown about how SARS-CoV-2 affects the human body, patients who 
have tested positive for COVID-19 will be identified and relevant information collected. All 
patients should provide documentation of any testing for COVID-19, if available, along with the 
test results, at screening for enrollment and/or during the study. Prior test results should be 
reported, if available, for any patient who has previously tested positive for COVID-19 
SARS-CoV-2 titers (antiviral immunoglobulin G [IgG] and immunoglobulin M [IgM]). These 
data will be entered into the patient’s study-specific record. 
Any patient-reported illness of COVID-19 during the study should be recorded as an AE. If a 
patient reports infection with COVID-19, the investigator may discuss with the Medical Monitor 
whether the patient can continue on study. 
11.2.4.8. Death 
All events leading to the clinical outcome of death occurring during the SAE reporting period 
(from the signing of the informed consent through 30 days after the last investigational agent 
administration) are to be reported to the Sponsor or its designee as an SAE and recorded on the 
AE eCRF. 
11.2.5. 
Reporting of Expedited Safety Observations by the Investigator, Including 
Serious Adverse Events 
11.2.5.1. Immediate Reporting of Serious Adverse Events or Pregnancy by the 
Investigator to the Sponsor 
All SAEs from the time of signing informed consent through 30 days of receiving the last dose 
of investigational agent, including SAEs from screen failure patients, will be reported to the 
Sponsor or designee within 24 hours of the investigator’s first knowledge of the event, even if 
the experience does not appear to be related to the investigational agent.  
Serious AEs should be communicated on an SAE Report form as follows: 
Sumitomo Dainippon Pharma Oncology, Inc
Pharmacovigilance Department Contact Information: 
Email: BBISafety@bostonbiomedical.com 
Fax: +1.617.674.8660 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (eg, an end date for the AE, 
laboratory values received after the report, or a hospital discharge summary) must be 
documented on a follow-up form. All follow-up information must be reported in the same 
timelines as the initial information. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 85 of 122 
At any time after completion of the AE reporting period (ie, 30 days post-treatment), if an 
investigator becomes aware of an SAE that is suspected by the investigator to be related to the 
investigational agent, the event must be reported to the Sponsor or designee.  
11.2.5.2. Immediate Reporting of Adverse Events of Special Interest, Occupational 
Exposure, Overdose, or New Cancers 
Any occupational exposure or exposure of an individual not enrolled in the study to the 
investigational agent must be reported to the Sponsor or designee within 24 hours of the 
investigator’s first knowledge of the event, even if the exposure does not result in an AE. 
Unintentional exposures should be communicated on the SAE Report form, as described above 
for SAEs. 
Any overdose of the investigational agent must be reported to the Sponsor or designee within 
24 hours of the investigator’s first knowledge of the event. Overdose should be communicated 
on the SAE Report form, as described above for SAEs. 
Any new cancer must be reported to the Sponsor or designee within 24 hours of the 
investigator’s first knowledge of the event, even if the overdose does not result in an AE. New 
cancers should be communicated on the SAE Report form, as described above for SAEs. 
11.2.5.3. Reporting COVID-19 Infections 
Suspected or confirmed COVID-19 infections, including asymptomatic infections and positive 
COVID-19 tests are adverse events of special interest (AESIs) and therefore immediately 
reportable events, even if the events do not meet SAE criteria. 
Serious COVID-19 events will be reported on an SAE Report form within 24 hours of the 
investigator’s awareness, according to Section 11.2.5.1. 
Nonserious COVID-19 events will be reported on a COVID-19 Report form within 5 calendar 
days of the investigator’s awareness, to the same email/fax for reporting SAEs described in 
Section 11.2.5.1. 
Updates or follow-up information for COVID-19 events should be reported on an SAE Report 
form (serious events) or a COVID-19 Report form (nonserious events) within the same timelines 
as the initial reports. 
11.2.5.4. Reporting Pregnancies 
If a female patient or the female partner of a male patient becomes pregnant during the study, the 
investigator must report the pregnancy to the Sponsor/designee using the Pregnancy Reporting 
form within 24 hours of becoming aware of the event. 
If not all information on the Pregnancy Report form is available at the time of the initial report, 
follow-up pregnancy reports will be completed and submitted within 24 hours of becoming 
aware of the new information. The investigator is required to follow up on the pregnancy until it 
is completed. The pregnancy outcome and the status of the newborn (if applicable) will be 
reported on the Pregnancy Report form within 24 hours of becoming aware. SAEs associated 
with the pregnancy, including fetal death, miscarriage, or congenital anomalies must be reported 
as SAEs, according to Section 11.2.5.1.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 86 of 122 
If the female partner of a male patient becomes pregnant, the investigator must obtain consent to 
collect pregnancy information from the pregnant partner (including the status of the newborn, if 
applicable).  
11.2.5.5. Expedited Reporting by the Sponsor to a Regulatory Health Authority 
The Sponsor will manage the expedited reporting of relevant safety information to concerned 
health authorities, competent authorities, and Institutional Review Boards (IRBs)/Independent 
Ethics Committees (IECs), in accordance with local laws and regulations. 
11.2.5.6. Safety Notifications by the Sponsor to the Investigator 
Investigators will receive prompt notification of any suspected adverse drug reaction that is both 
serious and unexpected, or any finding that suggests a significant risk for patients, in accordance 
with local laws and regulations. The investigator will promptly inform his/her IRB/IEC of the 
notification and insert the notification into the Investigator’s Regulatory Binder, in accordance 
with local regulations. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 87 of 122 
12. 
STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be maintained by the 
Sponsor/designee.  
12.1.
Statistical Methods 
Statistical analyses will be descriptive in nature. No formal sample size calculations will 
be performed for this study.  
 All antitumor parameters including response will be evaluated on the per-protocol 
population, as defined in Section 12.2, and summarized using descriptive statistics. 
Patient response will be assessed based on RECIST or iRECIST; Kaplan-Meier estimates 
of PFS will be generated. Data listings and summaries may include tumor markers, 
additional imaging, or other response data. Potential relationships between PK, 
pharmacodynamics, and other response data may be evaluated.  
 Adverse events will be assessed based on the safety population, as defined in 
Section 12.2, according to CTCAE v 5.0 when appropriate, and will be evaluated by 
grade and SOC. Adverse event listings and tabulated summaries of categorized TEAEs 
will be generated for each dose level and for patients overall. Additionally, the number 
treated, number evaluable for dose escalation, and number with DLTs will be described 
for each dose level and for the study overall. Vital signs, laboratory data, and ECG data 
(stratified by dose level and overall) will be summarized for changes over time on study 
and each postbaseline visit together with the change from baseline.  
 Descriptive statistics (n, mean, standard deviation, median, and ranges for continuous 
variables; frequencies and percentages for categorical variables) will be provided by dose 
level and/or visit, if applicable. All data will be listed by patient, dose level, and visit 
where applicable. All summaries, statistical analyses, and individual patient data listings 
described below will be completed by using SAS v9.3 or later (SAS Institute, Inc, Cary, 
North Carolina, USA).  
12.2.
Definition of Study Populations  
The Full Analysis Set (FAS) in this study consists of all patients who entered the study and 
received one dose of study treatment (DSP-0509 or pembrolizumab).  
The safety population is the same as the FAS. 
The DLT population will consist of all patients who met the prespecified criteria for being 
evaluable for DLT detailed in Section 7.6.   
The Per-protocol Set (PPS) will consist of patients who meet all the following criteria:  
 Received at least 2 consecutive doses of DSP-0509 as scheduled  
 Had a baseline (Screening) tumor assessment  
 After initiation of therapy, had at least 1 objective disease assessment according to 
RECIST or iRECIST  
The determination of the PPS will be finalized following a complete data review by both Syneos 
Health and/or the Sponsor representatives before the database lock. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 88 of 122 
The PK Set (PKS) will be all treated patients with at least 1 measurable PK value. 
The Efficacy Set (ES) includes all patients from the FAS who have responded to treatment 
(CR/PR), assessed as progressed on treatment without regard to length of treatment, or have been 
on the treatment for 6 months or more without regard to tumor response status. 
12.3.
Determination of Sample Size 
The study is exploratory in nature; there is no hypothesis test and thus no power calculation has 
been performed. 
12.3.1. 
Dose Escalation and Dose Expansion 
Dose Escalation (Phase 1) 
The exact number of patients to be enrolled in each dose-escalation cohort cannot be specified in 
advance because of the dynamic features of BLRM (see Section 7.4.1). The actual sample size 
may vary depending on the incidence of DLT events and the number of dose levels studied.  
It is envisaged that approximately 21 to 30 patients will be enrolled (aimed to complete treatment 
and assessments) in each dose-escalation Arm (A or B), for a total of 42 to 60 patients. 
 
Dose Expansion (Phase 2) 
Approximately 20 to 40 patients will be enrolled in the dose-expansion Combination Arm C, for 
a total of 62 to 100 patients overall. This is considered clinically adequate for the preliminary 
assessment of PK, pharmacodynamics, and efficacy data.  
A Bayesian approach will be used to continuously assess the posterior probability of the ORR. 
If the probability of the posterior probability i
<10% (stopping zone), enrollment may be stopped and the final actual sample size may be less 
than 40, depending on the enrollment rate. If the probability of the posterior probability in the 
target ORR rang
 
With 20 patients enrolled who meet the ES criteria, and the true ORR is 15%, there will be an 
82% probability to observe a minimum of 2 objective responders. 
12.4.
Planned Analyses 
All safety analyses will be performed on the safety population, and all efficacy analyses will be 
based on the PPS. Efficacy analyses also may be conducted in all patients who receive at least 
1 dose of study drug (DSP-0509 or pembrolizumab), ie, FAS.  
12.4.1. 
Demographic and Other Baseline Characteristics 
All demographic and baseline characteristics information will be summarized using the FAS and 
the PPS. 
12.4.2. 
Safety Endpoints 
Safety evaluation will include assessments of TEAEs, DLTs, serum chemistry tests, hematology 
values, urinalysis, pregnancy, performance status (ECOG score) evaluations, study drug 
exposure, vital signs, physical examinations, ECGs, MUGA/ECHO scans, xrays, and eye tests. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 89 of 122 
Patient incidence rates of all TEAEs/DLTs will be tabulated by SOC and preferred term. Tables 
and/or narratives of on-study deaths and serious and significant TEAEs, including early 
withdrawals due to TEAEs, also will be provided. The extent of study exposure also will be 
summarized descriptively. 
12.4.3. 
Efficacy Endpoints Analysis 
The efficacy endpoints are PFS, DoR, TTP, OS, DCR, and ORR. The Kaplan-Meier method will 
be used to estimate and visualize the distribution of PFS. For the calculation of PFS, 
progressions assessed by CT or MRI will be used as events. The calculation approach for PFS 
considering the various situations for censoring will follow the FDA Guidance for Industry 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 2007 (Center for 
Drug Evaluation and Research, 2007). Further details for the analysis of the PFS will be 
provided in the SAP. 
 
For the dose-expansion Combination Arm C, the ORR will be monitored and used to adjust the 
patient enrollment as follows:   
•After 10 evaluable patients, assess posterior probability ORR: 
—
 
—
 
—
 
primary or acquired resistance or both).   
12.4.4. 
Pharmacokinetic Analyses (Secondary Endpoints) 
The PK concentrations and parameters will be derived for DSP-0509, and the relationship of PK 
parameters with dose (dose-proportionality) will be evaluated by statistical methods. 
The following standard PK parameters will be analyzed: AUCt, AUC24h, AUCinf, Cmax, 
accumulation ratios (Racc) for Cmax and AUC, C0
1/2, VC, Vz, CL, Ae, Fe (%), and CLR. 
Additional parameters may be added as needed. 
PK concentration at 4 hours postdose on Days 15, 29, and 43, and trough PK concentrations on 
Days 15, 29, and 43 will be used to evaluate the attainment of steady state. The Racc will be 
calculated for Cmax and AUC and compared between Day 1 and the next DSP-0509 infusion for 
which dense PK sampling is available. 
Descriptive statistics will be provided for the PK parameters and concentrations. 
Dose-proportionality, attainment of steady state, and Racc will be assessed. Correlation of 
exposure with response, and correlation with pharmacodynamics parameters such as response 
and survival, may be conducted. PK data may be analyzed in conjunction with data from other 
studies (for example, for population PK analyses). Each of the above PK analyses will be 
conducted where data permits. 
The details of statistical analyses and presentation of the PK data will be discussed in the SAP. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 90 of 122 
12.4.5. 
Pharmacodynamic Analyses (Secondary Endpoints) 
Descriptive statistics will be provided for actual measured data in tumors at Screening. The 
results of the testing of plasma cytokine levels will be presented in listings and summarized by 
tumor type and cohort. The relationship between the baseline and on-treatment cytokines levels 
and efficacy results will be evaluated as prognostic factors by statistical methods as the data 
allow. Graphical presentations will also support preliminary inferential analyses. The 
pharmacodynamics summaries and exploratory analyses will be described in the SAP in greater 
detail. 
12.4.6. 
ECG Analysis  
The analysis of ECG results will be based on patients in the safety analysis set and will follow the 
ICH E14 guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs (Thomson, 2018). 
Exploratory analysis may be conducted to assess the relationship between DSP-0509 plasma 
concentration and QT interval length from the Holter ECG data using a PK/pharmacodynamics 
modeling approach. The intensive ECGs from the Holter recordings will be analyzed by an ECG 
core laboratory, and details of the analyses will be provided in a separate SAP and/or report.  
12.4.7. 
Subgroup Analyses 
Details of subgroup analyses as appropriate will be presented in the SAP.  
12.4.8. 
Protocol Deviations 
All deviations related to study inclusion or exclusion criteria, conduct of the study, patient 
management, or patient assessment will be identified, evaluated, and closed before database lock 
and will be described in the final clinical study report. 
Major and minor protocol deviation criteria will be defined prospectively before study analysis. 
Major deviations are those considered likely to affect the reliability of the results of the study or 
the safety of the patient. Minor deviations are those considered to be unlikely to have an impact 
on the reliability of the results, but which still contribute significant deviations from this 
protocol.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 91 of 122 
13. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
13.1.
Study Monitoring 
During the study, a monitor from the Sponsor or its designee will have regular contact with the 
investigational site, to: 
 Provide information and support to the investigator and study staff 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that DSP-0509/pembrolizumab accountability 
checks are being performed 
 Perform source data verification (SDV). This includes a comparison of the data in the 
eCRFs with the patient’s medical records at the hospital or practice, and other records 
relevant to the study. SDV will require direct access to all original records for each 
patient (eg, clinic charts, ECHOs) 
 Record and report any protocol deviations not previously sent to the Sponsor 
 Confirm that any AEs, SAEs, and AESIs have been properly documented on eCRFs, and 
confirm that any SAEs have been forwarded to the Sponsor, and that those SAEs that met 
criteria for reporting have been forwarded to the IRB/IEC 
The monitor will be available between visits if the investigator(s) or other staff need information 
or guidance. 
During the COVID-19 public health emergency, traditional on-site monitoring might be difficult 
for the following reasons:  
(1) sites may not be able to accommodate monitoring visits (eg, due to staffing limitations or 
site closures) 
(2) monitors may not be able to travel to study sites. When planned on-site monitoring visits 
are not possible, the reason should be documented and available for review by the 
Sponsor and during FDA inspections 
13.2.
Audits and Inspections 
Authorized representatives of the Sponsor, any regulatory authority having an interest in this 
study, or the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) may visit 
the site to perform audits or inspections. The purpose of audit or inspection by the Sponsor is to 
examine all study-related activities and documents systematically and independently, to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP) guidelines of the 
International Council on Harmonisation (ICH), and any applicable regulatory requirements. The 
investigator should contact the Sponsor immediately if notified by a regulatory agency about an 
inspection. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 92 of 122 
13.3.
Institutional Review Board/Independent Ethics Committee 
The investigator must obtain IRB or IEC approval for the study. Initial IRB/IEC approval of the 
protocol and all materials approved by the IRB/IEC for this study, including the patient informed 
consent form (ICF) and any recruitment materials must be maintained by the study 
site/investigator and made available for inspection by the study monitor or any regulatory 
authorities with an interest in this study. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 93 of 122 
14. 
QUALITY ASSURANCE AND QUALITY CONTROL 
14.1.
Audit and Inspection 
Study sites and study documentation may be subject to a Quality Assurance audit during the 
course of the study by the Sponsor or its nominated representative. This would include routine 
clinical audits or directed or for-cause audits. In addition, inspections may be conducted by 
regulatory authorities at their discretion. 
14.2.
Monitoring
Data for each patient will be recorded on an eCRF. Data collection must be completed for each 
patient who signs an ICF. 
In accordance with current GCP and ICH guidelines, the study monitor will carry out SDV at 
regular intervals to ensure that the data collected in the eCRF are accurate and reliable. 
The investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities’ direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of the data contained in the eCRFs. 
14.3.
Data Management and Coding 
The Sponsor or Syneos Health will be responsible for the activities associated with data 
management of this study. This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data generated 
from this clinical study will be handled according to the relevant standard operating procedures 
of the Data Management and Biostatistics Departments of Syneos Health. 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for 
concomitant diseases and AEs and World Health Organization Drug Dictionary for medications. 
Missing or inconsistent data will be queried in writing to the investigator for clarification. 
Subsequent modifications to the database will be documented. 
14.4.
Data Collection/Electronic Data Capture 
The Sponsor/Syneos Health will provide eCRFs. Results from Screening and data collected 
during the study (except clinical laboratory test results) will be recorded in the patient’s eCRF.  
Study sites will use an electronic data capture (EDC) system that is compliant with relevant FDA 
regulatory requirements per title 21 Code of Federal Regulations Part 11. Password-protected 
access to the EDC system will be enabled via a secure website. Data queries and data corrections 
will be handled through the same system. All transactions within the EDC system are fully 
documented within an electronic audit trail. Each set of completed eCRFs must be reviewed and 
electronically signed and dated by the Investigator. 
The database will be locked after completion of the study, when all data have been checked for 
plausibility and corrected to the extent possible, and all coding and assessments have been 
completed. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 94 of 122 
14.5.
Records and Supplies 
14.5.1.
Drug Accountability
On receipt of study drug, the investigator (or designee) will conduct an inventory of the supplies 
and verify that study drug supplies are received intact and in the correct amounts before 
completing a supplies receipt. The investigator will retain a copy of this receipt at the study site 
and return the original receipt to the study monitor. The study monitor may check the study 
supplies at each study site at any time during the study. 
It is the responsibility of the study monitor to ensure that the investigator (or designee) has 
documented correctly the amount of study drug received, dispensed, and returned on the 
dispensing log that will be provided. A full drug accountability log will be maintained at the 
study site at all times. The study monitor also will perform an inventory of study drug at the 
close-out visit to the study site. All discrepancies must be accounted for and documented. 
14.6.
Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between Syneos 
Health and the Sponsor. 
14.7.
Compensation 
The patient will be treated and/or compensated for any study-related illness/injury pursuant to 
the information provided in the Compensation for Injury section of the ICF and the site clinical 
trial agreement (CTA). 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 95 of 122 
15. 
ETHICS 
15.1.
Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study site, the protocol, the ICF, other written material 
given to the patients, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB. Written approval of the study and all relevant study information must be 
obtained before the study site can be initiated or study drug is released to the investigator. Any 
necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study, such as amendments to the protocol, the ICF, or other study documentation. The written 
approval of the IEC/IRB, together with the approved ICF must be filed in the study files. 
The investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of patients or conduct of the study. The investigator will submit written 
summaries of the study status to the IEC/IRB, as required. On completion of the study, the 
IEC/IRB will be notified that the study has ended. 
15.2.
Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of participating 
countries, according to local/national requirements, for review and approval before beginning the 
study. On completion of the study, regulatory authorities will be notified that the study has 
ended. 
15.3.
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in adherence 
with the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and 
applicable national and local laws and regulatory requirements. 
15.4.
Informed Consent 
The process of obtaining informed consent must be performed in accordance with applicable 
regulatory requirement(s) and must adhere to ICH GCP. 
The investigator is responsible for ensuring that no patient undergoes any study-related 
examination or activity before that patient has given written informed consent to participate in 
the study. 
The investigator or designated personnel will inform each patient of the objectives, methods, 
anticipated benefits, and potential risks and inconveniences of the study. The patient should be 
given every opportunity to ask for clarification of any points s/he does not understand and, if 
necessary, ask for more information. At the end of the interview, the patient will be given ample 
time to consider the study. Patients will be required to sign and date the ICF. After signatures are 
obtained, the ICF will be kept and archived by the investigator in the investigator’s study file. A 
signed and dated copy of the patient’s ICF will be provided to the patient or the patient’s legally 
authorized representative. 
A patient may refuse to enter the study or to withdraw from the study at any time, without 
consequences for further care or penalty or loss of benefits to which the patient is otherwise 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 96 of 122 
entitled. Patients who refuse to give or who withdraw written informed consent should not be 
included or continue in the study. 
If new information becomes available that may be relevant to a patient’s willingness to continue 
participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and regulatory 
authorities, if required). Study patients will be informed about this new information and 
reconsent will be obtained. 
15.5.
Patient Confidentiality 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the FDA, as well as that of any other applicable 
regulatory agency(ies), will be granted direct access to the study patient’s original medical 
records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the patient to the extent permitted by laws and regulations. In any presentation 
of the results of this study or in publications, the patient’s identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be managed by 
the investigator and his/her staff with adequate precautions to ensure the confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act and 
applicable national and/or local laws and regulations regarding personal data protection. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 97 of 122 
16. 
REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
The complete publication policy for the study will be described in detail in the clinical study 
agreement. To avoid disclosures that could jeopardize proprietary rights, the investigator agrees 
to give the Sponsor the right to review all publications, including, but not limited to, 
manuscripts, abstracts, and presentations related to this study, with adequate time prior to their 
submission for publication or presentation. The Sponsor may use these data now and in the 
future for all purposes, including presentation or publication at the Sponsor’s discretion, for 
submission to government regulatory agencies, or for purposes of inclusion in patent-related 
filings and submissions. Publication authorship among investigators will be based on the extent 
of significant contribution, including scientific and clinical. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 98 of 122 
17. 
REFERENCES 
American Cancer Society. Cancer Facts & Figures 2017. https://www.cancer.org/research/cancer-facts-
statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html.  
Aranda F, Vacchelli E, Obrist F, Eggermont A, Galon J, Sautès-Fridman C, et al. Toll-like receptor 
agonists in oncological indications. Oncoimmunol. 2014;3:e29179.  
Babb J, Rogatko A, Zacks S. Cancer Phase I clinical trials: efficient dose escalation with overdose 
control. Stat Med. 1998;17:1103-1120.
Bakhribah H, Dy GK, Ma WW, Zhao Y, Opyrchal M, Purmal A, et al. A phase I study of the toll-like 
receptor 5 (TLR5) agonist, entolimod in patients (pts) with advanced cancers. DOI: 
10.1200/jco.2015.33.15_suppl.3063. J Clin Oncol. 2015;33(15):3063. 
Bhatia S, Ibrani D, Vendeven N, Miller N, Shinohara M, Byrd D, et al. Pilot study of intratumoral G100, 
toll-like receptor-4 (TLR4) agonist, therapy in patients with Merkel cell carcinoma (MCC). DOI: 
10.1200/jco.2015.33.15_suppl.3083. J Clin Oncol. 2015;33(15):3083. 
Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab 
with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck 
(KEYNOTE-048): a randomized, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. 
(accessed online at: https://pubmed.ncbi.nlm.nih.gov/31679945/. 23 February 2021.) 
Chan E, Kwak EL, Hwang J, Heiskala M, de La Bourdonnaye G, Mita M. Open-label phase 1b study of 
FOLFIRI plus cetuximab plus IMO-2055 in patients with colorectal cancer who have progressed 
following chemotherapy for advanced or metastatic disease. Cancer Chemother Pharmacol. 
2015;75:701-709.   
Chi H, Li C, Zhao FS, Zhang L, Ng TB, Jin G, et al. Anti-tumor activity of toll-like receptor 7 agonists. 
Front Pharmacol. 2017;8:304. 
Center for Drug Evaluation and Research. Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2007. 
https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf 
Centers for Disease Control and Prevention. Cancer Data and Statistics 2017. 
https://www.cdc.gov/cancer/dcpc/data/index.htm. 
EMA: European Medicines Agency. Guideline on clinical trials in small populations. 
CHMP/EWP/83561/2005. 2006. 
Fucikova J, Moserova I, Urbanova L, Beze L, Kepp O, Cremer I, et al. Prognostic and predictive value of 
DAMPs and DAMP-associated processes in cancer. Front Immunol. 2015;6:402.  
Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. 
Nat Rev Drug Discov. 2012;11:215-233.  
Gay NJ, Symmons MF, Gangloff M, Bryant CE. Assembly and localization of Toll-like receptor 
signaling complexes. Nat Rev Immunol. 2014;14:546-558.  
Hoffman ES, Smith RE, Renaud RC Jr. From the analyst's couch: TLR-targeted therapeutics. Nat Rev 
Drug Discov. 2005;4:879-880.  
Iribarren K, Bloy N, Buqué A, Cremer I, Eggermont A, Fridman WH, et al. Trial Watch: 
Immunostimulation with Toll-like receptor agonists in cancer therapy, OncoImmunology. 2016;5:3. 
Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and 
immunity. Immunity. 2011;34:637-650.  
Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, 
CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:273-290. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 99 of 122 
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev 
Immunol. 2013;31:51-72.   
Machiels JP, Kaminsky MC, Keller U, Brümmendorf TH, Goddemeier T, Forssmann U, et al. Phase Ib 
trial of the Toll-like receptor 9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and 
cetuximab as first-line palliative treatment in patients with recurrent/metastatic squamous cell 
carcinoma of the head and neck. Invest New Drugs. 2013;31(5):1207-1216.  
Merck and Co, Inc. Pembrolizumab prescribing information: KEYTRUDA® (pembrolizumab) for 
injection, for intravenous use.  Revised January 2020. Whitehouse Station, NJ, USA. (Accessed 
online at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s066lbl.pdf; 
24 February 2021.) 
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. 
Management of Immunotherapy-Related Toxicities. Version 1.2020 – December 16, 2019. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer 
trials. Stat Med. 2008;27:2420-2439.
Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009;9:57-63.  
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. Translation of innovative designs 
into Phase I trials. J Clin Oncol. 2007;25:4982-4986. 
Schmoll H-J, Wittig B, Arnold D, Riera-Knorrenschild J, Nitshe D, Kroening H, et al. Maintenance 
treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients 
with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-
blind, placebo-controlled trial. J Cancer Res Clin Oncol. 2014;140:1615-1624.   
Smith DA, Conkling P, Richards DA, Nemunaitis JJ, Boyd TE, Mita AC, et al. Antitumor activity and 
safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and 
bevacizumab in advanced or metastatic non-small cell lung cancer patients who have progressed 
following chemotherapy. Cancer Immunol Immunother. 2014;63:787-796.   
Thomson J. New NCCN Guidelines: recognition and management of immunotherapy-related toxicity. J 
Natl Compr Canc Netw. 2018;16(5.5):594–596. 
Tsitoura Ambery C, Price M, Powley W, Garthside S, Biggadike K, et al. Early clinical evaluation of the 
intranasal TLR-7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm 
target engagement. Clin Pharmacol Therapeutics. 2015;98(4):369-380. 
Weihrauch MR, Richly H, von Bergwelt-Baildon MS, Becker HJ, Schmidt M, Hacker UT, et al. Phase I 
clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours. 
Eur J Cancer. 2015;51:146-156. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 100 of 122 
18. 
APPENDICES 
18.1.
DSP-0509 Infusion Procedure 
DSP-0509 is to be given IV as a 10-minute infusion administered using an infusion pump.  
 This procedure is designed to assure the entire volume of dosing solution is delivered 
over 10 minutes at as constant a rate as possible. This is particularly critical to have valid 
monitoring of Cmax, which is required for this investigational product and is determined 
by dense PK sampling on Days 1 and 43 for all patients in dose-escalation cohorts.  
 This procedure has been developed based on extensive conversations with site clinical 
and pharmacy personnel. Individual sites may have preferences, experience, and/or 
equipment that could require modifications to the procedure. To accommodate this, sites 
may discuss those modifications with the Medical Monitor and may then submit a formal 
description of the proposed procedure. If approved, the modified procedure will be filed 
in the site's Trial Master File and the site will document that all personnel administering 
DSP-0509 have been trained in that procedure.    
Definitions of Key Materials Needed 
 "Dosing syringe" – provided by the pharmacy and containing the assigned dose of 
DSP-0509 in the volume specified below  
 "Saline syringe" – with approximately10 mL normal saline for injection (may be 
provided by the pharmacy or prepared by site personnel). Will be used (a) to prime the IV 
tubing before start of infusion, and (b) to administer the dosing solution remaining in the 
tubing after the dosing syringe is empty  
 IV tubing – to run from the Y-connector (see below) to the IV in the patient   
 Y-connector – will connect to the IV tubing just before the infusion pump; the two arms 
of the Y-connecter will go to (a) the dosing syringe and (b) the saline syringe 
Note: The following plastic materials used in syringes and tubing have been evaluated 
and confirmed as compatible with the dosing solution: polypropylene, polycarbonate, 
polybutadiene, acrylonitrile-butadiene-styrene copolymer   
 An accurate timepiece (eg, watch, clock) – to be available from start of the infusion for at 
least the next 4 hours, and during that period to be used as the source of the times 
recorded for all events associated with both the infusion and PK sample collection  
Preinfusion Activities  
 In advance of the infusion, get a reliable estimate of the total dead space (volume) of the 
tubing and the Y-connector  
– 
the site exceeds that, please discuss with the Medical Monitor.  
 Note: The simplest way to determine the total dead space is to assemble the items, attach 
a syringe with a known volume of saline and see how much saline must be injected to fill 
the tubing. Obviously, the actual components used for this purpose must be discarded, but 
the exact same make/model of tubing and connector products must be used for all 
infusions. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 101 of 122 
Preparation of Dosing Syringe in Pharmacy  
The pharmacy will prepare the Dosing syringe as described below.   
 The infusion should begin within one (1) hour after the syringe is prepared.   
 The DSP-
 
 At dose levels of 0.3 and 1 mg, the pharmacy will add saline (as indicated in the table 
below) to the dose volume as provided so the Dosing syringe contains at least 5 mL.  
Dose per 
infusion (mg) 
Dose volume (mL) 
as provided 
Volume (mL) of 
saline to be added 
Final volume (mL) 
in Dosing syringe 
0.3
1 
4 
5 
1 
3.33
1.67 
5 
 If the SRC recommends dose levels <1.5 mg not shown, the Sponsor will indicate the 
saline volume needed for that dose level.  
Assemble Tubing and Y-connector and Prefill with Saline 
 Identify the end of the tubing that will go into the patient's IV line.   
 Connect the opposite end of the tubing (the pump end) to the "base" of the Y-connector. 
 Connect the Saline syringe to one arm of the Y-connector.  
 Fill just that arm and clamp it.  
 Transfer the Saline syringe to the other arm of the Y-connector. 
 Fill that arm and the entire tubing.  
 Cap the "patient" end of the tubing.  
 Then, leaving the Saline syringe attached, clamp that arm of the Y-connector. 
Attach Dosing Syringe and Fill Tubing with DSP-0509 Solution 
 Attach the available arm of the Y-connector to the Dosing syringe.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 102 of 122 
 Place the Dosing syringe in the syringe pump 
 Set the syringe pump to deliver in 1 min  
– only the dead space volume of the connector and the tubing 
 Start the infusion pump.  
 When the infusion pump stops, reset the infusion pump to deliver in 10 min 
– the volume originally dispensed in the Dosing syringe (see table above) 
Infusion of DSP-0509 
 The delegated site personnel must remain at the infusion pump the entire procedure.  
 Start the infusion pump. Record the exact time as Start of Infusion.  
 Note: The Dosing syringe will be empty before the end of the 10 min infusion time.  
– The approximate time the Dosing syringe should be empty is  
10 min × The volume in the Dosing syringe 
 
The dead space volume 
The volume in the Dosing syringe 
 
 
 Note: On PK days, there are blood draws scheduled at  
–   8 (±0.5) min post-start of infusion, i.e., 2 (±0.5) min before end of infusion  
– 11 (±0.5) min post-start of infusion, i.e., 1 (±0.5) min after the end of infusion  
– It should be anticipated that an additional person will be needed to help collect 
these samples at the required timepoints.  
Using the Infusion Pump, Flush Tubing with Saline  
 When the dosing syringe is empty, there will still be time remaining on the pump. 
Pause the infusion pump. Do not cancel the program.  
 Do not administer the Dosing solution in the tubing by manual flushing of the line.  
 The remaining dosing solution must be administered using the following procedure.  
Please proceed as smoothly and quickly as possible:  
– Clamp the arm of the Y-connector attached to the Dosing syringe 
– Remove the Dosing syringe from the syringe pump 
– Place the Saline syringe in the syringe pump 
– Unclamp the Connector arm attached to the Saline syringe  
– Restart the syringe pump to complete the programmed 10 min infusion 
 At the end of the programmed 10 minutes, the pump should stop the infusion.  Record the 
exact time the pump stopped as the End of Infusion.  
 Disconnect the tubing from the patient’s IV line.   
 Attach the patient to Normal Saline; follow institutional KVO (keep vein open) procedure  
 Proceed with PK blood draws, if scheduled on that day.  
 Discard the Dosing syringe, Saline syringe, tubing, and Y-connector per institutional 
procedure. 
 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7
Confidential and Proprietary
Page 103 of 122
18.2.
RECIST 1.1 and iRECIST
Table 19:
Comparison of RECIST 1.1 vs. iRECIST


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7
Confidential and Proprietary
Page 104 of 122
Table 20:
Assignment of Timepoint Response using iRECIST


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7 
Confidential and Proprietary
Page 105 of 122
18.3.
Extracts from NCCN Guidelines for irAEs
The tables below are from the NCCN monograph "Management of Immune Checkpoint 
Inhibitor-Related Toxicities" (NCCN, 2020). 
Table 21: 
Principles of Routine Monitoring for Immune-Checkpoint Inhibitors 
[a] Prior to initiating treatment, counsel patients and caregivers on the warning signs and symptoms of immune-
related adverse events (irAEs). See Principles of Immunotherapy Patient Education (IMMUNO-B). 
[b] Closer monitoring may be required for patients with combination immunotherapy regimens.  
[c] After first four doses of immunotherapy, only as clinically indicated.


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
Amendment 7 
Confidential and Proprietary 
Page 106 of 122 
Table 22: 
Assessment and Grading of Infusion-Related Reactions  
Adverse Event 
Assessment 
Grading 
Infusion-related 
reactions [a] 
Physical Exam
Vital Signs 
Pulse Oximetry 
ECG (if chest pain or 
sustained tachycardia)
Grade 1: Mild, transient 
Grade 2: Moderate [b] 
Grade 3: Severe [c]
[a] Symptoms include: Fever/chills/rigors, urticaria/pruritus, angioedema, flushing/headache, hypertension, 
hypotension, shortness of breath, cough/wheezing, hypoxemia, dizziness/syncope, sweating, and arthralgia/myalgia. 
Refer to prescribing information for each individual immunotherapy agent for recommendations for premedication 
to prevent infusion reactions  
[b] Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, 
acetaminophen, NSAIDs, narcotics, intravenous [IV] fluids); prophylactic medications indicated for less than or 
equal to 24 hours.  
[c] Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement. Hospitalization indicated; life-threatening consequences; 
urgent intervention 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 107 of 122
18.4.
Bayesian Logistic Regression Model 
Operating Characteristics of the BLRM for Monotherapy Arm A 
Introduction 
In the dose-escalation part of the study, an adaptive BLRM with EWOC will be used to guide 
dose escalation and estimate the MTD(s) based on occurrence of DLT during Cycle 1. 
This appendix provides details on the statistical model, prior definitions, and operating 
characteristics in order to illustrate the performance of the design in estimating the MTD under 
various dose-toxicity relationships through simulations. Finally, hypothetical dose-escalation 
scenarios will be presented to illustrate the dose allocation in the first cohorts of the study. 
Dose Escalation Method 
Statistical Model
The dose-DLT relationship in the dose-escalation part of the study with a q1w schedule is 
described by a 2-parameter model (logistic model): 
( ) = log( ) +
log(
) ,
> 0,
> 0 
where 
( ) = log 
( )
( ) , 
( ) is the probability of a DLT at dose . Doses are rescaled 
as 
 with reference dose 
= 2.4 
 of DSP-0509. As a consequence,  is equal to the 
odds of toxicity at 
. Note that for a dose equal to zero, the probability of toxicity is zero.  
The MTD is the highest drug dosage that is unlikely (<25% posterior probability) to cause DLT 
in more than 33% of the treated patients in the first cycle of DSP-0509 treatment. 
Provisional Doses Level 
This study currently plans to conduct dose escalation with the provisional dose levels shown in 
Table 3. However, it is possible that intermediate dose levels may be added, that certain 
provisional dose levels may be skipped, or that certain provisional dose levels may not be tested 
during the course of the study. 
Notes: 
 The dose level as well as the reference dose level input into the BLRM can be expressed 
either as the individual administered dose level or the total planned doses to be 
administered in the DLT period (first 42 days) 
 If a new dosing schedule for DSP-0509 in the DLT period is added (eg, q2w), a new 
BLRM model with a similar form can be set up. The posterior distributions from the 
BLRM of the previous dosing schedule (eg, q1w) with available DLT data up to the new 
dosing schedule cohort start will be used to define the priors distribution for the new 
BLRM model. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol
Amendment 7
Confidential and Proprietary
Page 108 of 122
Prior Specifications
The bivariate normal prior for the BLRM parameters with a reference dose level of 2.4 mg is 
obtained as follows:
The following noninformative prior for (log( ) , log( )) was used:
The median DLT rate at the DSP-0509 reference dose (2.4 mg) was assumed to be 15%, 
ie, mean(log( )) = log(0.15/0.85).
A doubling in dose was assumed to double odds of a DLT, ie, mean(log( )) = 0.
The standard deviation of log( ) was set to 2, and the standard deviation of log( ) to 1, 
which allows for considerable prior uncertainty for the dose-toxicity profile.
The correlation between log( ) and log( ) was set to 0.
Table 23:
Prior Parameters for Bivariate Normal Distribution of Model Parameters
Parameters
Means
Standard deviations
Correlation
log( ),log( )
(-1.7346, 
0.000)
(2.000, 1.000)
0
Figure 5:
Prior Distribution of DLT Rates
Abbreviations: CI = confidence interval; DLT = dose-limiting toxicity.


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 109 of 122
Table 24: 
Prior Distribution Summaries Derived from Priors in Table 23 
DSP-0509 
Dose 
(mg) 
Prior Probabilities That 
Pr(DLT) is in Interval 
Mean 
SD 
Quantiles 
[0, 0.16)
[0.16, 
0.33) 
[0.33, 1]
2.5%
50%
97.5%
 
0.8424 
0.0773 
0.0803 
0.0841 0.1645 
0 
0.0129 
0.6576 
1 
0.723
0.1277
0.1493
0.1446
0.2104
0.0001
0.0479
0.7889
3 
0.4591 
0.178 
0.3629 
0.2992 0.2867 
0.0046 
0.1953 
0.9376 
6
0.3063 
0.1592 
0.5345 
0.4383 0.3382 
0.0078 
0.3733 
0.9968 
9 
0.2537 
0.1391 
0.6072 
0.5045 0.3503 
0.0102 
0.4926 
0.9997 
12 
0.2221 
0.1288 
0.6491 
0.5452 0.3539 
0.0124 
0.5694 
1 
16 
0.1966 
0.1196 
0.6838 
0.5812 0.3545 
0.0142 
0.6438 
1 
20 
0.1794 
0.1116 
0.709 
0.6063 0.3534 
0.0159 
0.6943 
1 
25 
0.1646 
0.1048 
0.7306 
0.6293 0.3513 
0.0175 
0.7409 
1 
30 
0.1525 
0.1015 
0.746 
0.6467 0.3491 
0.0191 
0.7745 
1 
Abbreviations: DLT = dose-limiting toxicity; SD = standard deviation 
Bold values – doses not meeting the overdose criterion (>25% chance of excessive toxicity) with prior information 
only. 
 
Note: This updated table includes the additional provisional dose levels from 6 mg to 30 mg, while keeping the same 
prior distribution of the DLT rate as in the original BLRM setup. Therefore, it shows high toxicity levels at the 
higher provisional dose levels. The DLT posterior from the BLRM will be mostly driven by the clinical study data 
after a few patients complete the DLT evaluation with minimum impact from the initial prior.  
 
Dose Recommended by the BLRM Method 
The dose allocation will start at the dose of 0.3mg. Patients will be included by cohort of 3 to 
6 patients. 
After each cohort of patients is completed, the dose recommendation by the model will be based 
on posterior summaries including the mean, median, standard deviation, 95% credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories: 
 [0, 16%) under dosing 
 [16%, 33%) targeted toxicity 
 [33%, 100%] excessive toxicity 
Following the principle of EWOC, after each cohort of patients, the recommended dose by the 
model is the one with the highest posterior probability of the DLT rate falling in the targeted 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 110 of 122
interval (16%, 33%) among the admissible doses fulfilling EWOC, ie, it is unlikely (<25% 
posterior probability) that the DLT rate at the dose falls in the excessive toxicity interval. 
Final Recommendation and Stopping Rules 
Dose escalation will continue until identification of the MTD(s) or suitable lower dose for 
recommended dose(s) for expansion. This will occur when the following conditions are met: 
 At least 6 patients have been treated at this dose  
 This dose satisfies one of the following conditions:  
– The posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or 
– A minimum of 21 patients have already been treated on the study 
 It is the dose recommended for patients, by review of all clinical data by participants of 
the end of cohort meeting 
Of note, the dose-escalation part could be stopped earlier by a joint decision from the Sponsor 
and the Investigators during a dose escalation meeting, by considering the model estimations and 
a global assessment of the safety, PK, pharmacodynamics, and preliminary activity data. 
Operating Characteristics 
Introduction 
This section presents the operating characteristics illustrating the precision of the design in 
estimating the MTD under various assumed true dose-toxicity relationships.  
True Dose-DLT Scenarios 
Multiple simulations for true dose-toxicity relationships were performed with MTD located at 
none, late, middle, or early, or lowest (all) of the provisional dose levels as shown in Table 24. 
Table 25: True Underlying DLT Probabilities 
True Dose-
DLT Scenario 
DSP-0509 Dose Level (mg) 
0.3
1
3
6
9
12
16
20
25
30
A 
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
B 
0.05 
0.07 
0.09 
0.11 
0.13 
0.15 
0.17 
0.19 
0.21 
0.23 
C 
0.05 
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
0.4 
0.45 
0.5 
D 
0.2 
0.25 
0.3 
0.35 
0.4 
0.45 
0.45 
0.45 
0.45 
0.45 
E 
0.36 
0.4 
0.45 
0.45 
0.45 
0.45 
0.5 
0.55 
0.6 
0.65 
Abbreviation: DLT = dose-limiting toxicity. 
Gray shading indicates doses with true DLT probability within the targeted toxicity interval (16%, 33%). 
Simulation Parameters 
For each dose-DLT scenario, 1000 clinical study replications were generated using R software 
version 3.4.4 on a x86-64 architecture on a Windows OS. The Markov chain Monte Carlo 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 111 of 122
(MCMC) estimation is obtained using Rjags R package with 5000 burn-in and 10,000 iterations 
on 2 chains (5000 each). The seed used for data generation is 123456789, and the seed used for 
MCMC estimation is 1 for chain 1 and 2 for chain 2.  
The following study simulation parameters were used:
 Cohort size: 3 
 Maximum number of patients: 30 
The dose allocation rule used in the simulations is identical to the rule presented above, ie, dose 
having the highest posterior probability of the DLT rate falling in the targeted interval (16%, 
33%) among the admissible doses fulfilling EWOC. 
Evaluation Metrics 
Operating characteristics were reviewed for the simulations to compare the relative performance 
of the design under each true dose-DLT relationship. The following metrics were: 
 Probability of recommending as the MTD: 
– An undertoxic dose level, ie, a dose with true probability of DLT in the 
under-dosing toxicity interval [0%, 16%) (Sponsor risk) 
– A targeted dose level, ie, a dose with true probability of DLT in the targeted 
toxicity interval [16%, 33%] (correct final decision) 
– An overtoxic dose level, ie, a dose with true probability of DLT in the excessive 
toxicity interval [33%, 100%] (patient risk) 
 Average number of patients per study exposed at: 
– An undertoxic dose level, as defined above 
– A targeted dose level, as defined above 
– An overtoxic dose level, as defined above 
 Summary of the total number of patients per study (average, first quartile, median, third 
quartile) 
 Average total number of DLTs observed per study 
Operating Characteristics of the Design 
Operating characteristics of the final design are reviewed to investigate performance of the 
model under each true dose-DLT scenario. Table 26 summarizes the results from the simulations 
performed. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 112 of 122
Table 26: 
Summary Metrics of the Simulations Performed 
True 
Dose-
DLT 
Scenario 
Probability of 
Recommending a Dose 
With True P(DLT) 
No MTD 
Recom-
mendation
Average Number of 
Patients Per Trial 
Receiving a Dose 
With True P(DLT) 
Average Number of Patients 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
Per Trial 
 
Experiencing a 
DLT per Trial 
A 
97.3 
0 
0 
2.7 
29.1 
0 
0 
29.2 
1.4 
B 
68.4 
27.5 
0 
4.1 
26.5 
1.8 
0 
28.6 
2.7 
C 
59.9 
32.1 
4.8 
3.2 
21.5 
5.8 
0.3 
27.9 
3.7 
D 
0 
60.9 
2.7 
36.4 
0 
16.3 
0.5 
19.2 
4.4 
E 
0 
0 
16.8 
83.2 
0 
0 
4 
9.7 
3.6 
Abbreviations: DLT = dose-limiting toxicity; MTD = maximum tolerated dose; NA = not applicable. 
The BLRM method with the specified prior performs well, with a high probability of correctly 
identifying a targeted dose level (60.9%) and a low probability of excessive toxicity (2.7%) 
under Scenario D, which is considered to be the most likely dose-toxicity scenario. The method 
performs reasonably well under the unlikely scenarios (Scenarios A and E).  
In general, the probability of selecting a targeted dose level is sufficiently high across the 
scenarios (except for Scenarios A and E), and the average number of patients treated at 
excessively toxic doses is low. In Scenario E, where all provisional doses are considered too 
toxic, the simulations show that the study will terminate early with the average of 9.7 treated 
patients, and MTD will not be determined more than 80% of the time. 
Hypothetical Dose Allocation Scenarios in Early Cohorts 
Aside from the overall operating characteristics studied above, the design should make 
reasonable decisions during a study based on the observed DLTs. After completion of a given 
cohort, the dose allocation for the subsequent cohort will depend on the recommendation of the 
model and medical review of all available data.  
Some scenarios to illustrate on-study dose allocation are presented in Table 27. These scenarios 
assume that each cohort has 3 evaluable patients, and the next recommended dose is based on the 
rule defined above, with the provisional doses as specified. However, during the study it may be 
possible to include 3 to 6 patients by cohort and to add new provisional dose levels. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 113 of 122
Table 27: 
Hypothetical Dose Allocation Scenarios in Early Cohorts 
Cohort  
[Scenario] 
Prior DLTs 
Dose 
(mg) 
Number of 
DLT(s) / Number 
of Patients 
Next Dose 
Level 
(NDL) 
Proposed 
(mg) 
Decisio
n † 
P(Target) 
NDL 
P(Overtox) 
NDL 
Median 
DLT Rate 
at NDL 
1
0.3
0/3
1.8
E
0.162
0.136
0.071
1/3 
0.3 
S 
0.288 
0.230 
0.168 
2/3 
--  
--  
--  
--  
--  
3/3 
--  
--  
--  
--  
--  
2a
0/3 DLT in 
Cohort 1 
1.8
0/3 
3 
E 
0.190 
0.148 
0.089 
1/3 
1.8 
S 
0.338 
0.236 
0.191 
2/3 
0.6 
D
0.270 
0.154 
0.129 
3/3 
0.3 
D
0.214 
0.144 
0.095 
2b 
1/3 DLT in 
Cohort 1 
0.3
0/3 
0.6 
E 
0.311 
0.160 
0.149 
1/3 
--  
--  
--  
--  
--  
2/3 
--  
--  
--  
--  
--  
3/3 
--  
--  
--  
--  
--  
3a
0/3 DLT in 
Cohort 1 
and Cohort 
2 
3 
0/3 
3 
S 
0.122 
0.030 
0.049 
1/3 
3
S 
0.335 
0.225 
0.183 
2/3 
1.8 
D
0.314 
0.127 
0.140 
3/3 
1.8 
D
0.262 
0.205 
0.144 
3b 
0/3 DLT in 
Cohort 1, 
1/3 DLT in 
Cohort 2
1.8
0/3 
1.8 
S 
0.287 
0.074 
0.118 
1/3 
1
D
0.299 
0.081 
0.124 
2/3 
1
D
0.400 
0.228 
0.208 
3/3 
0.6 
D
0.330 
0.219 
0.181 
3c
1/3 DLT in 
Cohort 1, 
0/3 DLT in 
Cohort 2 
0.6
0/3 
1 
E 
0.310 
0.126 
0.138 
1/3 
0.6 
S 
0.439 
0.216 
0.208 
2/3 
0.3 
D
0.465 
0.245 
0.227 
3/3 
--  
--  
--  
--  
--  
3d 
1/3 DLT in 
Cohort 1,   
1/3 DLT in 
Cohort 2 
 
0/3 
1.8 
E 
0.162 
0.136 
0.071 
1/3 
0.3 
S 
0.288 
0.230 
0.168 
2/3 
--  
--  
--  
--  
--  
3/3 
--  
--  
--  
--  
--  
Abbreviations: DLT = dose-limiting toxicity; EWOC = escalation with overdose control. 
† Decision E = escalate, S = stay, D = de-escalate.  


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 114 of 122
P(Target) NDL: posterior probability that the true DLT rate for the next recommended dose lies in the targeted 
interval (16%, 33%). 
P(Overtox) NDL: posterior probability that the true DLT rate for the next recommended dose lies in the excessive 
toxicity interval (33%, 100%). 
 
ing EWOC criteria 
 
In general, when no DLTs are observed in 3 patients at a dose level, the decision is made to 
increase the dose. When 1 DLT is observed in 3 patients, the decision is to stay at the current 
dose level or to escalate to the higher provisional dose level. When more than 1 DLT is observed 
in a 3-patient cohort, the decision is made to decrease the dose level or to stay at the current 
level. 
Operating Characteristics of the BLRM For Combination Arm B
Introduction 
This document defines the key elements of a dose-escalation design for a combination therapy 
based on Agent 1 (DSP-0509) and Agent 2 (pembrolizumab) using a BLRM approach.  
General Considerations 
A dose-escalation design for combination therapies based on a BLRM approach 
(Neuenschwander, 2008) will be used in this study to examine the number of DLTs in the 
individual patient cohorts and determine the MTD. The BLRM method will be applied along 
with the EWOC principle (Babb , 1998; Rogatko, 2007) to control the risk of exposing patients 
to toxic doses.  
BLRM Model 
A BLRM model that allows for an interaction between the 2 agents will be used in this study. 
The model has 3 components, namely, the marginal models for each agent and an interaction 
model.  
The marginal model for Agent 1 is given by 
logit(
) = log(
) +
log(
). 
Here 
 is the probability of a DLT as a function of the dose 
. Also, 
 is a standardized dose 
with respect to a predefined reference dose, eg, 
 is equal to 
, where 
is the reference 
dose for Agent 1, ie, 2.4 mg.  
The marginal model for Agent 2 is given by
logit(
) = log(
) +
log(
). 
As above, 
is the probability of a DLT as a function of the dose 
 and 
 is a standardized 
dose with respect to a predefined reference dose for Agent 2, ie, 200 mg. 
Finally, the interaction model is expressed in terms of the odds of a DLT. Let 
 denote the 
odds of a DLT at the combination dose (
,
). Similarly, let 
and 
 denote the odds of a 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 115 of 122
DLT for Agent 1 at the dose 
 and for Agent 2 at the dose 
, respectively. The interaction 
model is given by 
= (
+
+
) ( ,
,
), 
where  is the interaction parameter, and the interaction multiplier is defined as follows: 
( ,
,
) = exp(
). 
To enable Bayesian inferences, the following prior distributions will be used. The logistic model 
parameters for each agent are assumed to follow a bivariate normal distribution, and the 
 
Selection of Prior Distributions 
The prior distributions for the logistic model parameters log(
) and log(
) corresponding to 
Agent 1 will be selected from the posterior distributions derived from the dose-toxicity data 
collected in the monotherapy portion of the study.  
To illustrate the process, consider weakly informative priors for log(
) and log(
) and assume 
that DLT outcomes from 2 cohorts (0/3 DLTs at 0.3 mg and 1/4 DLTs at 1 mg in the 
monotherapy study) are available to compute the posterior distributions of the model parameters. 
The resulting posterior distribution for Agent 1 computed from the 2 cohorts in the monotherapy 
study are presented in Table 28.  
Table 28: 
Parameters of the Prior and Posterior Distributions for Agent 1 
Distribution 
Mean 
Standard Deviation 
Correlation 
(
) 
(
) 
(
) 
(
) 
Prior distribution 
-1.7346 
0 
2 
1 
0 
Posterior distribution 
-1.0944 
-0.1677 
1.2700 
0.5653 
0.5397 
Continuing to Agent 2, weakly informative priors will be selected for the logistic model 
parameters log(
) and log(
) (Neuenschwander, 2008). The weakly informative priors are 
defined as follows: 
 The median DLT rate at the reference dose is set to 0.5 and thus the mean of log(
) is 
equal to log(0.05/0.95). 
 A doubling of the dose is assumed to double the odds of a DLT; ie, the mean of 
log(
) is set to 0.  
 The standard deviation of log(
) is set to 2 and the standard deviation of log(
) is set 
to 1. These choices indicate considerable prior uncertainty for the dose-toxicity profile. 
 The correlation between the 2 logistic model parameters is set to 0. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 116 of 122
The resulting parameters of the prior distribution for Agent 2 are shown in Table 29. 
Table 29: 
Parameters of the Prior Distribution for Agent 2 
Distribution
Mean
Standard Deviation 
Correlation
(
) 
(
) 
(
) 
(
) 
Prior distribution 
-2.9444 
0 
2 
1 
0 
A general rule for selecting the prior of the interaction parameter is to set its mean to 0 and 
select its standard deviation based on a predefined characteristic of the interaction multiplier: 
( ,
,
) . 
Specifically, the standard deviation of  is chosen to ensure that the 97.5% percentile of the 
interaction multiplier’s distribution at the reference doses 
= 1 and 
= 1 ranges between 
3 and 9. The lower limit of this interval (3) corresponds to the case of moderate uncertainty, and 
the upper limit of this interval (9) indicates a considerable amount of uncertainty for the 
interaction parameter. In this study, the 97.5% percentile is set to 9, which means that  is 
normally distributed with mean = 0 and standard deviation 1.12. 
The dose level, as well as the reference dose level input into the BLRM can be expressed as 
either the individual administered dose level or the total planned doses to be administered in the 
DLT period (first 42 days). 
If a new dosing schedule for DSP-0509 in the DLT period is added (eg, q2w), a new BLRM 
model with a similar form can be set up. The posterior distributions from the BLRM of the 
previous dosing schedule (eg, q1w) with available DLT data up to the new dosing schedule 
cohort start will be used to define the priors distributions for the new BLRM model. For 
pembrolizumab, the 2 planned dosing schedules, eg, 200 mg q3w or 400 mg q6w results in the 
same total dose of 400 mg administered during the DLT period (first 42 days). For this reason, 
the dosing schedules will be considered equivalent when the BLRM model is fitted to the DLT 
data. 
Decision Rules 
Key components of the study design and decision rules are defined below. 
Toxicity Intervals 
The toxicity intervals will be defined in the study as follows: 
 Underdosing interval: DLT probability is less than 16% 
 Targeted toxicity interval: DLT probability is between 16% and 33% 
 Excessive toxicity interval: DLT probability is greater than 33% 
Overdose Control (EWOC) Criterion 
A combination dose is considered safe if the probability of the excessive toxicity interval is no 
greater than 25%. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 117 of 122
Dose Selection 
Patients will be enrolled in cohorts of 3 to 6 patients. After each cohort, the dose 
recommendation by the BLRM model will be based on posterior summaries including the mean, 
median, standard deviation, and credible interval for the true DLT rates across the dose 
combinations. In addition, the probability that the true DLT rate for each dose combination is 
within each of the toxicity intervals (underdosing interval, targeted toxicity interval, excessive 
toxicity interval) will be computed. Following the EWOC principle, the recommended dose 
combination will be the combination with the highest posterior probability of the DLT rate 
falling in the targeted toxicity interval among the admissible doses that meet the EWOC 
criterion. The following restriction will be imposed for the purpose of evaluating the operating 
characteristics of the dose-escalation design:
 Only 1 agent can be escalated at a time 
Stopping Rules 
Dose escalation will continue until an MTD or a suitable lower dose for expansion is identified. 
This will occur when the following conditions are met: 
 At least 6 patients have been treated at the selected dose/combination dose  
 This dose satisfies one of the following conditions: 
– The posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or 
– A minimum of 21 patients have already been treated in the dose escalation part of 
this study 
 It is the dose/combination dose recommended for patients, either per the model or by 
review of all available clinical data in the joint SRC/dose escalation meeting 
Clinical Study Simulations 
Extensive clinical study simulations will be performed to evaluate the operating characteristics of 
the dose-escalation design.  
The prior distributions defined in Table 28 and Table 29 will be used in the simulations. Other 
simulation parameters include: 
 Agent 1 doses: 0.3, 1,  3, 6, 9, 12, 16, 20, 25, and 30 mg 
 Agent 2: 200 mg 
 Patients/Cohort: 3 each in the first two cohorts; 4 each in the remaining cohorts 
 Maximum number of patients: 30 patients 
Simulations will be performed under the dose-toxicity scenarios (true DLT probabilities for each 
combination dose) shown in Table 32. These DLT probabilities are derived from the 
agent-specific dose-toxicity scenarios defined in Table 30 and Table 31 under the assumption of 
no interaction between the 2 agents. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 118 of 122
Table 30: 
Dose-Toxicity Scenarios (True DLT Probability at Each Dose) for Agent 1 
Scenario 
DSP-0509 Dose Level (mg)
0.3
1
3
6
9
12
16
20
25
30
1A 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
1B
0.05
0.07
0.09
0.11
0.13
0.15
0.17
0.19
0.21
0.23
1C 
0.05 
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
0.4 
0.45 
0.5 
1D
0.2
0.25
0.3
0.35
0.4
0.45
0.45
0.45
0.45
0.45
1E
0.36 
0.4 
0.45 
0.45 
0.45 
0.45 
0.5 
0.55 
0.6 
0.65 
Abbreviation: DLT = dose-limiting toxicity. 
Note: Gray shading = doses and scenarios with true DLT probability within the targeted toxicity interval (16%, 
33%). 
Table 31: 
Dose-Toxicity Scenarios (True DLT Probability) for Agent 2 
Scenario 
Pembrolizumab* 
2A 
0.05 
2B 
0.20 
Abbreviation: DLT = dose-limiting toxicity. 
Note: Gray shading indicates scenarios with true DLT probability within the targeted toxicity interval (16%, 33%). 
 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 119 of 122
Table 32: 
Dose-Toxicity Scenarios (True DLT Probability) for Agents 1 & 2 Combined 
Scena
rio 
for 
Agent 
1 
Scena
rio 
for 
Agent 
2 
Scena
rio 
Dose Level DSP-0509 (mg) / Pembrolizumab (mg) 
0.3 / 
200 
1.0 / 
200 
3 / 
200 
6 / 
200 
9 / 
200 
12 / 
200 
16 / 
200 
20 / 
200 
25 / 
200 
30 / 
200 
1A 
2A 
1 
0.098 
0.098 
0.098 
0.098 
0.098 
0.098 
0.098 
0.098 
0.098 
0.098 
2B 
2 
0.24 
0.24 
0.24 
0.24 
0.24 
0.24 
0.24 
0.24 
0.24 
0.24 
1B 
2A 
3 
0.098 
0.117 
0.136 
0.155 
0.174 
0.192 
0.212 
0.231 
0.25 
0.269 
2B
4 
0.24
0.256
0.272
0.288
0.304
0.32
0.336
0.352
0.368
0.384
1C 
2A 
5 
0.098 
0.145 
0.192 
0.24 
0.288 
0.335 
0.383 
0.43 
0.478 
0.525 
2B 
6 
0.24 
0.28 
0.32 
0.36 
0.4 
0.44 
0.48 
0.52 
0.56 
0.6 
1D 
2A 
7 
0.24 
0.288 
0.335 
0.383 
0.43 
0.478 
0.478 
0.478 
0.478 
0.478 
2B 
8 
0.36 
0.4 
0.44 
0.48 
0.52 
0.56 
0.56 
0.56 
0.56 
0.56 
1E 
2A 
9 
0.392 
0.43 
0.478 
0.478 
0.478 
0.478 
0.525 
0.572 
0.62 
0.668 
2B 
10 
0.488 
0.52 
0.56 
0.56 
0.56 
0.56 
0.6 
0.64 
0.68 
0.72 
Abbreviation: DLT = dose-limiting toxicity. 
-0509 every 2 weeks 
Pembrolizumab (per US labeling) = 200 mg IV every 3 weeks 
Operating Characteristics of the Design 
Operating characteristics of the dose-escalation design in the combination therapy study were 
evaluated under each of the 16 true dose-toxicity scenarios defined above using the assumed 
DLT outcomes from 2 cohorts in the monotherapy study (0/3 DLTs at 0.3 mg and 1/4 DLTs at 
1 mg). Table 33 summarizes the results from the simulation study. 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 120 of 122
Table 33: 
Summary Metrics of the Simulations Performed 
True 
Dose-
DLT 
Scenario
Probability of 
Recommending a Dose 
With True P(DLT) 
No MTD 
Recom-
mendation 
Average Number of 
Patients Per Trial 
Receiving a Dose With 
True P(DLT)
Average Number of 
Patients 
[0, 0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
[0, 0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
Per 
Trial 
Experiencing 
a DLT per 
Trial 
1 
0.952 
0
0
0.048 
27.4
0
0 
27.4 
2.6
2
0
0.629
0
0.371
0
15.8
0
15.8
3.1
3
0.953
0.014
0
0.033
27.1
0.2
0
27.3
3
4 
0 
0.628
0
0.372 
0
15.6 
0 
15.6 
3.2
5 
0.64
0.32
0
0.04
21.1
5.2
0 
26.3 
3.6
6 
0 
0.314
0
0.686 
0
15.5 
0 
15.5 
3.4
7 
0 
0.569
0.024
0.407 
0
14 
0.5
14.5 
3.1
8 
0 
0
0.223
0.777 
0
0
5.2
5.2 
1.4
9 
0 
0
0.154
0.846 
0
0
3.5
3.5 
0.9
10
0 
0
0.023
0.977 
0
0
0.5
0.5 
0.2
Abbreviations: DLT = dose-limiting toxicity; MTD = maximum tolerated dose. 
The simulation results presented in Table 33 indicate that the BLRM method performs well in 
the combination therapy setting. A targeted dose level is identified with a high probability (over 
60%) under Scenarios 2 and 4 that correspond to the most likely dose-toxicity scenarios. When 
the less likely or very unlikely scenarios are considered, eg, Scenarios 8, 9, and 10, under these 
scenarios, all provisional dose levels are overly toxic, eg, they range between 36% and 72%, and 
the probability of identifying an MTD is 22.3%, 15.4%, and 2.3%, respectively. The table also 
shows that the average number of patients exposed to excessively toxic doses is low. The highest 
number of patients treated at excessively toxic doses is achieved under Scenario 8, which is 
considered very unlikely, since all provisional doses are expected to be too toxic. Under the 
scenarios with very high toxicity levels, eg, Scenarios 8, 9, and 10, the method stops without 
determining the MTD about 80% or over 80% of the time. 
Hypothetical Dose Allocation Scenarios in Early Cohorts 
The dose-escalation rules in the combination therapy study are further illustrated by considering 
32 hypothetical scenarios in the first 3 cohorts (Table 34) using these assumptions:  
 The dose recommended for each subsequent cohort depends only on the model 
 There are 3 patients each in the first two cohorts and 4 patients in the third cohort. During 
the actual study, there could be 3 to 6 patients per cohort and new provisional dose levels 
Table 34: 
Hypothetical Dose Allocation Scenarios in Early Cohorts 
Scenario 
Cohort 
DLT in 
Cohort 1 
(0.3 mg) 
DLT in 
Cohort 2 
(1 mg) 
Dose of 
Agent 1 
(mg) 
DLT 
outcomes 
NDL for 
Agent 1 
P(Target
) NDL 
P(Over-
dosing) 
NDL 
1 
1 
– 
– 
0.3 
0/3 
1 
0.328 
0.168 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 121 of 122
2
 
– 
– 
0.3 
1/3 
0.3 
0.359 
0.229 
3
–
–
0.3
2/3
NA
NA
NA
4
–
–
0.3
3/3
NA
NA
NA
5
2A 
0 
– 
1 
0/3 
1.8 
0.294 
0.191 
6
 
0 
– 
1 
1/3 
1 
0.437 
0.218 
7
 
0 
– 
1 
2/3 
0.3 
0.375 
0.135 
8
 
0 
– 
1 
3/3 
NA
NA 
NA 
9
2B
1
–
0.3
0/3
0.6
0.415
0.148
10
1
–
0.3
1/3
NA
NA
NA
11 
 
1 
– 
0.3 
2/3 
NA
NA 
NA 
12 
 
1 
– 
0.3 
3/3 
NA
NA 
NA 
13 
3A 
0 
0 
1.8 
0/4 
1.8 
0.208 
0.037 
14 
 
0 
0 
1.8 
1/4 
1.8 
0.409 
0.178 
15 
 
0 
0 
1.8 
2/4 
1 
0.506 
0.121 
16 
 
0 
0 
1.8 
3/4 
0.6 
0.435 
0.092 
17 
 
0 
0 
1.8 
4/4 
0.6 
0.467 
0.166 
18 
3B 
0 
1 
1 
0/4 
1 
0.371 
0.063 
19 
 
0 
1 
1 
1/4 
1 
0.514 
0.194 
20 
 
0 
1 
1 
2/4 
0.6 
0.545 
0.178 
21 
 
0 
1 
1 
3/4 
0.3 
0.444 
0.166 
22 
 
0 
1 
1 
4/4 
NA
NA 
NA 
23 
3C 
0 
2 
0.3 
0/4 
0.6 
0.481 
0.122 
24 
 
0 
2 
0.3 
1/4 
0.3 
0.46 
0.128 
25
0
2
0.3
2/4
NA
NA
NA
26 
 
0 
2 
0.3 
3/4 
NA
NA 
NA 
27 
 
0 
2 
0.3 
4/4 
NA
NA 
NA 
28 
3D 
1 
0 
0.6 
0/4 
1 
0.363 
0.069 
29 
 
1 
0 
0.6 
1/4 
1 
0.49 
0.196 
30 
 
1 
0 
0.6 
2/4 
0.3 
0.491 
0.178 
31 
 
1 
0 
0.6 
3/4 
NA
NA 
NA 
32 
 
1 
0 
0.6 
4/4 
NA
NA 
NA 
DLT = dose-limiting toxicity; NDL = next dose level; P(Target) NDL = posterior probability that the true DLT 
rate for the next recommended dose lies in the targeted interval (16%, 33%); P(Overdosing) NDL = posterior 


Sumitomo Dainippon Pharma Oncology, Inc
BBI-DSP-0509-101 Protocol 
 
Amendment 7 
Confidential and Proprietary 
 
Page 122 of 122
probability that the true DLT rate for the next recommended dose lies in excessive toxicity interval (33%,
100%) 

SAP_001.pdf: 
Sumitomo Pharma Oncology, Inc. 
                           Protocol:  BBI-DSP-0509-101 
 
                                                                                  Statistical Analysis Plan – Version 2.0 
 
Confidential & Proprietary 
 
Page 1 of 18 
 
 
STATISTICAL ANALYSIS PLAN 
Date of Plan: October 31, 2022 
 
Based on Protocol Version:  
Amendment 1, 18 Jan 2018 
Amendment 2, 10 Jul 2018 
Amendment 3, 28 Feb 2019 
Amendment 3.1, 28 Feb 2019 
Amendment 4, 30 Apr 2020 
Amendment 5, 26 Mar 2021 
Amendment 6, 04 May 2021 
Amendment 7, 15 Sep 2021 
 
STUDY DRUG:  DSP-0509 
 
STUDY NUMBER: BBI-DSP-0509-101 
 
STUDY TITLE: 
A First-in-Human Phase 1/2 Trial to Determine the Safety and the Pharmacokinetic Profile of 
DSP-0509, a Synthetic Toll-Like Receptor 7 (TLR-7) Agonist, Administered as Monotherapy 
and in Combination with Pembrolizumab in Adult Patients with Advanced Solid Tumors 
 
Sponsor:  
Sumitomo Pharma Oncology Inc. 
84 Waterford Drive 
Marlborough, MA 01752 
USA 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 


Sumitomo Pharma Oncology, Inc. 
                           Protocol:  BBI-DSP-0509-101 
 
                                                                                  Statistical Analysis Plan – Version 2.0 
 
Confidential & Proprietary 
 
Page 2 of 18 
SIGNATURE PAGE 
 
Author:  
 
   
 
 
   
 
 
             
  
  Data Science, Sumitomo Pharma Oncology, Inc.                                                               Date                                
 
Approved by:  
 
 
   
 
 
 
   Data Science, Sumitomo Pharma Oncology, Inc.                                                              Date  
 
 
   
 
 
 
   Clinical Development, Sumitomo Pharma Oncology, Inc.                                                 Date  
 
 
 
 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 3 of 18 
Table of Contents 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
STUDY CONDUCT .....................................................................................................6 
2. 
INTRODUCTION ........................................................................................................7 
2.1. 
Study Design .................................................................................................................7 
2.2. 
Study Objectives and Endpoints ...................................................................................8 
3. 
ANALYSIS SET ........................................................................................................10 
4. 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES .................11 
4.1. 
Statistical Methods and Analytical Considerations ....................................................11 
4.1.1. 
Statistical Methods ......................................................................................................11 
4.1.2. 
Visit Windows ............................................................................................................12 
4.1.3. 
Handling of Dropouts and Missing Data ....................................................................12 
4.2. 
Patient Characteristics ................................................................................................13 
4.2.1. 
Patient Disposition ......................................................................................................13 
4.2.2. 
Protocol Deviations ....................................................................................................13 
4.2.3. 
Demographic and Baseline Characteristics ................................................................13 
4.2.4. 
Non-Cancer Related Medical/Surgical History ..........................................................14 
4.2.5. 
Cancer History ............................................................................................................14 
4.2.6. 
Prior and Concomitant Medications ...........................................................................14 
4.2.7. 
Concomitant Procedures .............................................................................................14 
4.2.8. 
Prior Cancer Therapies ...............................................................................................14 
4.2.9. 
Prior Cancer Surgery ..................................................................................................14 
4.2.10. 
Prior Radiation Therapies ...........................................................................................15 
4.3. 
Study Drug Exposure ..................................................................................................15 
4.4. 
Efficacy Analysis ........................................................................................................15 
4.5. 
Safety Analysis ...........................................................................................................15 
4.5.1. 
Adverse Events ...........................................................................................................16 
4.5.2. 
COVID-19 ..................................................................................................................16 
4.5.3. 
Physical Examination .................................................................................................17 
4.5.4. 
Vital Signs ..................................................................................................................17 
4.5.5. 
Electrocardiogram .......................................................................................................17 
4.5.6. 
Laboratory Parameters ................................................................................................17 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 4 of 18 
4.5.7. 
Evaluation of Eastern Cooperative Oncology Group (ECOG) Performance 
Status...........................................................................................................................17 
4.5.8. 
Echocardiogram/Multigated Acquisition (MUGA) Scan ...........................................17 
4.5.9. 
Chest X-rays ...............................................................................................................17 
4.5.10. 
Ocular Examinations ..................................................................................................18 
 
 
 
 
 
 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 5 of 18 
LIST OF ABBREVIATIONS 
Abbreviation or  
specialist term 
Explanation 
ADI 
Actual Dose Intensity 
AE 
Adverse Event 
BLRM 
Bayesian logistic regression model 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
ES 
Efficacy Set 
FAS 
Full Analysis Set 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
IDI 
Intended Dose Intensity 
iPR 
immune Partial Response 
iRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
PT 
Preferred Term 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMPO 
Sumitomo Pharma Oncology, Inc 
SOC 
System Organ Class 
SS 
Safety Set 
Std Dev 
Standard Deviation 
TEAE 
Treatment-Emergent Adverse Event 
TTP 
Time-to-Progression 
WHO 
World Health Organization 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 6 of 18 
1. 
STUDY CONDUCT 
In August 2022, Sumitomo Pharma Oncology, Inc (SMPO) decided to terminate this study and no new 
patients were enrolled after that decision was made. SMPO also decided to conclude this study with a 
synoptic CSR focusing on safety, and no efficacy analysis will be conducted.  
At the time of study termination, there were no patients enrolled in the dose expansion cohort, nor any 
Japanese patients enrolled in any cohorts. This Statistical Analysis Plan (SAP) only applies to all patients 
included in this study for the dose escalation cohorts (Arm A of Monotherapy: DSP-0509 and Arm B of 
Combination therapy: DSP-0509 + pembrolizumab).  
All statistical programs employed in the analysis, data reporting and statistical outputs will be validated 
by the Biostatistician/Programmer in charge of the study.   
 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 7 of 18 
2. 
INTRODUCTION 
This SAP details the planned methodology for summarizing data collected in the clinical study conducted 
under Sumitomo Pharma Oncology, Inc., protocol BBI-DSP-0509-101, and for comparing outcomes 
between cohorts of patients receiving various dosages of DSP-0509. The most current protocol 
amendment 7.2 (dated 17 Mar 2022) was developed to include Japanese patients. Since no Japanese 
patients were enrolled, this SAP is based on study protocol Amendment 7 (dated 15 Sep 2021). 
Additionally, the study protocol is a companion document to this SAP, thus aspects in the protocol 
unrelated to statistical issues (eg, patient eligibility criteria and descriptions of clinical materials) are not 
repeated here. 
2.1. 
Study Design 
This is a Phase 1 dose-escalation study (with 2 treatment arms) with a Phase 2 dose expansion to evaluate 
the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of DSP‑0509 
given alone or in combination with pembrolizumab in patients with advanced solid tumors. 
Monotherapy Arm  
• 
Arm A: Dose escalation, Phase 1  
Combination Arms  
• 
Arm B: Dose escalation (patients with advanced solid tumor with primary or acquired resistance 
to immune checkpoint inhibitors [ICIs]), Phase 1 
• 
Arm C: Dose expansion (patients with Head and Neck Squamous Cell Carcinoma [HNSCC] with 
primary or acquired resistance to ICIs), Phase 2 
Monotherapy Arm A: The primary objective of Monotherapy Arm A is to determine the maximum 
tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of DSP-0509 when administered as a single 
agent. Dose escalation uses a Bayesian logistic regression model (BLRM) approach. DSP-0509 will be 
administered on Day 1 and then every 2 weeks thereafter until discontinuation.  
Combination Therapy Arm B: The primary objective of Combination Arm B is to determine the RP2D 
of DSP-0509 when administered in combination with pembrolizumab. Dose escalation is guided by the 
BLRM approach. Combination Arm B will enroll patients with advanced solid tumors that are (a) 
metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) a condition for which 
pembrolizumab is an approved treatment, and (c) in patients who have shown either primary or acquired 
resistance to an ICI. Dose escalation of DSP-0509 in combination with 400 mg pembrolizumab every 
6 weeks (q6w) will start at the same dose of DSP-0509 as the highest (not exceeding the MTD) level 
tested in the combination regimen with 200 mg pembrolizumab every 3 weeks (q3w). Upon completion 
of the DLT evaluation period for the first DSP-0509 dose level tested in combination with 400 mg 
pembrolizumab q6w in newly enrolled patients, if this dose level is found not to exceed the MTD, any 
ongoing patients receiving DSP-0509 in combination with 200 mg pembrolizumab q3w will be allowed, 
at the investigator’s discretion, to transition to the 400 mg pembrolizumab q6w regimen, while 
maintaining the originally assigned DSP-0509 dose level.  
Combination Therapy Arm C: The primary objective of Combination Arm C is to determine the 
Objective Response Rate (ORR) of DSP-0509 when administered in combination with pembrolizumab. 
Combination Arm C will enroll patients with HNSCC tumors that are (a) metastatic or unresectable, and 
recurrent and/or refractory to available therapy, (b) in patients who have been treated with 
pembrolizumab or other PD 1 or PD-L1 inhibitors in monotherapy, and (c) in patients who have 
subsequently shown either primary or acquired resistance to ICIs.  


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 8 of 18 
DSP-0509 will be administered on Day 1 and q2w thereafter until discontinued. Pembrolizumab will be 
administered on Day 1 and q6w thereafter until discontinued. 
2.2. 
Study Objectives and Endpoints 
Complete details on how endpoints are calculated within treatment groups are presented in the 
subsections below. 
Table 1. 
Primary objectives and endpoints 
Primary Objectives 
Endpoints 
Monotherapy Arm A - Dose Escalation (Phase 1): 
To determine the safety, tolerability, and 
maximum tolerated dose (MTD) of DSP-0509 
administered intravenously (IV) as a single agent 
in patients with advanced solid tumors  
To identify a recommended Phase 2 dose 
(RP2D) of DSP-0509 monotherapy for patients 
with advanced solid tumors.  
Incidence of dose-limiting toxicities (DLTs) within 
the first 6 weeks of dosing 
Incidence and severity of treatment-emergent 
adverse events (TEAEs) and serious adverse events 
(SAEs) using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events 
(CTCAE)  
Incidence of dose interruption, dose reduction, and 
dose intensity 
Changes in clinical laboratory values (hematology, 
clinical chemistry, urinalysis), electrocardiogram 
(ECG) parameters, multigated acquisition (MUGA) 
scan/echocardiograms (ECHO) parameters 
Combination Arm B - Dose Escalation (Phase 1): 
To determine the safety, tolerability, and MTD 
of DSP-0509 administered IV in combination 
with pembrolizumab for patients with advanced 
solid tumors who have shown primary or 
acquired resistance to immune checkpoint 
inhibitors (ICIs)  
To identify an RP2D of DSP-0509 when given in 
combination with pembrolizumab for such 
patients  
Incidence of DLTs within the first 6 weeks of 
dosing 
Incidence and severity of TEAEs and SAEs using 
NCI CTCAE 
Incidence of dose interruption, dose reduction, and 
dose intensity 
Changes in clinical laboratory values (hematology, 
clinical chemistry, urinalysis), ECG parameters, 
MUGA scan/ECHO parameters 
Combination Arm C – Dose Expansion (Phase 2): 
To evaluate the preliminary antitumor activity of 
DSP-0509 in combination with pembrolizumab 
in patients with HNSCC who have shown 
primary or acquired resistance to ICIs 
Objective response rate (ORR), as assessed by 
Response Evaluation Criteria in Solid Tumors 
(RECIST), v1.1 and by Immune RECIST 
(iRECIST, modified RECIST for immunotherapy 
studies) 
 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 9 of 18 
Safety Assessments: 
Adverse events (AEs) will be collected from the time the patient signs informed consent to the End of 
Study (EOS) visit scheduled for 30 days after the last dose of study drug. AEs will be assessed according 
to NCI CTCAE v5.0. Additional safety assessments will include MUGA scans, ECHO, 12 lead ECGs, 
chest x-rays, vital signs, clinical laboratory tests, and ocular examinations (slit lamp, fundoscopy, visual 
field testing). 
Efficacy Assessments: 
SMPO decided to terminate this study with a synoptic CSR focusing on safety, and no efficacy analysis 
will be conducted.   


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 10 of 18 
3. 
ANALYSIS SET 
Full Analysis Set 
The Full Analysis Set (FAS) in this study consists of all patients who entered the study and received one 
dose of study treatment (DSP-0509 or pembrolizumab). 
Safety Set 
The safety set (SS) is the same as the FAS. Safety analysis set will be used for all safety related analyses 
such as AE, concomitant medication, laboratory tests, and vital signs and drug exposure evaluation.   
Dose-Limiting Toxicity (DLT) Set 
The DLT population will consist of all patients who met the prespecified criteria for being evaluable for 
DLT detailed in the following.  
The DLT period for dose-escalation review is from Study Days 1 through 42. During this period, treated 
patients will be monitored closely for AEs in general and for DLTs in particular.  
A patient will be considered evaluable for DLT if observed for 42 days following the first dose of 
DSP-0509 in monotherapy and with pembrolizumab in combination. Patients discontinued during the 
DLT period due to DLTs are considered as evaluable for DLT.  
Patients who do not meet the above criteria will be considered non-evaluable for DLT and may be 
replaced to provide sufficient evaluable patients to fully assess a given dose level. 
 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 11 of 18 
4. 
STATISTICAL METHODOLOGY AND STATISTICAL 
ANALYSES 
At the time of study termination, there were no patients enrolled in the dose expansion cohort, nor any 
Japanese patients enrolled in any cohorts. This SAP only applies to all patients included in this study. 
Statistical analyses will be descriptive in nature; no formal statistical hypothesis testing will be 
performed. Statistical analyses will be carried out by using SAS Version 9.4 or higher. Whilst every effort 
has been made to pre-specify all analyses in this SAP, if any additional exploratory analyses are found to 
be necessary, the analyses and the reasons for them will be detailed in the clinical study report (CSR).  
4.1. 
Statistical Methods and Analytical Considerations 
4.1.1. 
Statistical Methods 
This section describes analysis issues that relate to all or some of the analysis sections that follow. It 
describes general guidelines for analysis as well as the following.  
Patient data will be grouped for summarization within each dose level and each cohort (Monotherapy 
Arm A: DSP-0509 and Combination Arm B: DSP-0509 + pembrolizumab) of the dose-escalation phase. 
Details of dose levels are listed in the following. 
Dose escalation for monotherapy Arm A 
• 
A1. DSP-0509 at 0.3 mg, 3 minutes, q1w  
• 
A2. DSP-0509 at 1.0 mg, 3 minutes, q1w  
• 
A3. DSP-0509 at 1.5 mg, 3 minutes, q1w  
• 
A4. DSP-0509 at 1.5 mg, 10 minutes, q2w  
• 
A5. DSP-0509 at 2.4 mg, 10 minutes, q2w  
• 
A6. DSP-0509 at 3.5 mg, 10 minutes, q2w  
Dose escalation for combination therapy Arm B 
• 
B1. DSP-0509 at 0.3 mg 10 minutes, q1w + pembrolizumab (200 mg, q3w) 
• 
B2. DSP-0509 at 0.3 mg, 10 minutes, q2w + pembrolizumab (200 mg, q3w) 
• 
B3. DSP-0509 at 1.0 mg, 10 minutes, q2w + pembrolizumab (200 mg, q3w) 
• 
B4. DSP-0509 at 1.0 mg, 10 minutes, q2w + pembrolizumab (400 mg, q6w) 
Baseline will be defined as the last evaluable/non-missing observation/assessment prior to the first dose 
of study drug. For patients ongoing at the time of analysis, the last dose date will be considered the date 
of the most recent study visit in the database for that patient where a dose of study drug was recorded. 
Adverse events will be graded by the Investigator based on the National Cancer Institute (NCI) CTCAE, 
Version 5.0, and will be coded for summarization using the Medical Dictionary for Regulatory Activities 
(MedDRA® Version 21.0 or higher). Concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary (Enhanced + Herbal B3 March 2018). 
Tabulations will be produced for appropriate demographic, baseline, and safety parameters. Continuous 
variables will be summarized by reporting the number of observations, mean, standard deviation (Std 
Dev), median, minimum, and maximum. Categorical variables will be summarized using the number and 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 12 of 18 
percentage of patients within a particular category, where the denominator is the number of non-missing 
values for the variable at the given time point (unless otherwise specified).  
Means and medians will be presented to 1 more decimal place than the recorded data. The Std Devs will 
be presented to 2 more decimal places than the recorded data. Confidence intervals about a parameter 
estimate will be presented using the same number of decimal places as the parameter estimate. 
By-patient data listings will be produced for data collected on the electronic Case Report Forms (eCRFs) 
throughout the study (eg, labs). All data listings that contain an evaluation date will contain a relative 
study day (Study Day). Pre-treatment and on-treatment study days are numbered relative to the day of the 
first dose of study medication, which is designated as Day 1. The preceding day is Day -1, the day before 
that is Day -2, etc.  
In general, the listings will be sorted by study arm, dose level, patient number, and assessment date (and 
time) if applicable.  
If a patient has multiple assessments (eg, multiple laboratory results) at a given time point (planned, 
repeat, and unscheduled), only the earliest non-missing value will be included in summary tables unless 
specified otherwise. The other values will be included in the listings, but not the summary table. 
4.1.2. 
Visit Windows  
All data will be tabulated per the nominal visit as recorded on the eCRF, even if the assessment is outside 
of the visit window. Unless otherwise stated in the analysis sections below, unscheduled visits will be 
included in data listings only.  
4.1.3. 
Handling of Dropouts and Missing Data 
In general, missing values will not be replaced by imputed values unless indicated otherwise.  
The following general rules will be used for AEs: 
• 
If the start day is missing but the start month and year are complete, an AE will be excluded as 
being treatment-emergent only if the start month/year of the AE is before the month/year of study 
drug administration or if the stop date/time of the event is before study drug administration. 
• 
If the start day and month are missing but the start year is complete, an AE will be excluded as 
being treatment-emergent only if the start year of the AE is before the year of study drug 
administration or if the stop date/time of the event is before study drug administration. 
• 
If the start date is completely missing, an AE will be considered treatment-emergent unless the 
stop date is before study drug administration. 
• 
If the relationship to study treatment is missing, then that AE will be assumed to be related to 
treatment. 
For partial dates of medications, the following approach will be taken: 
• 
If the start day is missing but the start month and year are complete, a medication will be 
excluded as being concomitant only if the start month/year of the medication is before the 
month/year of study drug administration and if the stop date (either full date, month and year if 
missing day, or year if missing month and day) is before study drug administration. 
• 
If the start day and month are missing but the start year is complete, a medication will be 
excluded as concomitant only if the start year of the medication is before the year of study drug 
administration and if the stop date (either: full date, month and year if missing day, or year if 
missing month and day) is before study drug administration.  


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 13 of 18 
For cancer, surgical, or medical history, a date of first diagnosis with incomplete dates will be considered 
as: 
• 
Day is missing then day is set to the first day of the month;  
• 
Day is missing and month is missing then date will be set to 01 January; 
• 
Complete date is missing then will be set to missing. 
4.2. 
Patient Characteristics 
4.2.1. 
Patient Disposition 
All patients who provide informed consent will be accounted for in this study. Disposition information for 
all patients will be provided in patient listings. 
Patient disposition will be presented by dose level and overall for Monotherapy Arm A, Combination 
Arm B, and for Arm A and Arm B combined. Tabulation will include the number of patients screened, 
number (%) of patient's screen failed, number (%) of patients included in various analysis sets (FAS, SS 
and DLT set), as well as the number (%) of patients discontinuing study treatment and the reason for 
treatment discontinuation. In addition, this table will summarize the number of patients discontinuing the 
study and the primary reason for study discontinuation.  
Patients excluded from the various analysis sets will be listed by dose level.   
4.2.2. 
Protocol Deviations 
Protocol deviation data will not be summarized or listed.  
4.2.3. 
Demographic and Baseline Characteristics 
Summaries of baseline characteristics will be statistics that are appropriate for continuous (eg, age, height, 
weight) and categorical (eg, sex, race, ethnicity) variables. Separate summaries may be produced for the 
safety and per-protocol patient populations. Patient age in years on the date of enrollment will be 
calculated by dividing the number of days since birth (Day 1) by 365.25 and rounded down to the nearest 
integer.  
The following variables will be listed and summarized using both continuous and categorical descriptive 
statistics: 
• 
Age (years) 
• 
Age group (< 65 years and ≥ 65 years) 
• 
Gender 
• 
Ethnicity 
• 
Race 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI (kg/m2)  


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 14 of 18 
4.2.4. 
Non-Cancer Related Medical/Surgical History 
Medical/Surgical History as recorded at screening will be listed by system organ class (SOC) and 
preferred term (PT), and sorted alphabetically by SOC and by decreasing frequency of PT within each 
SOC using MedDRA coding dictionary version 21.0 or later in the summary table. Medical history events 
ongoing at the time of informed consent will be included.  
Medical/surgical history data listings will be sorted by study arm, dose level, patient ID, onset date, end 
date, SOC, and PT. 
4.2.5. 
Cancer History 
Cancer history will be collected as a baseline characteristic. The smoking history, primary cancer type, 
time since initial cancer diagnosis in days, time since most recent relapse/progression, histological grade, 
predominant histology, stage at initial diagnosis, stage at time of study entry, and staging system will be 
listed by study arms and dose level. 
4.2.6. 
Prior and Concomitant Medications 
Prior medications will be defined as any medication taken prior to the first dose of study drug.  
Concomitant medications are defined as any medication taken on or after the first dose of study drug. 
Medications with a start date prior to the first dose of DSP-0509 and an end date after the first dose of 
DSP-0509 (or ongoing) will be classified as both a prior medication and a concomitant medication. 
Medications missing both start and stop dates, having a start date prior to the first dose of study drug and 
a missing stop date or having a stop date on or after the last dose of study drug and a missing start date 
will be counted as a concomitant medication. 
Prior and concomitant medications will be coded using the WHO Drug Dictionary (Enhanced + Herbal 
B3 March 2018), and patient incidence will be listed by Anatomic Therapeutic Class (ATC) level 2 term 
(ATC2) and preferred term, by study arms and dose level using the safety set.  
All prior, concomitant, and post medications will be included in a by-patient data listing. 
4.2.7. 
Concomitant Procedures 
A listing will be created to present the relevant information on concomitant procedures, including the 
procedure name, date, relationship with the disease, and reason for the procedure. 
4.2.8. 
Prior Cancer Therapies 
Prior cancer therapies will be listed separately from other prior and concomitant medications. The 
classification of the cancer therapies includes regimen number, drug name, best response, and reason for 
stopping captured on the Prior Cancer Therapy eCRF page. 
The listing will be ordered by study arm, dose level, patient ID, and the start date of the therapy. 
4.2.9. 
Prior Cancer Surgery 
Prior cancer surgeries will be listed separately from other prior and concomitant procedures. It will 
include surgery description, and type of procedures. The listing will be ordered by study arm, dose level, 
patient ID, and the date of surgery. 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 15 of 18 
4.2.10. 
Prior Radiation Therapies  
Prior radiation therapies will be listed separately from other prior and concomitant therapies. The 
classification of the radiation therapies includes therapy received, anatomic site, total dose received, and 
settings captured on the Prior Radiation Therapy eCRF page. 
The listing will be ordered by study arm, dose level, patient ID, and the start date of the therapy. 
4.3. 
Study Drug Exposure 
Study drug exposure will be presented by dose level and overall, for Monotherapy Arm A and 
Combination therapy Arm B.   
The total cumulative dose (mg) received and the duration of exposure will be summarized, where duration 
of exposure will be calculated as:  
Duration of Exposure (weeks) = (Last dose date – first dose date + 1) / 7. 
Treatment compliance of DSP-0509 will be presented for the induction phase and the maintenance phase 
of the treatment. Compliance in terms of actual dose intensity (ADI) and relative dose intensity (RDI) will 
be calculated as follows: 
Actual Dose Intensity: The ADI is based on the dose (mg) taken by the patient and the duration of 
exposure (weeks) during the induction phase or the maintenance phase and given as: 
ADI (mg/week) = Total dose (mg) received/duration (weeks) of exposure during the induction phase or 
maintenance phase. 
Intended Dose Intensity (IDI): The IDI is based on the dose level assigned to the patient and the dose 
schedule. During the induction phase, IDI will be equal to the assigned dose level as the dose schedule is 
q1w. During the maintenance phase, IDI will be one-half, one-third or one-six of the assigned dose level, 
corresponding to the q2w, q3w or q6w dose schedule.  
Relative Dose Intensity: The RDI (%) is based on the ADI and the RDI given as follows: RDI (%) = 
ADI/IDI * 100. 
Dose exposure data will be also provided by a data listing ordered by study arm, dose level, patient ID, 
and the study day. 
4.4. 
Efficacy Analysis 
No efficacy analysis will be conducted.  
Tumor response assessment by iRECIST/RECIST, targeted/non-target/new lesion assessment by RECIST 
will be listed in settings captured on the eCRF page. 
4.5. 
Safety Analysis  
The primary objective for this study is to determine the safety, tolerability, and MTD of DSP-0509. All 
safety analyses will be performed using the Safety Set, unless otherwise specified. Relevant data 
supporting safety analyses will be listed by patient within DSP-0509 dose.  


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 16 of 18 
4.5.1. 
Adverse Events 
Adverse events will be graded according to the NCI CTCAE Version 5.0 coded using the MedDRA 
coding system, version 21.0, and displayed in tables and data listings by MedDRA SOC and PT. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, where 
treatment-emergent adverse event (TEAE) is defined as any condition that occurs after administration of 
the first dose of study drug or that is present at baseline but worsens in intensity after the first dose of 
study drug. 
If the start date of an AE is partially or completely missing, the date will be compared as far as possible 
with the date of the start of administration of study drug. The AE will be assumed to be treatment-
emergent if it cannot be definitively shown that the AE did not occur or worsen during the treatment-
emergent period (worst case approach). 
Adverse events are summarized via patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT (ie, the most related occurrence or the most 
intense occurrence). Missing relationship will be considered related to study drug. 
An overall summary of the number and percentage of patients reporting TEAEs, treatment-related 
TEAEs, serious TEAEs, treatment-related serious TEAEs, Grade 3 (or worse) TEAEs, AEs considered to 
be DLTs, TEAEs leading to dose withdrawal, and fatal TEAEs will be presented. An AE will be 
considered as treatment-related if it is possibly, probably, or definitely related to the study treatment.  
TEAE incidence summary tables will be produced and will include: 
• 
Overall summary of TEAEs 
• 
TEAEs by SOC and PT 
• 
Serious TEAEs by SOC and PT 
• 
DSP-0509-related TEAEs by SOC and PT 
• 
DSP-0509-related serious TEAEs by SOC and PT 
• 
TEAE with toxicity Grade 3 or higher by SOC and PT 
The summaries presenting incidence of AEs by SOC and PT will be ordered by overall descending 
frequency of SOC and then, within an SOC, by overall descending frequency of PT for the overall 
patients. 
No formal hypothesis-testing analysis of AE incidence rates will be performed. All AEs occurring on-
study will be provided in data listings. By-patient listings also will be provided for the following: DLTs, 
DSP-0509-related AEs, SAEs, DSP-0509-related SAEs, AEs leading to DSP-0509 discontinuation, and 
AEs leading to death. 
4.5.2. 
COVID-19 
Patients who have tested positive for COVID-19 are identified and relevant information collected. Any 
patient-reported illness of COVID-19 during the study is recorded as an AE. COVID-19 test results will 
be reported separately in a listing in parameters captured on eCRF page. 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 17 of 18 
4.5.3. 
Physical Examination 
Physical examinations will be conducted according to the Schedule of Assessments. A physical 
examination will include examination of the skin; head, eyes, ears, nose, throat (HEENT); chest including 
the lungs and the heart; abdomen; neurologic, and extremities and areas of major lymph node chains. 
Physical examination results will be reported in a physical examination listing. 
4.5.4. 
Vital Signs 
Vital signs will include systolic and diastolic blood pressures, pulse, respiratory rate, temperature, and 
weight.   
Body temperature will be summarized in °C. If body temperature is recorded as °F, then temperature will 
be converted to °C as follows: 
Temperature (°C) = (5/9) x [Temperature (°F) - 32] 
A listing of vital signs results will be presented for all Safety Set patients. 
4.5.5. 
Electrocardiogram 
A 12-lead ECG will be obtained in triplicate during the study. Electrocardiogram data will be provided in 
a by-patient listing. 
4.5.6. 
Laboratory Parameters 
All summaries of hematology and chemistry will be based on the results of Standard International (SI) 
system of units. Summary tables for hematology and chemistry laboratory variables will include the 
descriptive statistics for results in SI units and the corresponding change from baseline for all continuous 
variables by visit.  
All laboratory results in SI units will be presented in data listings. Tests will be listed in alphabetical order 
within their respective panels (hematology, clinical chemistry). Abnormal values will be flagged. 
Urinalysis, coagulation, pregnancy testing, and serology testing data will be listed only. 
4.5.7. 
Evaluation of Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
The actual value of ECOG performance status score and change from baseline to each visit will be 
descriptively summarized as a continuous variable by visit. A by-patient listing of all ECOG results will 
be listed by treatment group and dose level. 
4.5.8. 
Echocardiogram/Multigated Acquisition (MUGA) Scan 
Echocardiogram and MUGA results including left ventricular ejection fraction (LVEF) (%) will be 
presented in a by-patient listing. 
4.5.9. 
Chest X-rays 
Chest x-rays will be performed at screening to rule out pulmonary disorders and assess patient’s 
eligibility as described in the Schedules of Assessments. Chest x-rays can be performed during the study 
at the Investigator’s discretion on an as-needed basis. Chest x-ray data will be presented in a by-patient 
listing. 


Sumitomo Pharma Oncology, Inc.  
 
 
BBI-DSP-0509-101 
 
                                                                 Statistical Analysis Plan – Version 2.0 
Confidential and Proprietary 
 
Page 18 of 18 
4.5.10. 
Ocular Examinations 
Ocular examinations, including slit lamp examinations, visual field testing, and fundoscopy will be 
performed by a qualified ophthalmologist at Screening, Day 29, and the EOT visit as described in the 
Schedules of Assessments to monitor for potential ophthalmological toxicity. Ocular examinations data 
will be presented in a by-patient listing.